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ISSN 0115-1029
Volume 35- Number 2
July - December 2007
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A
COLLEGE
PHILIPPINE HEART ASSOCIATION, INC.
Efren R. Vicaldo, MD
President
Ma. Belen 0. Carisma, MD
Vice-President
Mr. Angelo B. Palmones
Vi ced-'residL'nr for EvternalAffiiirs
Mr. Romeo B. Cruz
Vice-President/br Finance
Maria Teresa B. Abola, MD
Secretary
Eleanor A. Lopez, MD
Treasurer
Isabelo V. Ongtengco Jr., MD
Director
Saturnino P. Javier, MD
Director
Eugenio B. Reyes, MD
Director
Cesar S. Recto II, MD
Immediate Past- President
çj.tT
(Ii.
EDITOR-IN-CHIEF
Annette B. Pizarro-Borrorneo, MD
ASSOCIATE EDITORS
Joel M. Abanilla, MD
Leandro C. Bongosia, MD
Mariano B. Lopez, MD
Norbert Lingling D. Uy, MD
EDITORIAL ASSISTANTS
Joyce S. Jurnangit, MD
Ma. Mildred Paz M. Luque, MD
Antonio C. Pascual, MD
Alexander A. Tuazon, MD
ADVISORY BOARD
Ramon F. Abarquez Jr., MD
Homobono B. Calleja, MD
Romeo A. Divinagracia, MD
MANAGING EDITOR
Myrna L. dela Cruz
;.
PIIILI1'I'UNlj()L N;\l, 1.)l ( Akl)101 (J(
Of}leial publication of the Philippine Heart Association and the Philippine College of Cardiology. ()iTicc at Unit 502 13, 5/F President
Tower Bldg.. 81 limog Avenue, Quezon Ciry
Editorial Correspondence
Annette B. Pizarro-Rorromeo, MI). (Editoi-in-Chief)
Philippine Heart Association, Tel. 929-1161, 929-1166 Fax (632) 929-1165
F- ilia il: heari/toztse@p/dw/s1. net or phil. hea rt @yahoo. coni
\Vebsi te: uiwuphi/hezrr. £)?t.
Subscription and Advertisements (Including change of address)
M y rna L. de la Cruz (Managing Editor) Philippine Heart Association
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EDITORIAL POLICIES
The Philippine Journal of Cardiology (PJC) publishes scientific
papers and communications pertinent to cardiology and allied fields.
These include basic research and clinical papers, case reports, articles
on fundamental cardiovascular principles and reviews on recent
developments in cardiology. Manuscripts should be sent to the Editorin-Chief at the above address.
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are nor being considered or published elsewhere except as an abstract.
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ETH ICS
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sponsoring
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PAPERS
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and legends).
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for Manuscripts Submitted to Biomedical Journals (updated
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LI\iL
.
1flIiHLI'JW ILL
[IIJILL'LIt L)LIILIILL
'lèrms from the Medical Subject Heading (MeSH) list of Index Medicus
should be used. For terms not recently included in the MeSIl, present
be
terms may
used.
iCII\Ifl I
iLf\Ii.l \j'jI.I.. KriLkL I
Philadelphia. WR Saunders Cuntpanv ltd. 19-75; r •'
References to press articles must state the name of the journal.
III 1.
O'l'H ERS
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after the title page. It must contain the objectives, methods, results and
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INTRODUCTION
The introduction should briefl y state the objectives of the study.
It should not include extensive review of the literature.
MATERIALS AND MET1I0DLsS
This section should be clear and detailed enough so that the reader
can understand it without studying the refirences directly. Well-accepted
research methods may be referred to for further clarification of the
stud y design. It should also he stated that the study conforms with
itistitucional and oilier applicable protocols and guidelines.
RESUlTS
Precise presentation of' results is imperative. Fable and figures,
which are essential for a better understanding of the text, may be used.
They should have brief descriptive titles and should be numbered as
they appear in the text.
DISCUSSION
The discussion should focus on the study being reported and
should not include a general review oft he topic. This section should
interpret and highlight the relevance of die results and contain a brief
discussion of the limitations of the study.
ACKNOWLEDGEMENT
The authors may indicate all proper acknowledgments following
the discussion. 'l'his should be limited to 100 words.
REFERENCES
References are to be cited consecutively in the text as superscript
tiumbers At the end of each article, references should be listed
consecutively at the order of numerals as they appear in the text. The
form of references should be as follows:
For journal articles: surname and initials ofauthor(s). title ofarticle,
nanic of journal, year; volume number, page; thus:
I. 'liipasiTE. Kanckiao 0. \ltnotite MA. Streptococcal surveillance
in the school populatiott: Ihe asvtnptotllatic carrier. Phil J Cardiol
1977; 5:144.
For hooks: surname and initials of author(s). title and subtitle,
edition, city, publishing house, year; page, as specific references,
Thus:
Friedberg CK. Disease of the Fleart (3rd ed) Philadelphia, \X'B
2.
Saunders Company. 1966; p. 25.
For articles in books: surname and initials of author(s), title of
article, chapter number (ifanv), title of hook, edition (other than
first), editor, city, publishing house, year; page. Thus:
Cur ) , PVL. Fundamentals of arrhvthmias-niodern methods of
3.
itt Vest igation(Chap. 3). In Cardiac Arrhytlimias: The Modern
Footnotes must he minimized and should be typed at the foot of
the appropriate page and separated from the text by a line. Iihles should
be typed on separate sheets with the corresponding numbers and titles.
Symbols for unites must be confined to column headings. All data
should he checked for accuracy.
Illustrations should he submitted in duplicate, in gloss)'
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drawings, no larger thati the stattdar.i bond paper sue. FlIc title oft he
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figures should be typed consecutivel y on ;t separate page.
Indexing words should be submitted with each manuscript to
facilitate the preparation of the index for the year-end issue.
CHECKLIST FOR 'TI-IE AUTHOR
•
Cover letter (should include sectioti for which manuscript is
submitted)
•
Copyright transfer statement signed by all authors
•
Original article
•
Diskette
•
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•
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•
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•
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•
CASE REPORTS
These should itsclude a written informed consent from the
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LETTERS/READER'S COMMENTS
The Editor encourages the reader to send comments regarding
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why the letter should he published and the writer's full name and city.
The letter regarding a particular article should be received within 2
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REPRINTS
'Pwetity-five reprints are given free to senior authors ofthis journal.
Additional reprints will be furnished to contributors when ordered in
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Individual reprints of'all article may he obtained by writin g- directly to
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The editor and publisher do not guarantee, warrant or eitdorse
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guarantee an y claim made by the manufacturer of such prOdUCI or
service.
(4:)
vi
President's Message
Lj6en 1?. V/ca/i/o, MD
vii
109 Natural History of Patients with 50-69%
Internal Carotid Stenosis: A PHC Experience
Kathleen G. Go Mi)
/as,nm Melissa B. Jicriia,y/o ML)
Editorial
R€i,non I? /Jhinyjz(t'z Jr All)
90 Perceptions of Filipinos About Hypertension
Data from 1RESYON 2
Emma Gaspar- Trinidad, Ml)
Lea/i Patricia Al. Arceo,MD
Jose Antonio L. Bautista, Ml)
Philip U Chua, ML)
May Donato- Tin, MD
/?aul L. Lapitan, MD
Reynaldo (7. A''ri, liviD
JiltOfli() G. PJI1JZIiI(i1l, j4L)
Jorge A . S/son, ilfffl
Dennis Jznuc iV. Torn's, AID
Irma Marie I? wipe. MD
98 Success Rate of Radio-Frequency Ablation from
January 1996 to November 2006 at the
Philippine Heart Center. A Descriptive Analysis.
Rev (.'.Aharez, MI)
100 The Effect of Exercise Training on the Six Minute
Walk Distance of Children Enrolled in Pediatric
Cardiac Rehabilitation ProgramPreliminary Result
Emily (7. Anupal,. All)
105 Calcific Aortic Stenosis, Can Statins Stop it?
A Meta-Analysis
Arnold S. Dc Guzman, ML)
Peter Jay S. Dumana, A'ID
Rodney Al. Jimenez, MD
118 The Use of Aerosolized Prostacyclin Analogue
(iloprost) in the Prevention of Post-operative
Pulmonary Hypertensive Crisis Among
Children With Left-to-Right Shunts and
Moderate to Severe Pulmonary Artery
Hypertension
Rt,zenette i-'liciias R. Hernandez, MD
7/rn/ic, I. Balderas, Ml)
Bland/na Irnzidad F Ferrein, MD
Maria Eloisa R. Lazaro, MD
Magdalena /. Laganmyo, MD
Ala. Lourdes Si?. Owes, ML)
130 The Effect of Combination of Angiotensin
Converting Enzyme inhibitor and Angiotensin
II Receptor Blocker on the Systolic Function in
Patients with Chronic Heart Failure:
A Meta-Analysis
Ia/in/Ce l.o,ie Tuason, lvii)
Zari,ia Lorenzo, ML)
Regina Yao, MD
Marcel/us Francis I. Ramirez, MD
136
The Value of Human Heart-type Cytoplastic
Fatty Acid Binding Protein (H-FABP) as a
Marker for the Early Diagnosis of Acute
Coronary Syndrome
i1rlaureen V Valentin, ML)
Alan Regin S Malva; MD
Marcel/us Francis I.. Ra;nirez, MD
Orlando T Bugarin, MD
NI//agros E Yamamoto, MD
Eduardo Vicente S. Gtç'nioa, MD
• (I^ !
'
1I
This edition is another good COP>' which offers a selection of topics that are current issues. The in-depth
articles are informative and insightful and are evidently imbued with accuracy and neutrality.
Each article's being an analytical piece is a reflection of the breed of editorial ream that steer the journal, to
the new PJC editorial staff, which has the dynamic Dr. Annette P. Borromen as its helm, welcome on board
and more power!
,^L "kuEiRIN
R. VIcALD0, MD
5T 5Ss0
iZS ;
°°L LEGE O
j
COMPLIMENT AND MODERATE OUR CME NEEDS
Time there was when continuing medical education (CIvIE) was via journals, book reference and conferences.
For every urge to travel was an out of pockets made. Such being the situation, every opportunity was
directed to maximize attendance to as many sessions, time permitting. Exhibition booth visits were minimal.
Hotel accommodations were affordable even to a budding practitioner. What counts is the thirst for
updates, new information and skills. Of course the peso value, then, was 2-4:1 to the dollar.
Domestic conventions were very modest and austere. Native lectures dominated the conferences. Those
trained abroad did not hesitate to give lectures, a passport for recognition and a badge of pride and clout.
Simultaneous lectures were not the norm. Discussions were very vicious and at times emotionally charged
that borders on what impose their vast experiences to emphasize a point. A young properly trained consultant
would have to resort to emphasizing literature reviews and case series to support his viewpoints. There
were very few randomized trials then. Evidences in support of an opinion were mostly anecdotal.
Authoritative text hooks had 2 to 3 years old references. Changes came quickly after the late Dr. Yolando
QM. Sulit encouraged Astra Pharmaceutical Philippines to bring to the Philippines forei g n lecturers and
researches for an out-of-town live-in symposium. Subsequently other multi-national companies joined
the band wagon, importing foreign speakers to the country. That was yesterday, before and during the
early martial law years.
CLirrcntl y, thank God, parochial training origin issues are gone with the wind. Thus, we are one in domestic
and foreign CML trips that are fully sponsored, side trips included. Despite steep registration fees, almost
a thousand dollars, queuing is often needed to get into preferred sessions. Much worse, admission fees are
collected in some USA meetings. Furthermore, the symposium of your interest maybe fully booked.
More importantly, once inside the session hall and you decide to skip the subsequent lectures you can not
easily enter other sessions. You end up killing time in the exhibit booths area. Or is this an excuse to shop,
go sight-seeing, or eat outside the convention venue? However, if you are research oriented you can visit
the poster sessions. Of course you do not get free meals unless you are attending an industry-based
symposium. For first-timers, scientific meetings attendance is an excellent CME opportunity. For repeaters,
Your guess is as good as anyone else.
1--low can we now make CM l. cost efficient' With II iiiodc ot communication and eas y access even to unpublished
break through papers, reviews and meta-anal yses, local or foreign CML activities should be merely excursions in
disguise. If foreign CML activities are documented and for sale, would it not be more prudent to bu y such tapes
or CDs? Replay of the sessions can be appreciated by a bigger audience in whatever venue the sponsors deem
pertinent and attractive to the majority. Furthermore, such sold proceedings can be presented during any national
Society scientific sessions. \X"hy not create a "sharing session" wherein those privileged to have attended foreign
CML sessions can share newly acquired information. Appropriate reactors can the augment such CML meetings.
Innovative options should compliment our CML needs. Most importantly, certainly NO demands or implied
"request" for expensive meals or wine, go]fsessions, entertainments, etc. Worse is imposing sponsored payment of
EXCESS BAGGAGES. "Quo \adis" CME? PHA members should set the appropriate CML values, culture and
conduct.
R7( J
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Perceptions of Filipinos About Hypertension
Data from PRESYON 2
Emma Gaspar-frmnidad,MD, Leah Patricia M. Arceo,MD, Jose Antonio L. Bautista, MD.
Philip U. Chua, MD, May Donato-Tan, MD, Raul L. Lapitan, MD, Reynaldo C. Neri, Ml),
Antonio G. Punzalan, MD, Jorge A. Sison, MD, Dennis James N. Torres, MI),
Irma Marie P Yape, MD
Council on 1-J1pertension - Philippine Heart Association, Report on Survey of Hypertension
OBJECTIVES
I.
2.
3.
METHODS
To determine consukation patterns and blood pressure monitoring practices ;sllioIlg
Filipinos
To determine how Filipinos define h y pertension and its management
To understand wh y compliance with hypertension therapy remains poor
l'hc data was derived from PRESYON 2, a randomized nationwide survey conducted thru
multi-staged stratified sampling involving 3,415 individuals aged 18 and above pins a booster
population of 390 hypertensive individuals. Questionnaires were used.
RESULTS 79% of Filipinos have consulted a doctor. Iwenty one percent have never consulted a doctor
but go to a midwife, hulot, albulary o, nurse, or kumadrona, with 14 9,10 never having consulted
any health care worker. Sixty four percent of Filipinos have had their 13P checked, with 52 %
of whom go to a health center. Sixty nine percent of aware hypertensives consult a doctor for
treatment, 46% of whom are not really particular about the doctor's specialization, while the
rest see a general practitioner, internist, cardiologist, 013-G y necologist, surgeon, pediatrician.
or neurologist, in decreasing order of frequency. Majority of aware hypertettsives go to the
hospital or clinic for consult.
Only 49 % of aware hypertensives take a drug for hypertension but only 74% of them take it
daily. Sixty six percent take their medicines at the dose prescribed and 68% at the length of
time prescribed. l'hirty six percent of aware hypertensives on medication have switched brands
because the previous medicine was more expensive (32%), was changed by the doctor (23%).
previous brand was not effective (23%), the subject changed doctor and medication was changed
(6%), and various other reasons pertaining mainly to side effects and adverse reactions to the
drugs (29%). The class of drug and number of drugs being taken arc other factors that affect
compliance. Hypertensives who consult a doctor say that only 709 10 of doctors tell them how
long to take their medications, with 77% of doctors instructing them that maintenance
medications are required and 10% instructing that medications are to be taken when needed
only.
Fourty one percent ofaware hypertensives know that diet and exercise are helpful in controlling
lIPN, 25% take alternative treatments with 110 proven benefits, and 25 0% do not do anything
else other than take their medications. Only 36% of Filipinos define l-IPN according to the
level of BP with 73% of them recognizing FIPN at levels greater than or equal to 160 mm Hg
systolic and/or greater than or equal to 100 mm Hg diastolic. Majority of hypertensives define
hypertension based on perceived symptoms due to Fl PN, personality trans, physical changes,
and complications caused by HPN.
Cost of treatment of hypertension based on medication and constiltation alone averages about
8478.93 pesos or a monthly expense of about 706.59 pesos.
INTRODUCTION
lhcrc is overwhelming evidence that hypertension
(1IPN) is a major risk factor for cardiovascular morbidity
and mortality and that control of HPN leads to significant
reduction in cardiovascular evcnts.' \olumes of research
work have been done and continue to he done to look for
better drugs and strategies to effectivel y control blood
pressure (H)) and prevent or dela y the consequences of
hy pertension. It astonishes that despite all the efforts and
attention given II PN, its good control remains elusive.
Reported control rates are as low as 25 0 o in the United States,
13" in Canada. 6°o 111 I ngland, 2I.3 in Korea. and 8. 1° n
in Taiwan.° In the Philippines, control rates were less
then 10° o as reported in PRESYON 1 (1998) and 13" 0 in
PRES-.-,-ON 2 (2007). Clearly ' much more needs to be done
to achieve better control of I IPN to goal HP levels.
Chobanian,et al, in the JNC 7 Report have said,
"Behavioral models suggest thet the most effective therapy
prescribed b y the most careful clinician will control
hypertension only if the patient is motivated to take the
prescribed medication as directed, and to establish and
maintain a health promoting lifestyle."'
(.iiiural t)cIWk, practices, and previous cxperictice S with
the health care system will greatl y affect patient perceptions
and attitudes about i IPN. '1'Icse perceptions and attitudes
must be determined and taken into consideration whenever
the clinician dcsigiis a plan to control the patients I [P-N.
OBJECTIVES
'this stud y was conducted id): I .I)etermine consultation
patterns and BP monitoring practices among Filipinos, 2.
Determine how Filipinos define I IPN and its management
and 3. I)ctermine factors that lead to poor compliance with
I I PN i herapv among Filipinos.
TABLE 1. PRESYON 2 ADULT SAMPLE BY AGE
GROUP
PRESYON 2
SAMPLE
%OF
N
TOTAL
NSO 2008
POPN
%OFN
TOTAL
AGE GROUP (YRS.)
18-29
30-39
40-49
50-59
60-69
70 & Up
TOTAL 18 & UP
18,543,199
11,835,273
8.761,362
5,876,421
3,448,304
2,230,693
37
23
17
12
7
4
50,695,249
100
951
849
675
455
313
172
28
25
20
13
9
5
3,415
100
METHODOLOGY
Ll
'11)c PR I 'SY( )N 2 is a ran(lotnized nation-,vide survey
on I IPN conducted b y the Council on II Pl\ of the
Philippine I leart Association from I)ecember 2006 to March
2007. lield researchers recruited and trained b y an
Independent professional survey group were retrained b'
the C.uicil on I IPN menibers. Selection of samples of the
survey involved a multi stage stratified sampling per region
based on five stages of randomization: selection of sample
proillice per region, selection of sample cities or towns
province, selection of sample barangav per cit y or town,
selection of saniple household per barangav, and finally,
selection of one responder per household. 'l'hc Krish-( ;rid
method was used if there was more than one qualified
responder per household. A c]uestionnalre was used for data
gathering in this specific part of the TRFSYON 2 S'IDY
Further details on the methodolog y are discussed in the
PRFSYON 2 '101) paper of Sison, et al.'
TABLE 2.
CLASS
PRESYON 2
ADULT SAMPLE BY SOCIO ECO
PRESYON 2
SAMPLE
%OF
TOTAL
N
SOCIAL ECONOMIC CLASS
AB/C+
Broad C
D
F
TOTAL 18&UP
64
511
2,158
682
2
15
63
20
3.415
100
RESULTS
3115 responders eighteen years old and above were
interviewed. For ijuestlons pertaining to hypertensive
subjects, an additional 389 were added from the booster
p olnilation of hypertensives. There was an almost fifty/fifty
lt'eetut distribution of rural '49.7'-o) and urban (50.3":(,)
responders. [lie soeio-eeonornic distribution of responders
was 2" u from class AB/C+, lS"(, from class broad C, 63"0
from class I). and 20" r, from class F. (Fable I). Fift y percent
were males and fift y percent were females, with age
distribution almost similar to the National Statistics Office
200)) age distribution for ages 18 and above except for a
slight under representation of the 18 to 29 age group (Fable
2).
Seventy nine percent of responders said that they have
at some time consulted a doctor, with 50" 0 having consulted
within the last y ear, while 29" have seen a doctor more
than a year ago. ' l 'wciitu' one percent have never seen a doctor
4" o have gone to a inidwtl'e, 2" '' to a hilot, <0,5"/o to an
albularvo, <0.5tYo to a nurse, while 14° o have never sought
c' niult Ironi any health care giver liable 3.
TABLE 3. CONSULTATION PATTERNS
Li Consulted a doctor
21%
11 midwife
• Hilot
Albularyo
• Nurse
• none
Those who Consulted a doctor
3 mos. ago or less
Over 3 - 6 mos ago
Over 6-12 mos ago
More than a year ago
26%
9%
15%
29%
79%
1 he reasons for ci 1051111 were varied: lU asarec1ulrcmenr
for annual ph y sical examination, insurance, or preeinplovirient purposes. I 0"o due to pregnanc y, 6' for routine
laboratory examinations, and the rest for various medical
problem s ('Fable 4).
TABLE 6. VENUE FOR BP CHECK-UP
PERCENT (%)
60
50
TABLE 4. REASONS FOR CONSULT
40
PERCENT(%)
30
10
• p.9noy. p.-not&
• InTl organ problem
8
ro,t,.lob
6
UENI
—
• Coc,laT
10
I
0
HPN
Total
7L
0
I Hospital
I Clinic
DAHS
• Neighbor
I Mall/Church
20
1
2
HC
U
I i U
•Home
I—i
Non HPN
Body pain,
______
oth-
' I 'hirty six percent f responders have never had their
BP checked. Sixty lout percent have had their BP checked,
among whom 52"r, go to the health center. 1 7' " o check it at
home, 13" o at the hospital. 1 10u at the clinic, 3°o by an
amI)ulatorV health worker, 2° by their neighbor. 10 0 from
BP stalls at the Mercur y drugstore or churches or malls, and
° at the Office or school or during medical missions ('Fable
5). Ihe same pattern of areas of consultation was noted
whether the responder was hypertensive or not (Fable 6).
46° o do not know the doctor's specialization, 22° o go to a
general practitioner, 17"o go to an internist, 3 to an
obstetrician-g ynecologist, 3°o to it surgeon. 2° to a
pediatrician, and l°j to a neurologist ('Fable 7). lhc venue
of consultation was usuall y i he hospital (48').(,), the clinic
(38°o), the health center (131), or a mobile or ambulatory
health service worker (K 1 0 '. (Table 8)
TABLE 7. CONSULT WITH A DOCTOR FOR TX OF HPN
'Ihe average frequenc y Of BP checking was 1.07 times
in a month. \\ith it greater frequenc y among hvpertensives
(2.26 x) compared to non-hvpertcnsives (1.64 x).
Ihirt y one percent of those who are aware they have
111"N have never consulted a doctor. Only 69 have
GP
22%
•IM
17%
13 Card..
6%
• OD/Gyn
3%
• 6gon
3%
EJPndo
2%
1%
IDonTknw
pcc,olzation
L1 NO
consulted a doctor for treatment of H PN - among whom
46%
TABLE 5. BP CHECK-UP
Base popn: those who are aware they have HPN
-r.
El YES
64%
_________________ NO
BP CHECK DONE AT:
Health Center
Home Hospital
Clinic AAHW
Neighbor
Mercury/Church/Mall
School/Office/MM
TOTAL
TABLE 8. VENUE FOR CONSULTATION WITH AN MD FOR TX
60
40
52%
17%
13%
11%
3%
2%
1%
1%
100%
Percent
20
PERCENT(%)
0
Hosp
Clin
HC
AHS
ft\ 3 L
not take an y medication. l'orry nine percent take drugs for
I IPN (I'ablc 9) - among which are beta blockers (410
TABLE 9. TAKING DRUGS FOR HPN
.:•
=
)11I\ hui' \\'n,, \ere t\\are the y had i 11'N and
were taking medications sud they were informed b y their
doctor on how long they had to rake their medicines. Seventy
seven percent were told to take it lifetime or as maintenance,
1000 when needed or when they feel something. 11 0 ,, for six
months or less, io more than six months, and P, were told
to just finish the available medicines (Table 12). Sixty eight
percent alwa y s complied with the prescribed length of time
of drug intake, l jo most of the time. 130 a sometimes, and
4°o rarely (Fable 13). l'hirtv six percent used a different brand
of medicine before. The reasons given for brand switching
Base pupa tt'ose wno are
aware they have HPN
TABLE 12. PRESCRIBED DURATION OF TX FOR HPN
calcium antagonists 1'37`n), angiotcnsin converting enzyme
inhibitors (14`0), angiotensin receptor blockers '8.0,
centrall y to, 4"o said six months or less, l'said until the
prescription is consumed (Table 10). When asked ho- vell
they complied with the prescribed close, 66".. said always.
TABLE 10. HOW LONG DO YOU INTEND TO USE THE DRUG
PERCENT(%)
80,
JUfeilme
60.
• pm
U '6 mos.
40-
D6mos. - lyr.
PERCENT(%)
• 'r
20-
80
1
• Consume Rx
70 ----60-!
ppn
*nose who are told by M
regordoL &ratoo of medication
Base
5040
- -'
I4
6it.
were because the previous brand was expensive (32° '. the
prescription was changed by the doctor (23"V), the previous
brand was not effective in controlling RP (23° ). change of
30—
20
10
0most of the time, 4' someuncs, 4"', ' rarely,
and Po never (l'ahlc 11). Ninet y ninc percent felt that the
current medicine the y were taking were effective.
TABLE 13. COMPLIANCE W/ PRESCRIBED LENGTH OF TIME
13" o
PERCENT(%)
70-
TABLE 11. COMPLIANCE WITH PRESCRIBED DOSE
.-
AIways
60 'H 6
50•
PERCENT(%)
40-
70
60 50
40
30
2010-
0-
4e
Most of the
Time
30 19 Sometimes
20 -'
DPercent
ri
-
'-1 Rarely
14%
Bose popn
•11
eebr 0
J<
tho
L
'9a'C-3 &rotan of
me6cwton.
doctor who subsequently also changed the prescription
and various other reasons which were mainl y related to side
effects or adverse reactions To the drtts (29''
Ihc class of drug used fur h ypertension may have an
effect on compliance with medications. Compliance with
beta blockers was 57, calcium antagonists 70',,, ACE-!
800 , and A R13s 87°, with compliance with calcium blockers
sigmficantiv better compared to beta 1)lockers, compliance
with ACE-1 also significantly better compared to beta
blockers but not to calcium antagonists, and compliance with
ARI3s significantl better compared to beta hhckers and
calcium antagonists but not when compared to ACE-1 (Table
14).
TABLE 16. COMPLIANCE BASED ON NUMBER OF DRUGS
PERCENT(%)
100
80
60
pliant
40
•_Non- Compliant1
20
TABLE 14. COMPLIANCE, NON-COMPLIANCE
WITH PRESCRIBED TX
0
PERCENT(%)
1 drug 2 driq 3 drug*
ob
a
a
"small
100
80
60
40
Li Compliant
20
S Non-Compliant
0
B- Ca
bloc ant
ACEIARB*
w,aH bo. op
Since the 1990's there has been a move to recommend
combination therap y for better control of I IPN.' In this
stud y, the aware hypertensives on medication were also asked
about the number of drugs the y were currentl y taking for
I !PN. Seventy live percent said the y were taking univ I drug.
21' were raking 2 drugs. and 45" were taking 3 drugs (Table
15).
Those who were aware the y had II PiN were asked if there
was any other way of treating hvpertetisi n other than taking
medications ('I able 17).
Forty one percent said they diet, another 41'),, said they
exercise, 19' o said the y take herbal medicines. 3'. o said they
take pineapple juice, 1° each said they rest, take water
TABLE 17. TREATMENT OF HPN: OTHER WAYS
PERCENT(%)
o Exercise
bO
• Diet
40
• Herbal
30
DPme apple ju ic e
rest
20
• water
TABLE 15. NUMBER OF DRUGS PRESENTLY TAKEN
10
4O
0
[i
Tx
IN Acctçuncture
PERCENT(%)
::
base
popn.
none
H
Percent
Base popn:
Aware hypertensive s
L]Frcq.
20
-
idrug 2
3
^
4
drugs drugs drugs
Those on 3 drugs were more compliant with their intake
of medications (91" o), compared to those who were on two
drugs (70") or one drug unIv (63") (Table 16).
therap y, or accupunetLire, while 22",, do not do any other
tli ing to help control their BP other than take their
medication.
Questions on treatment expenses were also asked (Fable
1$). Expenses on drugs alone cost an average of 7,372.29
pesos a year per individual h y pertensive or a monthly expense
of about 614.36 pesos. [he average cost p e r consultation
for l-TPN was 241.1 pesos (246.61 pesos in urban areas and
228.96 in rural areas), there being no significant difference
in cost per consulation for classAB/C+ (271.28 pesos). class
TABLE 18. DRUG TREATMENT EXPENSES FOR HPN
PERCENT(%)
25
TABLE 19. PERCEPTIONS ABOUT HPN
527.001 - 20.000
Increase SP
Pain
Dizziness
Hot Temper Stress
Dietary Effect
Hereditary
Serious Side Effects
Physical Changes
Weakness, Tiredness
Ij U__ t$. 00.000
SOB,CP
- F.WC.'d
Heart Complications
Clotting Problems
Sleepiness
fl 1.000 - I.
U 1.000 - 3, boo
03,061
20
- 0.000
00001 - 9.000
UNDO
15
111112.001
. s,.000
U 15.001 - 10.000
C tI.DOi - 01.000
10
• I.001 - 24.000
o 24.001 - 27.000
5
0
U.'t h.
Ave.
1 year expense P7,372.29
Monthly equivalent
<18yo
28
31
25
19
4
3
2
5
2
>=18yo.
36
32
28
15
8
2
4
3
5
4
2
1
2
1
3
2
P614.36
TABLE 20. LEVEL OF BP PERCEIVED AS HPN
PERCENT(%)
broad C (236.84 pesos), class D (243.6 pesos), and class E
(204.88 pesos). The average frequency of consultations a
year was 6.99 (7.39 in urban areas and 6.13 in rural areas),
being more frequent for class broad C (9.85 x a year) and
almost -similar for the other socio-economic classes (7.46x a
year in class .\B/C±, 5.81x for class 1). and 6.74x for class
F) . Ihe average yearl y expense per individual hypertensive
for consultations was 1106.54 pesos (1161.26 pesos in urban
Ofl$C,',.,flM W,S,
K
NOfrljSnI
•
IC.
b.o,,nth,I6I,4w
•0.
I'
31.
:
L
-I .:::.
areas and 985.87 in rural areas). Computed on a inoiithlv
basis, this will amount to 92.21 CSO5 a month for
15
IC SIoG.. C
I
'IC 5 4041X'131
74
consultation per individual h ypertensive (96.7 7 pesos in
urban areas or 82.16 in rural areas). Comparing socioeconomic classes, expenses for consultation per monti) was
141.99 pesos for class AB/C+. 107.31 for class broad C.
81.85 for class D. and 61.35 for class F. The average expenses
for laboratory and diagnostic tests arc available but have not
vet been computed.
All the responders were asked how the y would explain
I IPN to a friend. Thirty six percent of responders 18 years
of age or higher and 28° o of responders aged 18 and below
defined l-IPN as an increase in 1W level. Majority of the
responders defined I IPN based on signs and svmploms
perceived to be due to I IPN such as headache, nape pains
or bod y pains, dizziness, personality or behavioral changes,
and perceived complications of 1 IPN(Fable 19). When asked
what level of LW was perceived as I IPN, l''o values between
12() to 139 iiml-Ig systolic and/or $0 to 89 mm JIg diastolic,
160 o gave values between 140 to 159 mm Jig s ystolic and/
or 90 to 99 mm l-lg diastolic, while gave values >160
mm I Ig s y stolic and /' or > 100 mm I ig diastolic. (Table 20)
SUMMARY
Seventy nine percent of Filipinos have consulted a
doctor for various reasons. Twenty one percent have never
consulted a doctor but go to a midwife, hilot, albu]aryo,
nurse, or kumadrona, with 14°0 never ever having consulted any health worker.
Sixty four percent of l-ilipinos have had their BP
checked, 52° c, of whom go to a health center.
Only 69 of aware hypertensives consult a doctor for
treatment. Majority are not particular about the specialization
of the doctor (46). The rest see a general practitioner,
internist, cardiologist, OB-Gvnecologist, surgeon,
pediatrician, or neurologist.
Forty nine percent of aware h ypertensives take a drug
for hypertension but onl y 74 percent of them take it dail
Seventy four Percent know the y have to take their medicine
lifetime, 21' will continue until their doctors tell them, 4°
will stop in 6 months or less, and 1° will stop when their
prescription is consumed. Only (ió take their medicine at
the dose prescribed and 68',) at the length of time prescribed.
1 hirtv six percent of those who take medications have
switched brands for various reasons like failure to control
13P, prescription change by the doctor, higher Cost of
previous medication, and various side effects and adverse
reactions to the drugs.
From the point of view of hypertensives who seek
consult, onl y 70'o are instructed bs their doctors on how
long the y should take their medicines. with 771io instructed
to take medicines for I IPN lifetime. 1) 0 only when needed,
and the rest for a specified period of time only or when the
prescription is cons timed.
Foriy one percent of aware hvpertensivcs know that
exercise and dict are helpful in controlling I IPN aside from
medicines. Twent y five percent take alternative treatments
\viihout proven benefits, and 211° do not do an y thing else
other then take their medicines.
Onl y 36° of adUlt Filipinos detine I IPI\ according to
level of HP. with 74 of them recognizing I IPN at levels
greater then or equal to 161) s y stolic and/or greater than or
equal to 100 diastolic. Majorit y will define I IPN b y various
S y mptoms percej\'edl to be due to I I PN, or personality traits,
ph y sical changes, and its complications.
I Ivpertensives spend an average of 7372.29 pesos per
year for medicstions. On a monthl y basis, the average cost
was 614.3$ p es os.The average cost per consultation with a
doctor is 241.10 pesos. .1 he average CXCflSCS for consultation
was 1106.54 pesos per y ear or a monthl y equivalent of 92.21
pesos. Expenses for laboratory and other diagnostic tests
have not vet been computed.
DISCUSSION
The data presented was taken from responders 18 years
old and above and subsequentl y si.ibsetted to hvpertensives,
aware hvpertensives, and aware hvpertcnsives on medication.
This initial report is onl y on the general data. We can do
further subanal y sis by cross-referencing the data according
to region, urban vs. rural, sc)cio-economic class, educational
attainment, occupatl( >0, age, and gender. Take note that in
this report, there is equal distribution of subjects between
male and female, and rural and urban. B y socio-economic
class, most of the responders belonged to class D, which
also reflects the actual socioeconomic distribution in the
Philippines based on the National Statistics Office 2000
census. While the data presented is reflective of the
perceptions of the Filipinos in general, it ma y represent more
the perceptions of class D and F. It will be interesting to
look into differences in perception according to socioeconomic class and educational attainment and see how these
affect 1 IPN control.
.\ stud y b y Pctrella, et a! 12 on the impact of social
marketing media campaign on public awareness of 11 PN
showed that in the short term, media awareness program
increased the number of respondents who claim to have I IPN
this was not
and patient self efficienc y for BP control but
maintained because the y did not change the knowledge of
the respondents about I IPN. its consequences, and the
importance of good HP control. This survey conducted
nationwide show that Filipinos have inadequate knowledge
about the definition of hypertension, its clinical presentation,
and proper management. This ma y account for the low level
of awareness and control rates for II PN as noted in
PRESYON 1 in 199$ and again in PRESYON 2 in 21107.° I
o separate papers, b y Oliveria, ci al , and Egan, et al on
I IPN knowledge, awareness and attitudes among hypertensive
population in the U.S., patients were also found not to have a
comprehensive understanding about I IPN and this emerged
as a greater barrier to HP control than cost of medication.
Based on the data obtained in this stud y, the Council on
l-IPN of the MIA would recommend that: 1.) Fducation
programs on I IPN must be prioritized not onl y for patients
but for health care givers as well. Fmphasis should be placed
on the fact that I IPN is usuall y asymptomatic and that the
diagnosis is currentl y based on accurate HP determination.
The level of optimal BP. HI > N. and target B)? levels for good
control of II PN must be made ver y clear. Precise instructions
Oil dose and duration of treatment must be given; 2.) Filipinos
must be informed about the importance of lifestyle
modification in the control of II PN. Programs at the
communit y level must be encouraged to adapt a health y lifestyle
which has proveneffects, while existing myths must be
debunked: 3.) 1ocus must be given to barangav health workers
who man the health centers where most Filipinos go for HP
determination; and 4.) Guidelines for management of I IPN
among Filipinos must be drafted inorder to optimize cost/
benefit ratios of laborator y and diagnostic tests, consultations.
and prescriptions. \Ve now have the local studies on I 1l'N to
ttive support to this.
REFERENCES:
(tiohaniaii. ci at. Ilic Svnth Report of the loint National
I.
Iuaiu ii>, Alld I r(atmcnt Of
( .1 >mrnitrcc on t > rcvci>n in. I )ctection. I
I ugh Oh >id l'rcssi>rc. I \ \ I \. 2003: 289: 2531 2573.
\\orld I Icalth ( )rganisatioil - Itimeritatiotial Society nil Ivpertcnsion
2.
\\irking Group. 2003 WI !( )/ (St I Statement on the Managenieni of
I IPN. Journal of I II >N 2003;21: 1933-1982.
Kannel. WK Franiiogliain Sooty Insights into I I eperrensive risk of
3.
CardiovactiIar I )iscasc. I Ivpertens Roe 1995; 181 196.
4. jotfrcs M.R, et A. Distribution 1 OP and I I PN in Canada and t5he
I_S. \m jour of I II >N. 2001: 14: 1099 1105.
(.ollioun, 11.%1, ci al. blood Pressure '(reeninp.
Management, and Control in England: results from the
I Icalth Survey for England, 1994. Journal of 1-IPY 19198:
16: 747-752.
Inho Jo, et al. Prevalence, Awareness, Treatment, Control,
6.
and Risk Factors of HPN in Korea: the ANSAN stud.
Journal of I IPN, 2001; 19: 1523-153-2.
7.
Pan, WE-I, ci al. Prevalence, Awareness, Treatment, and
Control of 1-IPN in Taiwaii: Results of Nutrition and Health
Surve y for Taiwan (N.\1-ISIT) 1993-1996. Journal of
Human 1IPN, 201)1; 15: 793 . 98.
8.
Sison, J, et al. Philippine I leart Association Council
H y pertension Report on Surve y of I lvperrenston
(PRESYON). Phil Journal of Cardiolog y. 1998; 26: 31 -34.
9. Sison, jet al. PRESVON 2 - Target Organ Damage.
Presented at the Philippine Heart Association Annual
Convention, \ la y 21117
Ill. Bakris.G.L. Managing I Ivpertension: The Current Clinical
Strategies. I lvpertension Disease Management (.uidc PDR
20113, third edition: 101 . 133.
Il. BetancourtJR, ci al, Hypertension in Multi cultural and
Minorit y Populations: Linking Communication to
(:oiiwli:iiice. Current I lvpertcnsion Report, 1999; 1: 482488.
12. Peirella. et al Impact of Social'
ocial Marketing Media Campaign
on Public Awareness of I Ivperrcnsion.. \ni Jour of II l'\.
2003; 18:270-275.
13. Ohvena, SA. et al H ypertension Knowledge. Awareness,
and .ttitudes in a I Ivperrcnsivc Population. jour of Gen
Internal Med ,20(5; 20: 219-225.
14. Egan, B.\1,awarcncss, Knowledge, and Attitude- of Older
Americans About I Ivpertension: Implications of Health
Care Poky, Education, and Rcasearch. Arch Internal Mcd,
Mar 24, 2004; 163: 681-68-7.
:.
4
Success Rate of Radio-Frequency Ablation from January
1996 to November 2006 at the Philippine Heart Center:
A Descriptive Analysis.
Rey C. Alvarez, MD
Division of Adult Cardiology, Philippine Heart Center
BACKGROUND Radio-frequency catheter ablation has replaced antiarrhythmic drug therapy for the treatment
of many types of cardiac arrhythmia. It is highly effective with a low complication rate. In
2004, the heart rhythm that are treated with radio-frequency ablation include supraventicular
tachycardia, atrial fibrillation, atrial flutter, and ventricular tachycardia. It shows a success rate
>90% in SVT, 80-90% in those with idiopathic ventricular tachycardia, 50% in ventricular
tachycardia with structural heart disease, 75-80% in younger patients with atrial fibrillation,
only 25% for older patients with chronic atrial fibrillation [1].
OBJECTIVE
The aim of the study is to determine the success rate of radio-frequency ablation from January
1996 to November 2006 at the Philippine Heart Center.
METHODS AND RESULT Between January 1996 to November 2006,53 patients aged 19-72 years old underwent
radio-frequency ablation at the Philippine Heart Center. Successful radio-frequency ablation
was achieved in 49 patients (92.5%) with 2 patients having complications (3.7%)
CONCLUSION This study demonstrated the efficacy of radio-frequency ablation for the treatment of a wide
variety ofarrhythmias supporting other literatures regarding the success rate of the procedure.
It also appears that the risk of complication was low.
INTRODUCTION
Several reports have demonstrated that radio-frequency catheter
ablation provides effective control of variety ofarrhythmias with
low incidence olcomplication. However, the efficacy has not yet
been reported in our institution.
This report details the result ofradiofrequency ablation in 53
patients on a 10-year period at the Philippine Heart Center.
METHODOLOGY
From Januar y 1996 to November 2006, 53 patients who
underwent radiofrequency ablation at our institution were included
in thissiudy with mean age oi44 years (range 19-76 y ears), 30 male
(566%) and 23 female (3.40%).
Total number of patients
Age (years)
Men
Women
Men to women ratio
Symptoms:
palpitation
pre syncopelsyncope
dizziness
shortness of breath
chest pain
CF arrest
Co morbid Conditions:
Hypertension
Diabetes
CAD
Hypertension + Diabetes
Hypertension + DM + CAD
Cardiomyopathy
it
44
(range 19-76)
30
23
130:1
38(71.7)
6 (11.3)
3 (5.7)
3 (5.7)
2 (3.8)
1(1.8)
6 (54.5)
1 (9.1)
1 (9.1)
1 (9.1)
1 (9.1)
1 (9.1)
Baseline characteristics are shown in Table l. The most common
s y mptom was palpitation (38 patients, 71.7%), followed by
presyncope/syncope (6 patients, 11.3%), dizziness (3 patients, 5.7%),
shortness of breath (3 patients 5.7°M), chest pain (2 patients, 3.89/6),
and CP arrest (1 patient. 1.8%). The most common co morbid
condition was hypertension (6 patients, 54.5%). Indications for
radiofrcquency ablation and location of the pathway is shown in
Tables 2 and 3 respectively. The most common indication was
supraventricular tach ycardia (27 patients. 50.9%), followed by WolfParkinson White Syndrome (14 patients. 26.4 9/b), Idiopathic VT (8
patients, 15.3%) VT due to structural heart disease (2 patients,
3.7°/n), and Atrial fibrillation (2 patients, 3.7 %) The most common
pathway is the accessory pathway (30 patents, 56.6%), AV nodal
pathway (14 patients, 26.49/o), and RVOT (9 patients, 17%).
Table 2. Indications for Radiofreguency ablation
Indication
Supraventricular tachycardia
Wolf-parkinsons white syndrome
Idiopathic Ventricular tachycardia
Ventricular tachycardia due to CAD
Atrial fibrillation
No. of Patients (%l
27(50.9%)
14(26.4%)
8 (15.3%)
2 (3.7%)
2 (3.7%)
Table 3. Location of
1. Accessory pathways
la. posteroseptal
lb. anteroseptal
lc. posterolteral
Id. anterolateral
1e. sub eustachian isthmus
if. lateral Kent bundle
2 AV Nodal pathways
2a. Slow pathway
30 (56.6%)
12 (40%)
3 (10%)
9 (30%)
4 (13.4%)
1 (3.3%)
1 (3.3%)
2b.Fast pathway
2c. Slow and Fast
14 (26.4%)
9 (64.3%)
3(21.4%)
2 (14.3%)
3.RVOT
9
(17%)
STATISTICAL ANALYSIS
A descriptive analysis was applied to the data gathered
and will be reported as proportions and percentages.
RESULTS
Out of 53 subjects, successful radio-frequency ablation
was noted in 49 patients (92.5%), while in 4 patients it
was not successful. Median procedural and fluoroscopy
time were 4 hours and 20 minutes (range 2 - 7 hours and
20 minutes) and 85 minutes (range 30 - 300 minutes)
respectively. Only 2 complications were noted (3.7%).
DISCUSSION
4
Radiofrequency is the most widely used and effective
form of energy applied during catheter ablation. It is an
alternating current delivered at cycle lengths of 300 to
750 kHz that causes resistive heating of the tissue in
contact with the electrode /21. The power of RF pulses is
typically controlled by the catheter tip, temperature and
system impedance. Most ablation centers have a 4-mm
distal electrode and create lesions approximately 4 to 6
mm in diameter and 2 to 3 mm deep. The acute lesion
created by radiofrequency current consists of a central done
of coagulation necrosis surrounded b y a zone of
inflammation f3J.
The procedure usually takes 2 to 4 hours. In our
institution the median procedural time was 4 hours and
20 minutes Radio-frequency ablation procedures require
fluoroscopy, and the amount of radiation exposure
depends on the equipment and the technique used. Radiofrequency ablation usually can be accomplished with less
than 60 minutes of fluoroscopy. Our center has an average
of 85 minutes of fluoroscopy time. Radio-frequency
ablation advantages include relief of symptoms,
improvement in functional capacity and the quality of
life, elimination of the need for lifelong antiarrhythmicdrug therapy, and long-term cost savings [4].
Possible complications vary with the specific
tachycardia diagnosis. These are perforation of the heart
with leakage of blood into the sac surrounding the heart,
perforation of a blood vessel with leakage outside it,
inadvertent interruption of normal conduction (which
requires a pacemaker), stroke, heart attack, and even death.
These are all very rare. A pacemaker is needed in less than
I in 200 cases and other, more serious complications occur
in less than 1 in 500 /51. In this study the 2 complications
noted were hematoma at access site located at the right
inguinal area and a minimal skin burn secondary to
defibrillation due to ventricular fibrillation thus aborting
the procedure.
Radio-frequency catheter ablation has replaced
antiarrhythmic drug therapy for the treatment of many
types of cardiac arrhythmias. In 2004, the heart rhythms
that were treated with radio-frequency ablation include
supraventicular tachycardia, atrial fibrillation, atrial flutter,
and ventricular tachycardia. it showed a success rate >90%
in SVT, 80-90% in those with idiopathic ventricular
tachycardia, 50% in those with ventricular tachycardia
with structural heart disease, 75-80% in younger patients
with atrial fibrillation, only 25% for older patients with
chronic atrial fibrillation [1]. No studies have ever been
published regarding the success rate of radio-frequency
ablation done here at the Philippine Heart Center. In this
report, the overall success rate of radiofrequency ablation
was 92.5%. Out of 27 patients with SVT, 2 were
unsuccessful giving a success rate of 92.6%. Out of 14
patients with WPW the success rate was 100%. Out of 8
patients with idiopathic ventricular tachycardia the success
rate was also 100%. Out of 2 patients who have VT, I
patient have Cardiomayopathy was unsuccessful ly ablated
thus giving only 50% success rate. I out of the 2 patient
swith atrial fibrillation has also unsuccessful radiofrequency ablation leading as low to a 50% success rate,
however was done in a 64 year old patient.
CONCLUSION
In summary, radio-frequency ablation has become a
major tool in the treatment of different arrhythmias with
a very high success rate and a very low incidence of
complications was demonstrated in this study. For
individuals who are bothered enough by episodes of
abnormally racing heart that they need some type of
treatment and radiofrequency catheter ablation is an
excellent option. In this study the success rate for SVT
was 92.6%, 100% for Idiopathic Ventricular Tachycardia,
50% for Ventricular Tachycardia with structural heart
disease, and 50% for Atrial Fibrillation. A study done by
Dr. Koo [4], showed > 90% success rate for SVT, 8090% for Idiopathic ventricular Tachycardia, 50% for
Ventricular Tachycardia with structural heart disease, and
25% for older patient with atrial fibrillation. Therefore,
the success rate of Radio-Frequency Ablation in our
institution is comparable with those rated in other known
centers.
REFERENCES:
1.
Radio-Frequency Ablation, Dr. Koo, 2004- Associated
cardiovascular consultants, PA. H trp. www.accnj.com .ed art/32004.hrm.
2.
Borgreffe, M. eta], Catheter ablation using radio frequency
energy. Clinical cardiology, 1990; 13: 127-31.
3.
Radio-Frequency Ablation as a first procedure for atria flutter
treatment. Maurisio Scaravaca, HI, San Ramio University, Brazil,
Dec 2003.
4.
Radio-Frequency Ablation, F Morad y, New England journal. feb
5.
18, 1999, vol 340 No.7, pp. 534-541.
Catheter ablation of arrhvthmias, J Mu et al, Circulation 2002;
106; 203-205.
The Effect of Exercise Training on the Six-Minute Walk
Distance of Children Enrolled in Pediatric Cardiac
Rehabilitation Program: A Preliminary Result
Emily G. Anupol,, MD
Division of Pediatric Cardiology Philippine Heart Center
OBJECTIVES
I TO determine the change in six-minute walk distance of children and adolescents who were enrolled in pediatric cardiac rehabilitation program (PediaCaRe)
determine the effect of exercise training on the heart rate, respiratory rate, oxygen saturation,
To
2.
systolic and diastolic blood pressure of these children.
BACKGROUND After surgery, children and adolescents were enrolled in PcdiaCaRc in order to restore normal
baseline exercise tolerance prior to surgery, to rehabilitate patients with exercise limitations prior to
surgery so their full potential could be realized and to provide recommendations for safe exercise
and sports activities that could be safely undertaken by post- surgical patients.
METHODS
Interventional study
Exercise training: enrollment in Pediatric Rehabilitation (PediaCaRe)
program.
PARTICIPANTS Pediatric patients enrolled in PediaCaRe who have completed at least the
phase 1 of the program and who have pre- and post- exercise training sixminute walk distance and vital signs before and after the six-minute walk
distance test.
Tertiary Pediatric Cardiovascular center
SETTING
STUDY DESIGN
INTERVENTION
RESULTS 1vcnty-six patients were included as subjects for this study. There were 16 female and 10 male
patients ages 5 to 18 years old (mean 12.3 ± 3.93). Majority (85%) had congenital heart disease
while 15% had rheumatic heart disease. Eighty eight percent of patients underwent open-heart
surgery. Paired T test done to compare difference of the six-minute walk distance showed statistically
significant difference between the pre- and post- rehabilitation six minute walk distance (299.81
± 141.19 vs 453.77 ± 125.60) with a p value of 0.000, heart rate (97.65 ± 18.2 vs 87.92 ±
17.22) with a p value ofO.0l4, systolic blood pressure (96.92 ± 11.92 vs 10 1. 15 ± 11.07) with
a p value of 0.046, while no statistically significant difference was noted in the respiratory rate
(21.81 ± 4.51 vs 20.73 ± 4.27) with a p value of 0. 10, oxygen saturation (97.85 ± 2.38 vs 98.23
± 2.58) with a i' value of 0. 195, and diastolic blood pressure 62.69 ± 8.74 vs 62.31 ± 9.92) with
a p value of 0.824. There was no statistical difference when the six-minute walk distance obtained
after rehabilitation was compared with the reference values.
CONCLUSION The improvement of the six-minute walk distance of children enrolled in a progressive exercise
program approximates the respective reference values. The beneficial effects of a progressive
exercise training program can he measured not only in terms of better well being or improved
quality of life or functional capacity but can be measured objectively using simple test such as the
six minute walk distance.
KEY WORDS
six-minute walk test, six-minute walk distance, exercise training
INTRODUCTION
Adults and adolescents with congenital heart
disease have impaired exercise tolerance even after
surgery. The diminished exercise tolerance among these
patients result from the long-standing injury incurred
by the heart while corrective surgery has not been done
or as a result of the surgery. Among the causes of
diminished exercise tolerance are the following: inability
of the heart to increase rate appropriately in response
to exercise in cases of damage to sinus node; inability
to increase myocardial contractility in cases of chronic
volume or pressure overload and chronic hypoxemia;
inability to maintain appropriate cardiac filling among
patients who underwent Fontan operation; diminished
delivery of oxygen on the exercising muscles such as
in patients with cyanotic congenital heart disease or in
ciictati )11 ut the i ita. Reduced CNCICISC pert )1i[iiC
ma y also reflect lack of regular exercise among
overprotected individuals.
The section of Pediatric Cardiac Rehabilitation
(PediaCaRe) has established a supervised progressive
exercise-training program for children and adolescents
who underwent cardiac surgery. The main objectives
of the said program are: to restore normal baseline
exercise tolerance prior to surgery, to rehabilitate
patients with exercise limitations prior to surgery so
that their full potential could be realized, to provide
recommendations for safe exercise and to recommend
sports activities that can he safely undertaken b y postsurgical patients.
Since its implementation, there are a number of
patients who completed the program with good results
in terms of improved exercise capacity, functional
classification and quality of life. However, these
improvements, although apparent on the patients, have
no objective documentation.
Formal testing of exercise capacit y is often needed
before prescribing exercise to patients with congenital
heart disease preferabl y with measurement of oxygen
uptake to measure the effects of sub-maximal and
maximal exercise and for reassuring these patients.
However, performing a formal exercise test is often
limited by the cost, cumbersome equipment and
complicated procedure. The patients may not be able
to complete a strenuous exercise test, more so those
who have congenital heart disease and after surgery.
Walk tests were originally developed as
nonlaboratory estimates of ph ysical fitness and was
shown to correlate with maximal oxygen uptake. One
of such test is the six-minute walk test. Its simplicity
and ease of administration makes it an ideal choice for
a sub-maximal exercise test. Since patients have limited
exercise capacity after surgery, their ability to complete
a maximal exercise test such as a treadmill test or peak
oxygen uptake test is hampered. The six-minute walk
test is also reflective of the capacity to undertake
activities of daily living and is widely accepted for its
ability to evaluate functional capacity in different
groups of patients.
The main objective of this study is to determine
the change in the six-minute walk distance of children
enrolled in exercise training program such as the
Pediatric Cardiac Rehabilitation (PediaCaRe) program.
tidy \\ nUd iIs deeriiiitic 111C ettcct of exercise
1 Ii
training on the heart rate, respirator y rate, s ystolic and
diastolic blood pressure and the oxygen saturation
which are also measured during the administration of
the six minute-walk test
MATERIALS AND METHODS
SUBJECTS
This stud y was conducted from Januar y to
December 2005. Consecutive patients who underwent
cardiac surgery during the said period and complied
with the inclusion criteria were included as subjects.
Patients who underwent cardiac surger y who were
enrolled in the pediatric cardiac rehabilitation program
and had completed at least the phase I of the program
were included. The six minute walk distance upon
program enrollment and after completion of the phase
I program were compared with one another and with
the reference values of the six minute walk distance
for age and sex. The vital signs during the six-minute
walk test were recorded and compared with the initial
test and upon completion of phase I program.
Excluded are patients who did not have an initial
six-minute walk distance prior to the exercise training
or after completion of the exercise training. Patients
who did not complete at least two months of supervised
and unsupervised exercise training were likewise
excluded.
THE SIX- MINUTE WALK TEST
The venues for conducting the six-minute walk test
are in the corridor at the children's ward and at the
oval tract at the 8th floor. In accordance with the
recommendation of the American Thoracic Society,
the six-minute walk test should he performed indoors,
along a long flat straight enclosed corridor with a hard
surface that is seldom traveled. The corridor along the
children's ward is 35 meters while the oval tract
measures 88 meters.
The recommended equipments such as timer/
stopwatch, mechanical lap counter, source of oxygen,
sphygmomanometcr, and pulse oximeter were
available. A defibrillator is available in the vicinit y of
the test area.
The patients are instructed to wear comfortable
clothing and appropriate shoes for walking, and the
patient took a light meal before early morning or early
afternoon tests.
Before the start of the walk, the patients were asked
to sit comfortably in a chair for about ten minutes.
During this time the patient is observed for
contraindications and vital signs were taken and
recorded. The patient is then instructed to walk for six
minutes. They were told to walk back and forth in the
hallway or around the oval as far as possible without
running or jogging. They were informed that they could
slow down or stop and rest if necessary but to resume
walking as soon as able. Standard encouragement was
given every minute and then the distance walked in six
minutes is recorded at the end of the test. If the patient
fails to finish walking in six minutes, the distance
covered, the time stopped and the reason for stopping
is noted. After the test, the patient is congratulated
and offered a drink of water.
The reference values of the six minute walk distance
was derived from the equation developed by Pura, et
al when they studied the six minute walk distance of
healthy Filipino adolescents.
The reference equation for the six-minute walk
distance (6N-1W!)) in Filipino children is as follows:
BO YS. 6MWD 584.37-5.703 (AGE IN YEARS)
GIRLS:6MWD = 540.22-4.597 (A GE IN YEARS)
THE PediaCaRe PROGRAM
The PediaCaRe program is divided into the
following components: exercise training, health
education, nutrition education and psychosocial
counseling. The phases of the cardiac rehabilitation
program arc:
Phase 1- for inpatients from 1 to 15 days after surgery
Phase 2- from discharge up to 2 months as out patient
Phase 3- maintenance (from 2 months to 1 year)
For this study, those patients who were able to
complete the first four sessions of the program were
included. However, there is an overlap of time between
phase I and phase 2 because some patients were
discharged within I week after surgery. Due to
demographic considerations, the exercise training was
done based on patient's availability and capacity and
does not necessarily fit into the time frame described.
Hence even though the patients were able to complete
on 4 sessions of supervised exercise training, the time
it
covered extended up to 2 months after the surgery.
The patients were encouraged to do unsupervised
exercises at home at least 3 times a week. The y were
instructed to do the exercise level that they were able
to perform during the supervised exercise training.
The exercises include warm up, stretching, range
of motions, walking, running and final stretching. For
each of the session, a rehabilitation nurse, a physical
therapist and a pediatric cardiology fellow or consultant
is available to supervise the progress of the patient's
exercise training. 1he patient's progress is then recorded
in their individual record. The occurrence of exercise
related complications were likewise noted and
recorded. The maximum heart rate of the patient is
computed at the start of the program using the
following formula:
Max heart rate = 220 - age in yrsx% allowable rate inc
Table 1. Allowable percentage of maximum heart rate during
exercise
Duration of Exercise Training
1" week
2d week
3 11 week
4" week
Percent of Maximum
Heart Rate
50%
60%
70%
80%
Ilie percentage of the maximum heart rate which
patients were allowed to reach during exercise depends
on the duration of exercise training of the patient.
The maximum heart rate serves as a gauge to stop
or slow down with the exercise training. Once the
allowed heart rate is reached, patients are allowed to
slow down or rest.
STATISTICAL ANALYSIS
Paired T test was used to determine the differences
of the cardiace rate, respiratory rate, oxygen saturation,
systolic and diastolic blood pressure and the six-minute
walk distance before and after the exercise training
program. A p-value of less than 0.05 with a confidence
interval of 95% was considered statistically significant.
RESULTS
11iere were 26 patients included as subjects in this
study. There were 16 female and 10 male patients. The
patients were aged 5 to 18 years old with a mean of
12.5 ± 3.92 years old.
Table 2 shows that majority of patients who \verc
enrolled in the PediaCaRc program has congenital heart
disease, while those with rheumatic heart disease
comprise 15% of the cases.
Table 2. Diagnosis of patients who underwent cardiac
rehabilitation program:
Diagnosis
Frequency
Percentage
Congenital Heart Disease
Atrial Septal Defect
ASDw/MR
ASD&VSD
Ventricular Septal Defect
TOF/POF
Patent Ductus Arteriosus
Single Ventricle
Marfans Syndrome w/ MR
Rheumatic heart Disease
RHDMR
RHDMS
RHDMSAR
TOTAL
22
4
1
1
7
5
2
1
1
4
1
2
1
26
84.50%
15
4
4
27
19
7.5
4
4
15.50%
4
7.5
4
100%
Table 3 shows the type of surgery done on these
patients. Majorit y of them underwent open-heart
surgery.
Table 3. Type of surgery done
Type of Surgery
Open heart surgery
Closed Heart Surgery
Total
Frequency Percentage
23
88%
3
12%
26
100%
In order to determine the significance of the
differences of values obtained before and after
completing 4 sessions of cardiac rehabilitation, paired
T test were done. A p value of less than 0.05 with a
confidence interval of 95% is statisticall y significant.
Table 4 shows the mean values of the vital signs
and the six-minute walk distance before and after
completing four sessions of pediatric cardiac
rehabilitation (PediaCaRe) program. The corresponding
p values obtained after doing a paired T test was also
shown and highlighted to show significant results.
Table 4. Mean values of vital signs and six-minute walk distance
before and after cardiac rehabilitation:
Rehabilitation
Cardiac Rate
Respiratory Rate
Oxygen Saturation
Systolic BP
Diastolic BP
6MND
Expected 6MWD
PreRehabilitation9765 ± 18.2
21.81 ± 4.51
97.85 ± 2.38
96.92 ± 11.92
62-69 ± 8.74
299.81 ± 141.19
Post
p value
87.92 ± 17.22
20.73 ± 4.27
98.23 ± 2.58
101.15 ± 11.07
62.31 ± 9.92
453.77 ± 125.60
0.014*
0.1
0.195
0.046*
0.824
0.000*
1.132
Pie- rehabilitation- values obtained before the start of supervised and unsupervised
exercise
Post- Rehabilitation- values obtained aftn the Oomplelion of Phase 1 and wit at least 2
months supervised and unsupervised exercise training
Based on the above-pured 1 test results, the heart
rate decreased significantly from the baseline with a p
value of 0.014 and mean difference is 9.73. The systolic
blood pressure increased by 4.23 mmHg with a p value
of 0.046. The six-minute walk distance increased by
153.96 meters with a p value of 0.000 as compared
with the baseline. We should note that there is no
statistical difference between the reference values of
the six minute walk distance for age and the six minute
walk distance achieved after 4 sessions of pediatric
cardiac rehabilitation with a p value of 0.132.
DISCUSSION
It is clear that exercise training improves
cardiovascular function through changes in maximal
aerobic power V02 max). A meta-analytic review done
by LeMura, et al, studied the effect of exercise training
on the V02 max in children. Based on this stud y, in
order to consider a training protocol significant, the
standard frequency is three times per week, minimum
duration of six weeks and sufficient exercise intensit.
Our studs' which included patients who completed
phase one of the PediaCaRe program, did not strictly
complied to the adequacy of the exercise training. The
patients in this study had limited supervised exercise
training. The records were not specific on the frequency
of their unsupervised exercise at home. But all of the
patients had at least 2 months of mixed supervised and
unsupervised exercise training. The intensity of the
exercise is determined by the ability to reach at least
70tL
of their maximum heart rate. The vital signs that
we reported here were derived (luring the administration
of the six-minute walk test and not during the exercisetraining program. It is be yond the scope of this studs,
to determine intensity of the exercise training given to
the patients.
A stud y done b y Haass, et al, showed a good
correlation of the six-minute walk distance with the
maximal aerobic power VO, max) among patients with
congestive heart failure. The stud y was also able to
correlate the six-minute walk distance with the mortality
and morbidity of these patients and established 3(.)0m
or less six-minute walk distance (6MWD) to he
associated with 50% one-year mortalit y and increased
rate of hospitalization. But we should note that the
study was done among an adult population. Among
children, the six-minute walk test was used among
severely ill patients who are awaiting heart lung
transplant. The six-minute walk test correlated with the
max but not with the peak heart rare and
concluded that the six-minute walk test may provide
an alternative method for assessing functional Capacity
in severely ill children.
Several modalities are available for the objective
evaluation of exercise capacit y . Some tests
complete assessment of all s y stems involved in exercise
performance while others provide basic information but
are simpler and easier to perform. The choice of specific
test would depend on the clinical question to be
addressed and the available resources. Traditionally, the
assessment of functional capacit y is based mainly on
patients' recollection of their abilit y to climb a flight
of stairs and the distance the y could walk before the y
y provide over estimationbecomrathls.Ty
or underestimation of their true functional capacity.
Objective measurements reflect better the true
functional capacity than self-report.
The six-minute walk test is a simple test that rcc1uires
at least a 30-meter hallwa y but no exercise equipment
oradvanceci training for technicians. The strongest
indication of six-minute walk test is for measuring
response to treatment or medical intervention in patients
with moderate to severe heart disease. In this stud y the
ifltetveflt.1OI1 is the exercise -trali1iflg program, \vhmch is
a progressive exercise training to improve physical
fitness. Although the six-minute walk test has been
used in different groups of patients, it does not mean
that this is the best test for determining functional
capacity or improvement of functional capacity. This
is simpl y one stud y that would like to determine the
utilit y of the six-minute walk test for such circumstances
and further test are needed in order to expand current
knowledge on the practical application of the six-minute
walk test among patients with cardiac illness.
Although the effect of physical training has been
clearly documented among adults, there is still lacking
evidence of the effect of exercise training among prepubertal children. Several studies done showed that
ph y sical training among males did not significantl y alter
the V02 max. The different investigators postulated
that a critical time is needed for the maturation of the
neuromuscular s y stem and hormonal levels before
changes in the V02 max is attained, literature search
on the effect of exercise training among post-surgical
children specificall y those who underwent correction
Or palliation of their cardiac condition is lacking. To
the knowledge of the author, this is the first attempt to
document the changes in the six minute walk distance
and vital signs that happen after exercise training among
children. Based on this stud y, the patient's six-minute
walk distance improved significantl y. This is associated
with less fatigue, more endurance and more energ y after
exercise training. On the cellular level, the exercise
training brought about increase in the numl)er of
mitochondria and increase in threshold for lactic
L14^
It is not the objective of this stud y to determine
the factors that brought about the improvement in the
6MWD that we observed, but rather, to offer an
explanation for the change.
acidosis.
CONCLUSION
This study has clearl y demonstrated the beneficial
effects of exercise training among p atie nts recuperating
from cardiac surger y. The six-minute walk distance did
not onl y improve but approximated reference values
for age and sex of comparable normal children. The
beneficial effects of a progressive supervised exercise
training program can be measured not only in terms of
improvement of well being or qualit y of life but can
also be measured objectively using a simple test such
as the measurement of the six- minute walk distance.
BIBLIOGRAPHY
l)cantield . 1 F. I Tullen s, 1Ierii1a) • t- t )S. ( .oflgenht.il I ti;irt t)is.asc in
Adolescents and Adults. In: .\nderson R Nlacartncv RV Shinebourne
I-I Baker F Rigby NI Tynan NI editors Paediatric Cardiolog y 2
I Wition la indori: I larcourt I'ublishers Limited 2002 p1903
Bun vi MI. (Tasas Nit., Standard ( )pc raring Procedures in: Guidelines
2
in PediaCaRe Policy 006 Revision Dared jul y 2002
3 American Thoracic Societ y Board of Directors -VI'S Statement:
;uidelin for the six minute walk test. :\m j Rcspir Crit Care Med
Vol 166 p 111-117, 2002
1 Pura NI!, t'unzal P. Bautista Ni. de Leon N, Six minute walk distance
of Filipino high schoo l students. Phil I leart ( Tenrer Journal Vol 9,
2002 p 31-34
,eNlura I,, vont )tillivard S. Carlonas R, Andrcacci J. Can exercise
training improve maximal aerobic p wer (Vt )2max) ill Childrcn: a
Jan- Dec
S
I
meta-analvtic review I dkmtinc Vol 2 No 3. 2 (3): 122. 1999
6 1 Iaass Ni, Zugek C. Kuhler \V . ..lie Onimnure walking test: a Costeffective alternative to spiro-ergoilicirv in patients with chronic
heart failure :, carticle in Gciman abstract V. Kardiol. 2000 Fh 89
2) 72-80.
Calcific Aortic Stenosis, Can Statins Stop it?
A Meta-Analysis
Arnold S. Dc Guzman, MD, Peter Jay S. Dumana, MD, Rodney M. Jimenez, MD
Heart Institute, St Luke's Medical Center
BACKGROUND It is onl y in time that we can stop it. Once calcific aortic stenosis is severe, death is imminent and
surgery is the only option, Calcification of the aortic valve is the third leading cause of heart
disease in adults and the most common cause of valve replacement in developed countries.
Compelling data now suggest that it is an active disease process similar to atherosclerosis. Hence,
it raises the possibility that the treatment used in preventing or slowing the progression of
vascular atheroscicrotisis may be effective in patients with aortic stenosis. In limited observational
studies, aortic stenosis progressed at a slower rate in patients who received statins than in those
who did not. The objective of this meta-analysis is to determine whether statin therapy can
prevent the progression of calcific aortic stenosis.
METHODS Clinical trials were identified from Medline search, PUBMED, and Cochrane collaboration databases
from 1999 to 2006 using the following ke y words: statins, aortic stenosis, aortic valve calcification,
randomized controlled trials and MESH terms hydroxymethvlglutaryl-CoA reductase inhibitors,
heart valve disease. A total of 7 articles were queried, 2 of which were randomized controlled
trials and were subjected to data extraction and quality scale assessment. Independently quality
assessment scale and the inclusion criteria were strictly applied. Included studies were randomized
controlled trials involving a total of 294 patients with mild to moderate calcific aortic stenosis
(Vmax 2.0— 3.9m/s). Patients with coexisting more than mild aortic regurgitation, severe mitral
valve stenosis, left ventricular d y sfunction (e)ection fraction, <35 percent), planned sortie valve
replacement, intolerance to statins, statin therapy or to potential benefit from statin therapy
(according to the treating physician) and baseline serum cholesterol of less than 150mg per
decilitre, and presence of a permanent pacemaker or eardiodefibrillator were excluded..
RESULTS The analsvsis of the rate of annual peak aortic velocity (rn/s/year) of the two trials showed to
he homogeneous (Chi-square = 0.14, dfl, P0.70). The result showed that the use of statins
did not significantl y improve the rate of annual peak aortic velocity from the baseline as compared
with the placebo with p value of 0.75 with mean duration of more than 24 months.
CONCLUSIONS
Staun therapy favors trend towards benefit but did not reach statistical significance in terms of
slowing the rate of change in aortic-jet velocity nor did induce it regression.
REVIEWER'S Statin therapy is neither cost-effective nor recommended for patients with mild to moderate
calcific aortic stenosis. Large, prospective, randomized controlled trials should be done using
statins in the different stages of calcific aortic stenosis to determine its definite value and
effectiveness
The most common reason for valve replacement
in the United States is calcific aortic stcnosis. It is only
in time that we can stop its progression. Once aortic
steriosis is severe, death is imminent unless surgical treatment is done. New perspectives are now being
considered that calcific aortic stenosis has its-similarities
with atherosclerosis. 3-hvdroxv3-mcthylglutarvl
(HMG)-CoA reductase inhibitors, commonly called
statins, are now, considered not only in dvslipidcmia
and coronary artery disease but in calcific aortic stenosis
as well. In observational, retrospective studies, aortic
stenosis progressed at a slower rate in patients who
received statins than in those who did not.
Calcific aortic valve disease is a slowly progressive
disorder of calcification and thickening of aortic valve
without obstruction to flow, termed as "aortic sclerosis"
or to impairment of leaflet motion or :aortic stenosis".
The lesion shares histologic similarities with
atheromatous coronar y artery disease, whose
development and progression are linked to various
traditional risk factors for atherosclerosis However,
Mohler, et. iii. 2 recently reported a common finding
of heterotopic ossification and active bone remodeling
in diseased aortic valve. Genetic mechanism of an
increased prevalence of the B allele with the gene
encoding the vitamin I) receptor is now considered as
cited by one author. Indeed, some having few, one, or
none of the risk factors develop this lesion, hence, the
mystery is yet to unfold.
It is consistent however that up until this decade,
no proven medical therap y has yet been proven to alter
the natural histor y of calcific aortic stenosis. Such
need for valve
therapy might dela y or even obviate the
replacement in these subset of patients. It is therefore
the objective of this meta-analysis to determine the
efficacy of statin treatment among patients with calcific
aortic stenoSis.
METHODS
Trials included in this meta-analysis are randomised,
placebo-controlled studies. A total of 294 patients
with mild to moderate calcific aortic stCflOSiS (Vmax
2.0 3.9m/s ) were included. Patients with coexisting
more than mild aortic regurgitation, severe mitral valve
stcn( )S1S, left ventricular dy sfunction (e)ection fraction,
< 35 percent), planned aortic valve replacement,
intolerance to statms, statin therap y or a potential benefit
from statin therap y (according to the treating physician)
and baseline serum cholesterol of less than I 5Omg per
deciliter, and presence of a permanent pacemaker or
cardio-defibrillator were excluded. Subjects were
blinded to either statin treatment or placebo for more
than 24 months (mean follow-up of 34 months). The
primary end point is the change in aortic-jet velocit y in
meters per second per year.
Clinical trials were identified from Medline search,
PVBi\lliI), and Cochrane Collaboration databases from
1999 to 2006 using the following ke y words: aortic valve
sclerosis, randomized controlled trial, heart valve
diseases, aortic valve calcification,
hvdroxvmethvlglutarvl-Co\ reductase inhibitors, and
s ta tins.
The Review Manager version 4.28 was used to
combine data from individual trials. This method
entails analysis of data in continuous variable with
confidence interval set at 95° for each trial.
Independent quality assessment was utilized during
the review of the studies included. The titles, abstract,
introduction, and results were removed initiall y from
the copies to minimize bias among assessors. Quality
assessment scale was subdivided into: selection bias if groups being compared are balanced of known
determinant outcome: performance bias - if groups
treated equall y in terms of medication received,
frequenc y of follow-up and general quality of care;
exclusion bias - if the drop-out rates between groups
are comparable; and detection bias - if the outcomes
used are similar in both groups. Qualit y was categorized
as A, B, and (2 with adequate, inadequate, and unclear
classification respectivel y. (Table 1)
'lable 1. Quality Scale for Meta-Analysis Review
Cowell, et. al.
Canterin, et. al.
Selection Bias
Performance Bias
Exclusion Bias
Detection Bias
A
A
A
A
A
A
B
A
The studies were enumerated in tabular form
according to the number of respondents, the type of
intervention, the outcome considered and the
methodolog y applied (fable 2). Included studies were
assessed b y three independent reviewers with their
corresponding evaluation and qualrv assessment scales.
Table 2. Characteristics of trials included in the
Meta-analysis
-
P
o
M
]
Canterin, et. al.
190 patients
Simvastatin 15 + 5 mg.
Atorvastatin 13 + 7 mg
Pravastatin 21 8 mg
Fluvastatin 50 + 20 mg
Cerivastatin 0.3 + 0.1 mg
Aortic jet velocity (m/s)
RCT
/'()/V//d/thFJ. 1— !111P1')1t1O/i.
Cowell, et. al.
104 patients
Atorvastatin 80 mg
Aortic jet velocity (m/s)
ROT
C) - ')II/U/?lC. \[ -
RESULTS
:\ total of articles were queried, 2 of which were
randomized controlled trials and were subjected to data
extraction and quality scale assessment. The two trials
included are by Cowell SJ, Ncwbv DE, Prescott RJ,
Bloomfield R, Reid J, Northdridge DB, Boon N.-\:
Scottish Aortic Stenosis and 1 'ipid Lowering Trial,
Impact of Regression (SAl .TIRI1) Investigators and
Antonini-Canterin F, Popescu BA, Huang G, Korcova
Miertusova R, Rivahen D, Faggiano P. Pavan R, Bolls
A, (iavattone A, Nicolosi (L; Progression of Aortic
Valve Sclerosis to Aortic Valve Stenosis: What is the
role of Statin Trcatment
A total of 294 patients with mild to moderate calcific
aortic stenosis (Vmax 2.0 - 3.9m/s) The analy sis of
the rate of annual increase in peak aortic velocity (mI
s/year) of the two trials showed to be homogeneous (
cIii-squarc = 0. 14, df = 1, 1' = 0.70). The result showed
that the use of statins did not significantly improve the
rate of annual peak aortic velocity from the baseline as
compared with the placebo with p value of 0.75 and
mean duration of more than 24 months (Table 3)
Table 3.
Mean Aortic Jet Velocity (mis) after> 24 months of
Statin Treatment
Review
Comparison
Outcome
Statns in Calcific Aortic Stenosis
01 Aortic Jet Velocity
02>24 months of Stalin Treatment
Study
orsub-cateoorv
Cowell
Canteriri
Treatment
N
Mean (SD)
49
017(021)
95
017(026)
Control
N
Mean 1S01
55
019)021
95
0.17(0.2C
WMD (fixed)
95% Cl
Quality
CONCLUSION
Total (95% Cl)
144
150
Test for heterogeneity Ch12 0 14. df = 1 (P = 070), F = 0%
Test for overall effect Z = 0.32 (P = 075)
>
Ot
hemodynamic progression of ealcitie aorUe stenosis severity.
It is also reasonable to think that with statins, the modifiable
risk factors for these lesions may also lead to slow down the
progression of calcific aortic stenosis. Up until this time, we
believe that this is the first meta-anal ysis done in these subset
of patients.
3
02S
03
Favcr,
DISCUSSION
Calcific aortic valve disease is a slowl y progressive
disorder, from its early stage with mild thickening without
obstruction of blood flow termed as "aortic sclerosis" to
severe calcification with impaired leaflet motion or "aortic
stenosis". It is more common among patients older than 65
years old. In one study, the morphological characteristics of
aortic sclerosis was found to be different from aortic stcnosis
as the latter is mainly calcium overgrowth rather than lipid
deposition and oxidation. It is well known that calcific and
atherosclerotic processes occur at the vascular level and that
valvular degeneration shares a continuum of endothelial
d y sfunction, inflammation, platelet deposition, lipid
infiltration, dystrophic calcification, and finally ossification.
This small percentage of progression to aortic stenosis
represents a significant impact in overall morbidit y and
mortality that the need for surgery is inevitable especially when
it presents with clinical heart failure manifestation. The
presence of moderate to severe valvular calcification, together
with rapid increase in aorflc-jet velocity identifies patients with
a %:cry poor prognosis. Close surveillance in the early stages
of this lesion is of paramount. importance.
Recent evidence show that the pathophvsiology of calcific
aortic stcnosis shares both histologic and architectural
similarities with atheromatous coronary artery disease. Its
development and progression are linked to various traditional
risk factors. Although age related changes in valve do occur,
aging is not synonymous with non-rheumatic aortic valve
disease. Traditional risk factors like cholesterol in
homozygous familial hypercholesterolemia ; diabetes and
cholesterol; LDL, Lp (a) and hypertension; (Stewart, 1997)
gender, and smoking offcred insights into the controversy
of aortic valve calcification and degeneration. Correlation
studies were also done with LDL cholesterol level and
progression of aortic valve calcification which showed
significant association and that lipid lowering therapy maybe
effective in decreasing its development and progression. These
risk factors and correlation studies ma y drive the initiation
and progression of aortic stcnosis and it is reasonable therefore
to consider shear mechanical stress imposed on the valve
itself such that the statement, "AS begets AS" is tempting to
consider as hypothesis.
3-hvdroxv-3-methv1glutarvl (I IM(;)-Coz\ reductase
inhibitors, commonly called starins, have significant effects
and proven to lower risk of cardiovascular morbidity and
mortality. Their pleiotropic effect has been emphasized in
various publications. Currently available data on statins mostly
retrospective studies consistently show marked lowering of
1;
Our findings showed that among patients with mild to
moderate aortic stenosis, statiri therapy favors trend towards
benefit, however, it did not reach statistical significance in
terms of slowing the rate of change in aortic-jet velocity.
Similarly it also failed to show regression of aortic valve
lesions. Large, prospective, randomized controlled trials
should be done using statins in the different stages of calcitic
aordc stenosis to determine its definite value and effectiveness.
The authors did not attempt to test the effectiveness of
statins in patients with advanced stage of the disease as this
may portend poor prognosis if surgery is not done on time.
A significant slowing of progression was however noted
among patients with aortic sclerosis, that needs further
investigation with more randomized controlled trials.
Finally, three years of treatment with statins among these
patients may not be sufficient to influence the natural history
and its over-all benefits. I lence, with the inclusion criteria in
our study, let alone the cost of treatment, continuing to
determine the effect of statins in calcific aortic stenosis may
not be cost -effective.
REFERENCES
1.
Novaro G, and Griffin B: Calcific Aortic Stenosis:Anorher Face
of Atherosclerosis. Cleveland Clinic journal of Medicine. May
2003;V61 70, NO. 5: 471-47
2.
3.
4.
5.
6.
7.
8.
9.
Mohler ER III, Adam T.P, Mc Clelland P, Graham L, Hathaway
DR; Bone Formation and Inflammation in Cardiac Valves.
Circulation 2001;103,152-1528
Cowdll SJ, Newby DE, Prescott RJ, Bloomfield R, Reid 3.
\orthclnclge DB, Boon NA; Scottish Aortic Stenosis and I.iptd
Lowering Trial, Impact of Regression (SALTIRE) Investigators.
New England journal of Medicine. June 2005;352:23892397
Antonini-Canterin F, Popescu BA, Huang G, KorcovaNlicrrusova R, Rivahen D, Faggiano P, Pavan R, Bolts A,
Ciavaitone A, Nicolost GL. Progression of Aoriic Valve Sclerosis
to Aortic Valve Stenosis: What is the role of Stattn Treatment?
Italian Heart Journal. February 2005;Vol 6: 119-124
IsnemJM, Sours I ii. Pans AL, Ferrans \'J, Roberts WC. Sudden,
unexpected death in avid dieters using the liquid-proteinmodified-fast diet. Observations in 1 7 patients and the role of
the prolonged QT interval. Circulation. 1979;60:1401-1412.
Sprecher 1)1., Schaefer Ej, Kent K:\1, et al. Cardiovascular features
of homozygous familial hvpercholesterolemia: analysis of 16
patients. Am) Cardiol. 1984;54:20 30.
[)eutscher S. Rocketie HE. Krishnaswami V Diabetes and
hypercholesteroleinia among patients with calcific aortic sienosis.
J Chronic Dis. 1984;37:407 115.
Ra j amannan NM, Subratnaniani M. Spningett NI, et al.
.-\torvastatin inhibits hypercholestcrolemta_indueed cellular
proliferation and bone matrix production in the rabbit aortic
valve. Circulation. 2002;l05:2660-2665.
Rosenheck R. Rader F, J.oho N. Gabriel H, I leger NI, Klaar U,
Scbernper NI, Binder T, Manner C, Baunigartcr El. Statins l)uI
Not Angio ten sin -Converting Rnivnie Inhibitors Delay
Progression of .'\ortie Stenosts Circulation 2104:110:1291 1295
Ej
'lADlE 4. Clinical Prolile of the ' tu,I PiiptiI.itioii Stratified
and Negative H-FABP
APPENDIX
10)11
l'i,iti,i'
I TABLES
Characteristics
o
.\ge (y)57.34tl3.69
Study Population
35
Mali:
lemak 16(45.7'-)
c :atnn
(mean + SD)
Svniplorn duration
)h) (II (mean SD)
medianS
Svniptom duration
(6) (l'rirponin I)
(mean 4 SI))
mcdtan 6
I lvperteioion
Dvslipidcmta
l)iabctcs/ 3ileltiius
smoking
Famit history of
1111)
Previous ."tNll
I leart Failure
,'\n y lirm,a
Death
ICL.!(\'L' Stay
mean j,Sl)
I lospital Sta y
mean + SI)
19(54.3',,)
p value
HFABP
TABLE I. Clinical Profile of the Study Population/ Cohort
:\gc (y)
(mean ± Si))
Sex
Male
Female
Iroponrn I (ng/ml)
Creatinc
(mean ± SI))
Sy mptom duration
(h) (ll-I.-\ISP)
(Mean ± Si))
median
11 ypertensiun
Dyslipidemia
Diabetes Meulitu
Smoking
Family History of
II ID
Previous AMI
heart Failure
Arrhythmi.i
Dcrh
ICE/(VE Stay
(mean j:-SD)
Hospital Star
tnt It) ±51))
137±1.16
6.38+ 5.82
.SILS.IS
26,-4.3",.)
18( ;1 4',,)
-- I')
13 (i'
13(3- l 4
16(45 7" 4
10(21)0')
9 (25 7"
2(5.7)
1(2.9.)
1 54 - - 1 54
5.77-29-
+
(n= 11)
62.72± 13.78
(n=24)
54.88 ±J3.20
0.12
6
5
2.193 ±2.763
1.74± 1.24
13
II
(I.024±I.l.).118
1.22+ 1,1 1
W)1
0,26
8.77 ±8.89
529±3.41
((.10
5.5
II)
6
4
4
7
4
16
12
9
9
9
I). 13
1.1.8(1
0.60
0.64)
(1.15
4
4
0
I
1.91±1.58
6
5
2
(I
1.38- 1.52
((.35
0L28
0.49
(1.31
0.26
5.46±3.2(1
5.92±2.92
0.46
TABLE 2. H-FBP and Troponin 1 results
Total
Troponin
(+) (.)
H-FABP
7
()
II
Total
7
'Note: trilporilTi I
Control Line
Absorbent Pad
4
2-1
Capture Line
24
<Nitrocellulose
iS mg' nil wa% wed a' ciii il
TABLE 3. Diagnostic Parameters for H-FABI'
7' x '
21.21)s 1141
y cn,trivw
SpecIlivtR
PPV 7 , .' 11x 101'
Ni'' 24,'24x It 0
Ii"..
5$ -,
7-24) '35 x Ill'
,\ccurscv
880'
8acing
Conjugate can
1—I—FABP
Pressure seirsIlve adhesive
100
Sarinpie Pad
80
Ficure [.;% Schematic of the various components oh the CardioDetcel
CalrdioDelea
led
otLdmid
:
0
20
40
60
80
100
1$
ClirdioDe(.d'a1,
S
100- SpcciIciiy
Fioure 3. I(eci er operaiimz characteristics ( RI 11' ( curve 1iiialvs is of I F..\ Fil' 115111)2 ropollIn I as standard RI X' aloe was 0 020. 90 confidence
interval of 0 786 - 008 7 , p same of (I 011111
(..
nO
\ pIcture 11111 111I
MS (tell 10 right) a brand new card, a card o ill) a
1
hr-I '\lIl' and
colilioll lines indik;atin g, a plltls e Ic',)
l"ir.nure 2
SiOL'lC colilnhl hue indlealine a rreinall\'e lcl, atid a i'ai'ch 5)116 2
Natural History of Patients with 50-69% Internal Carotid
Stenosis: A PHC Experience
Kathleen G. Go MD, Jasmin Melissa B. Bernardo MD
Department of Adult Cardiology, Philippine Heart Center
OBJECTIVE
To determine the natural history of patients with 50-69 1!/o with internal carotid artery stenosis
(ICAS) according to plaque morpholog y in previously symptomatic and asymptomatic patients.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Patients with 50-69% ICAS seen at the Philippine Heart Center Vascular Laboratory from
January 1, 2004 to June 30, 2006.
MAIN OUTCOME
Clinical and demographic characteristics, proportion of symptomatic and asymptomatic patients;
incidence of ipsilateral stroke, liA, progression to ^!i70% stenosis and association of progression
of stenosis with the occurrence of neurologic events based on plaque morphology.
MEASURES
73 patients were entered into a protocol of carotid duplex scan surveillance and clinical
examination. Patients were scheduled for follow-up and repeal duplex ultrasound scan with a
minimum of 6 months since the baseline carotid duplex Imaging. Mean age was 73 * 8.86 'cars
and 69 9.04 years for the symptomatic and asymptomatic groups. Majority of the patients
were hy pertensive for both groups. Male gender, smoking history, diabetes mellitus, coronary
RESULTS The
4
artery disease and dyslipidenna failed to show any statistically significant difference between the
two groups. Ma j ority had type V plaque morphology, 70.% and 65.6% for the symptomatic
and asymptomatic group, respectively. Ipsilateral stroke occurred in 2 (4.9%) among the
symptomatic group while 2 (6.25%) among the asymptomatic group. More patients had ipsilateral
TL\, 9 (22°!'o) for the symptomatic group compared to 4 (12.5%) for the asymptomatic group
with mostly ty pe V plaques. Overall, there were more new neurologic events for patients who
were symptomatic at baseline with type V plaque morphology but it was not statistically significant.
Of the 16 patients who had a repeal carotid duplex scan, 43% percent had progression of the
stenosis of >70% over a mean period of 18 months. Progression of stenosis was not associated
with the occurrence of new neurologic events.
CONCLUSION Among the 73 patients with 50-69 0"o internal carotid artery stenosis, 56% were symptomatic
while 44°/o were as ymptomatic at baseline with meaii age of 73 4 8.86 years and 69 + 9.04 years,
respectivel y. Majority were hypertensive (78.1 to 82.9%). The plaque morphology failed to show
an y statistically significant difference in relation to the incidence of new ipsilateral stroke, l'l,\.
total neurologic events as well as progression of stenosis. Progression of the stenosis was not
associated with the occurrence of new neurologic events.
INTRODUCTION
BACKGROUND
S troke is the second most common cause of death
worldwide, exceeded onl y b y heart disease. With the
increasing aging population, the prevalence of stroke has
been gradually rising. Stroke is a major medical problem
because of the high rate of morbidity and mortality. 2 The
prevention of stroke is an obligation facing everyone involved
with delivering health care.
In 1995, the Asvmptomauc Carotid Atherosclerosis Study
'ACAS) concluded that the combination of carotid
endartcrectnmv (CE:) and best medical therap y significantly
reduced the risk of stroke. Compared with medical therapy
alone, in patients With > 6( asytriptomatic carotid stem sis
(.\CS). I)ata from both observational studies and the ACAS
and other randomized controlled trials suggest that the risk
of stroke without preceding transient tscheinic attack (TI:\)
ipsilaicral to the asymptomatic h ell) odvnamicallv significant
extracranial carotid arter y stenosis is about 2 percent
annuall y. In a meta-analysis of CE:\ for asymptomatic
patients with more than 50o carotid stenosis, it demonstrated
a ver y modest 1-2 °o absolute reduction in stroke or death
over three years.` Some clinicians are therefore reluctant to
recommend Cl ;\ for p a t ie nts with > 60' o ACS.Sevei'al
investigators have separatel y studied the correlation ot car( itid
plaque morphology and cerebrovascular symptoms.
has been suggested that ultrasonic carotid plaque morphology
may be as critical as severity of stenosis in determination of
ischernic neurologic events, and therefore, important in
selection of patients for CEA. Several studies have shown
that hypoechoic plaques and echolucent lesions are associated
with a higher incidence of hemispheric cerebrovascular
sy mptoms and cerebral infarcts than hvpercchoic lesions."'11
SIGNIFICANCE
Ihis study aims to determine the natural history of patients
with 50-69% carotid artery stenosis according ultrasonic
plaque morphology and its implication on treatment. It
should be noted that atherosclerosis of the internal carotid
artery is an important cause of stroke. Large multicenter
trials have demonstrated that risk of stroke is reduced by
endartcrcctoxny. 1 A recent trial showed that the risk of
stroke among patients with asymptomatic carotid artery
stenosis is relatively low and that not all strokes originate
from the stenosed arteries. Others may be due to cardiac or
lacunar causes. These observations have implications for the
use of endartcrectom in asymptomatic patients. \Vithout
analysis of the risk of stroke according to cause, the absolute
benefit associated with endarterectomy ma y be
overestimated. 0 Results of this stud y, therefore, will provide
a local hospital-based data that will serve as basis for future
surveillance and researches geared towards the management
of 5069 0 carotid arter y stenosis.
3. To determine the incidence ()t ipsilateral strokes based
on plaque morphology in patients with 50-69% internal
carotid artery stenosis
4. To determine incidence of ipsilateral TIi\ based on
plaque morphology in patients with 50-69% internal
carotid artery stenosis
To
determine the incidence of progression to > 70%
5.
stenosis or occlusion based on plaque morphology.
6. To determine association of progression of stenosis with
the occurrence of ipsilateral stroke or TIA.
METHODOLOGY
STUDY DESIGN
&
SETTING
This stud y employed a cohort study design. It was
conducted at Philippine Heart Center, a tertiary hospital in
Quezon City, Philippines.
STUDY POPULATION
This study population included 73 patients seen at the
Philippine I leart Center Vascu Laborator y aboratory from January
1. 2004 to June 30, 2006 with 50-69% internal carotid stenosis
based on color duplex ultrasonography
ICA peak systolic velocity of 125-230 cm/s
a.
ICA end diastolic velocity of 40-100 cm/s
1).
ICA/CCA PSV ratio of 2-4
C.
EXCLUSION CRITERIA
RESEARCH QUESTION
What is the natural history of patients with 50-69% carotid
artery stenosis according to ultrasonic plaque morphology?
OBJECTIVES
GENERAL OBJECTIVES
carotid
determine the natural history of 50-69 1.'o
artery stenosis according to ultrasonic plaque morphology.
TO
1. Patients with 50-69% carotid artery stcnosis on carotid
duplex imaging but with less than 50% or 70% or more
stenosis by carotid angiography.
2. Patients who previously underwent carotid stenting ofcarotid endarterectomv at an y time.
3. Patients with hemorrhagic stroke and severe neurological
disability during the time of the initial carotid duplex scan.
4. Patients with atrial fibrillation.
SPECIFIC OBJECTIVES
PLAQUE CLASSIFICATION
determine the clinical and demographic characteristics
of patients with 50-69° internal carotid artery stenosis
in terms of the following data:
a. Age
b. Sex
c. Predisposing factors
I. Smoking
ii. Hvpercholesterolemia
iii. l-lvpertension
iv Coronary artery disease
V. Diabetes mellitus
2. To determine the proportion of patients with 50-69%
internal carotid artery stenosis who are symptomatic and
asYniptorna tic.
The appearance of the plaque was classified as 'dpc I if the
plaque is uniformly ccholueent with Fibrous cap (homogenous
hypoechoic), Type II if the plaque is substantiall y echolucent
with small areas (<50%) of echogenecity (hcterogenous
hvpoechoic), Type III if it is predominantl y echogenic with
small areas (<50/o) of echolucency (heterogenous
hyperechoic), T y pe IV if it is uniforml y echogenic
(homogenous hvpercchoic) and Type V if it is calcified.
1. TO
4.
FOLLOW-UP AND OUTCOME MEASURES
1. All eligible Patients were entered into a protocol of carotid
duplex scan surveillance and clinical examination. All patients
were scheduled for follow-up visits and duplex ultrasound
scan with a minimum of 6 months since the baseline carotid
duplex imaging.
2. ! > , IiicIiL \verC iiisiruc j L o .i1i IL rcearciier it they
experience the following s ymptoms: dizziness, facial
as y mmetry, numbness or weakness on one side of the body,
slurring of speech, or transient blindness (amaurosis fugax).
3. The primary end point was the occurrence of hemispheric
TIA or stroke symptoms referable to the territory
appropriate to the affected carotid artery. Progression of
steflostS in rclauon to pla(luc morpholog y was also noted.
The progression of lesion in relation to the appearance of
neurologic symptoms was likewise noted.
4. Ischcmic strokes were defined as focal neurologic
symptoms lasting > 24 hours. Transient ischeinic attack
(iL\) was defined as ipsilateral focal neurological
s y mptoms lasting <24 hours.:
Ipsilateral stroke occurred In 2 T.)j aiiiortg the
symptomatic group, both having t ype V plaques while 2
(6.25) among the asymptomatic group, one with type III
and the other one with type V plaques (lablc 11).
Table II. Incidence of ipsilateral stroke based on plaque morphology in
patients with 50-69°I internal carotid artery stenosis
Plaque Morphology
Type
Type 11
Type lii
Type IV
Type V
P Value
Symptomatic
(n41)
0
0
0
0
2(4.9%)
0.698
Asymptomatic
jn32)
0
0
1(3.1%)
0
1(3.1%)
0.901
P Value
NA
NA
0.438
NA
1
STATISTICAL ANALYSIS
fl
The (Lila were atialvzed, and the results were presented as
lre(]uencv and percent distribution. Age was summarized as
mean and standard deviation. Association of the different
lactors (in nominal scale) with plaque progression and T1.\
or stroke events were carried out using a chi-square test,
Fisher Uxact Test and \lann \\hitnev U lest. A P value of <
0.050 was considered statisticall y significant. The odds ratio
(OR) and irs 95 confidence interval for each factor are
presented. TO adjust for the effect of plaque morpholog y in
its association with ilA/Stroke events, stratified X2 test was
applied to the data. .\ P value of < 11.051 was considered
s t:iusueallv sitii ficant.
RESULTS
eveni y ihree patients were included in tile siudv, 41 were
symptomatic while 32 were as ymptomatic at the time of tile
initial carotid duplex scan with a mean follow-up of 18
months. lhc clinical demographic data arc summarized in
[able I.
ihere were more patients Who had ipsilatcral transient
ischemic attacks, 9 (22°) for the s y mptomatic group
compared to 4 (I 2.5°. ) for the asymptomatic group with
mostly type V plaques (Fable III).
Table Ill. Incidence of ipsilateral TIA among symptomatic and
asymptomatic patients according to plaque morphology
Plaque Morphology
Type
Type II
Type III
Type IV
Type V
P_Value
-
Symptomatic
(n=41)
0
2(4.9%)
2(4.9%)
0
5(12.2%)
.0.513
Asymptomatic P Value
(n = 32)
0
NA
1(3.1%)
1
0
0.501
0
0
3(9.4%)
1
0.725
Overall, there were more new neurologic events for patients
who were s ymptomatic at baseline with type \ plaque
morphology but it was not statisticall y significant as shown
in Table IV
Table I. Characteristics of Patients with 50-69% Carotid Stenosis
Symptomatic
(n41)
Mean Age, years
73 -8.86
Male Gender
19(46.3%)
Smoking History
10(24.4%)
Hypertension
34 (82.9%)
Diabetes Mellitus
17(41.5%)
Coronary Artery Dse 19(46.3%)
Dyslipidemia
19(43.9%)
Plaque Morphology
Type I
0
Type II
3 (7.3%)
Type III
9 (22.0%)
Type IV
0
Type V
29(70.7%)
Asymptomatic
(n32)
69-9.04
18(56.3%)
9(28.1%)
25(78.1%)
16(50%)
17(53.1%)
16(50%)
0.054
0.546
0.927
0.828
0.624
0.734
0.778
1 (3.1%)
1 (3.1%)
9 (28,1%)
0
21(65.6%)
0.438
0.626
0.739
NA
0.832
P Value
Table IV. Incidence of all ipsilateral neurologic events among symptomatic
and asymptomatic patients according to plaque morphology
Plaque Morphology
Type
Type II
Type III
Type IV
Type
P Value
Symptomatic
n41
0
2(4.7%)
2(4.9%)
0
7(17.1%)
0.701
Asymptomatic
n=32
0
1(3.2%)
1(3.2%)
0
4(12.5%)
0.852
P Value
NA
1
1
NA
1
Among the 73 patients included in the study, only 16
patients had repeat carotid duplex scan done (Table V). Eight
were symptomatic while 8 were asymptomatic at baseline.
Forty-three percent (7 out of 16) showed progression of
the stenosis of equal to or more than 70% over a mean
period of 18 months.
Table V. Incidence of progression of stenosis to? 70% among symptomatic
and asymptomatic patients according to plaque morphology
Symptomatic Asymptomatic P Value
n8
n8
NA
0
0
NA
0
0
1(12.5%)
1
1(12.5%)
NA
0
0
4(50%)
0.282
1(12.5%)
5(62.5%)
2(25%)
Plaque Morphology
Type
Type 11
Type Ill
Type IV
Type V
Total
In Tables VI and VII, results failed to show an y association
between progression of the stenosis and the occurrence of
new neurologic events (p value = 1.000). This may be due to
the limited number of subjects who had a repeat carotid
scan done.
Table VI. Association of progression of stenosis to > 70% to the
occurrence of new neurologic events (Symptomatic Group)
New Neurologic
Events
No New Neurologic
Events
3
3
Progression
No Progression
P Value 1.000
Table VII. Association of progression of stenosis to > 70% to the
occurrence of new neurologic events (Asymptomatic Group)
New Neurologic
Events
No New Neurologic
Events
Progression
1
4
No Progression
* P Value = 1.000
0
3
DISCUSSION
Internal carotid artery stenosis (ICAS) is responsible
for approximately 30% of ischemic stroke". Currently,
stroke-risk assessment in patients with internal carotid
artery disease is based on the degree of stcnosis. Natural
history studies and clinical trials reveal a small increase
in stroke risk in patients with increasing degrees of
stenosis, especially in those with greater than 80%
diameter reduction. Paradoxically, this correlation
between stroke risk and degree of stenosis has not been
demonstrated in the asymptomatic CEA trials. In this
study, the plaque morphology correlated with patients'
outcome and progression of stenosis.
Several studies have identified risk factors ICAS
including age, hypertension, smoking and peripheral
vascular disease. Risk factors identified for the
development of stroke in patients with ICAS include
age, male, sex, hypertension, smoking, diabetes, degree
of ICAS, presence of ulceration, ischemic heart disease,
peripheral vascular disease, and obesity. t In this study,
the mean age range was 73 + 8.86 years old in
symptomatic patients and 69 ± 9.04 years old in
asymptomatic patients. The difference between the two
was not significant with p value of 0.054. Majority of
the patients were hypertensive, 82.9% for symptomatic
and 78.1% for asypmtomatic patients. The other risk
factors identified in this study (male gender, smoking
history, diabetes mellitus, coronary artery disease,
dyslipidemia) were not statistically significant between
the symptomatic and as y mptomatic groups. Majority
of the patients had type V plaque morphology which
has a more stable character compared to types I to IV
but majority of those with ipsilateral stroke and TIAs
during follow-up had this type of plaque. This is
probably because majority of the patients in this study
had type V plaques to start with. However, the plaque
morphology did not relate statistically with the incidence
of ipsilateral strokes, TIAs, total neurologic events and
progression of stcnosis. Compared with the results of
the study done by Gronholdt M, et al.V their study
showed 3.1 fold risk of ipsilateral ischemic stroke in
patients with echolucent carotid plaques compared with
echorich plaques in previously symptomatic but not in
previously asymptomatic patients with 17% absolute
risk increase, and among previously symptomatic
patients, echolusccnt 80-90% stcnotic plaques predict
an 8-fold risk compared with echorich 50-79% stenodc
Plaque with absolute risk increase of 28%. In the study
by Al)uRahma A, et al, patients with 60 to 69% I(;AS
with heterogenous plaque had a higher incidence of
late stroke, TIA, and progression top >70% stenosis
than patients with homogenous plaque. 7 This finding is
further supported by the study of Sabetai N-I, et al
showing plaques associated with hemispheric symptoms
are more hypoechoic and more stenotic than those with
no associated symptoms. Their study also stated that
plaques causing Tlr\ and stroke have the same
cchogenecitv and the same degree of stenosis 5 . Results
also failed to show any correlation between progression
of stenosis and the occurrence of the new neurologic
events. African Americans and Asians have been found
to have more intracranial atherosclerosis than whites.
The explanation is not known) Due to the limited
number of patients in this study who had a repeat
carotid scan during follow_up, relative risk was not
computed. Results will not be trul reflective due to
lack of power.
Potential limitations in this stud y aside from the lack
of number patient who had repeat carotid scan include
the fact that other origins of the stroke or , Ili\ other
than carotid plaques like those lesions coming from the
aorta or intracranial vessels were not excluded. Strokes
due to cardioembolic origin and hemorrhagic strokes
were excluded. Analysis of the natural history of patients
with 50-69°/ ICAS would have been more reliable if
all patients included in the study had a repeat carotid
duplex scan.
CONCLUSION
In this study, among the 73 patients with 50-69%
internal carotid artery stenosis, 56% were symptomatic
while 44°/o were asymptomatic at baseline. Mean age
of these patients was 73 + 8.86 years for the
s y mptomatic group and 69 ± 9.04 years for the
asymptomatic group. Majority of the patients were
hypertensive (78.1 to 82.9%). The plaque morphology
failed to show any statisticall y significant difference in
relation to the incidence of new ipsilateral stroke,
transient ischemic attacks, total neurologic events as
well as progression of stenosis. The study results also
failed to show an association between the progression
of the stenosis to the occurrence of new neurologic
events.
REFERENCES
Murray (.11 , I opcz AD. Mortality by cause for eight regions of the
world: global burden of disease study Lancet 1997;349:1269-76.
2.
Messina, L, Zelenock, G. Cerebrovascular Occlusive Disease,
ed, Suregrv scientific principles and practice, Greenficld, I. (Ed).
Lippincott-Raven, Philadelphia, 1997.p 1745
3
Barnett, 11. 1 M; Eliasziw,M. Evidence based cardiology : Prevention
of ischacmic stroke. BMJ 1999;318:1539-43.
1.
Executive Committee for the .\svinptomaric Carotid Atherosclerosis
Stud y. Endartrcctomv for asvmptomauc carotid artery stein)sis.JAM\
1995:273:1421-8.
5.
Sacco, RL, Ben j amin, FJ, Ct al. American Heart Association
Prevention (;onfcreiice IV: Risk Factors. Stroke 1997; 28:1507.
6.
Beriavente, 0, Moher, 0, Ct al. Carotid endartercctom y for
asymptomatic carotid stenosis: a meta-anal y sis. BI 'M 1998; 317:147.
7.
:\bu Ralima, AF ' et al. The correlation of ultrasonic plaque
morphology and carotid plaque hemorrhage: clinical implications.
Surgery 1998: 124:721-8.
8.
Scbatai M NI, et al. Hemispheric s y mptoms and carotid plaque
cchornotphologv. J Vase Stirg 2000: 31:3949.
9.
Montauban von Swijndregt Al), ci al. Cerebral ischcmic disease and
morphometnc analysis of carotid plaques. Ann \'asc Sur g 1999:
13:468-74.
10. Sterpetti .\V, et at 1_Itrasonographic features of carotid plaque and
the risk of subsequent neurologic deficits. Surger y 1988; 8:558-62.
II - Langsfekl M. et al. The role of plaque morphology and diameter
reduction in the development of new symptoms in asvmpruniaiie
carotid arteries. j Vase Surg 1989:9:518-57.
12. Barnett I IJNI, et al. Benefit of carotid cndarterectomv in p25aticnts
with s y mptomatic moderate or severe stenosis. N ElM
1998:339:1415-25.
13. North American Symptomatic Carotid Endartereetom y Trial
Collaborators. Beneficial effects of carotid emidareteretomy in
symptomatic patients with high-gradt carotid SteiIusis. NEIM
1991 ;325:445-53.
14. Insitarm 0, et al The causes and risk of rrokc in railciits with
asymptomatic internal carotid artery StefloSiS. NFIM
2000:342:1693-700,
15. (rant EG, Ct al. Society of Radiologist, in Ultrasound Consensus
Conference on Ultrasound and Doppler Diagnosis of Carotid
Stenosis. Radiology 2003:229:310-346.
16. Gronholdt. NI, et al. Ultrasonic ccholuscent carotid plaques predict
future strokes. Circulation 2001: 104; 68-73.
17, limsit SO, Sacco RI., Ct al. Early clinical differentiationof cerebral
infarction from severe atherosclerotic stenosis and cardjoembolisn).
Stroke. 1992; 23:486-491.
18. Dodick 0, Meissner I, er al. Evaluation of asympromatic carotid
artery stenosis. May o Clinic Proceedings. luly 2004, 79(7):937.9.14.
19. Sacco RL, er al. Race-ethnicity and determinants of intracranial
atherosclerotic cerebral infarction: [he Nc irtliern Manhattan Stroke
Study, Stroke. 1995;26:14-20.
Natural history of patients with 50-69% internal carotid artery stenosis
A Philippine Heart Center Experience
Patient's Data Form
Name:
Study Number:
Address:
Risk Factors:
Male Sex
Hypertension
Smoking History
P1 Diabetes Mellitus
11 Coronary Artery Disease
I Dyslipidcrnia
11 Obesity
= Atrial Fibrillation
Sex:
Age:
Study Date:
Hospital No.:
Contact No:
Medications:
Previous Focal Neurologic Symptoms
Dizziness
When:
I Transient Blindness
When:
1 TIA [Transient (less than 24 hours) weakness, numbness, slurring of speech]
Side of the Body: I Right = Left
When:
1 Stroke
Side of the Body: I Right
Li Left
When:
Baseline Carotid Duplex Scan Imaging
Plaque Morphology: I Right ICA [ Left ICA
Type I
Uniformly echolucent with fibrous cap (homogenous hypoechoic)
Type II
Substantially echolucent with small areas (<50%) of echogcnccitv
(Heterogcnous Hypoechoic)
Ii Type III
Dominantly echogenic with small areas (<50%) of echoluccncv
(1-1 crerogenous Hyperechoic)
1 Type IV Uniformly Echogcnic (Homogenous Hyperechoic)
1 Type V
Calcified
Parameters:
ICAPSV
ICAEDV ISA/CCA PSV Ratio
Right
11 Left
Status of Contralateral ICA
H Normal
L < 50% ICAS
1 50-69% ICAS
70-99%
H Total Occlusion
Follow-up:
No of months since initial Carotid duplex scan imaging
New Focal Neurologic Symptoms
I None
Dizziness
When:
H Transient Blindness
When:
I TIA [lransicnt (less than 24 hours) weakness, numbness, slurring of speech]
Side of the Body: [ 1 Right
H Left
When:
Stroke
Side of the Body: - Right
I Left
When:
Other events
Follow-up Carotid Duplex Scan Imaging
Progression of Stenosis
I With Progression
H 70-99%
H Total Occlusion
I No Progression
Plaque Morphology: I I Right ICA H Left ICA
Uniformly echolucent with fibrous cap (homogenous hvpocchoic)
Type I
Substantially echolucent with small areas (<50%) of cchogenecity
Type II
(Hctcrogenous H),poechoic)
Dominantly
echogenic with small areas (<50%) of echolucency
H Type III
(Heterogenous Hyperechoic)
I Type IV Uniformly Echogcnic (Homogenous Hvperechoic)
I Type V Calcified
Parameters:
ICA EDV ISA/CCA PSV Ratio
ICA PSV
H Right
Left
Plaque Morphology of Contralateral ICAS
Status of Contralateral ICA
I Type I
Normal
Type II
II < 50% ICAS
H' Type Ill
H 50-69% ICAS
1 70-99%
LI Type IV
Tvne \
Total Occlusion
PAGPAPAHINTULOT SA PAGSALI PAG-AARAL
PAMAGA!' NG PAG-AARAL: Ti 1k N\I1101. I IIS'lORY () I P\lIlNTS Will I 5069% INTERN.\l. (AR()ill) \RFIIRY Si l'N( )SlS: \
P1 Ill,lP1'l''l1 I iIRi (I'iI'I'R I:xI1l:RIN1'.cl
IS4ANANALIKSIK Kathleen G. Go, Ml)
LAYUNIN AT PAtJNANG KAALAMAN:
Ka yo ay ina;inyavali aug lu rnah i k sa I5iiig pai.-aaraI ng nagialavong rnalaniari ang U ti rig ''ultrasonic Piiuc riiorphi iii )gv' 5:1 nigu taulig may 50 to 69%
na paninikip o barado sa ugat fig keg. Ito a\' inakrkrra sa rsang eksaminasvon na 'carotid duplex scan".
\iig pag-aaral na ito av rsasaL'awa upang malanian aug natural na kasavsas an fig niga taung may 50-69% na paninikip o barado sa ugar ng keg. Ito
ay upang malanian kung kayo ay mw posibilidad na magkaroon ii uuIrt aug pagkahina o patnamanlud ng kalahating partc fig katawan sanhi rig atake
sa utak.
MGA GAGAWIN:
N apili kayo s:i p,ig-aarai nra ito dahii sa pagkapadala sit invo sa ospital kung sian nagawan kayo rig ''carotid duplex scan''. Sa simula kakapairavaniini
ka yo rig nananal I ksik upang ma kakuha rig impormasvon parungkoi sa I riv mg edad, kasarian, pail ni igarrivo, pagka ka n .ori rig rhang aki t at niga
slur u mas rig aLa ke sa u tak. Ku kunan p0 ka'ii rig isang fin rig pags usli ri sa ugar rig lecg aug ''carotid duplex scan''. .\ fig ncsulta iii Or ay ikukum pa ri sa
dati morig eksarirrriasvori. Kapapariavannn nut ka yo ng riairanaliksik upanig makakuha rig iriiponrnasVofl kung ka y iv nagkakani ii in rig ki rnplikisvori
kagava rig bagi Jug pamanianh id o inaniginli nra fig kaIaliatirii parte rig katawa n.
KA'IUNGKULAN NG ISANG KASALI SA PAG-AARAI.
:r paghasa rimvo sa kasul.u:ua Ito hiking pagsang-avori sit pagsali sa pag--aarai na ito, kayo av nagpaJalr.t. .e
sa ilivioat riiagliihigav rig un roil ,i svi m pat urucki ii Si iriv )ng sakrr magirig nasa bob in lahas ng nsprta I
KABAVARAN NG PAGSAI1:
-\ng pagsali nrrrv ),;.I p1g-11l n.i ii
ira rig nit ri,iiianalilssik.
iii .1
iv kusarig-loob at walarig kapalit fig hav;id. \ng gag:rwiiig cksainunavi iii av lihre
:11
eks.ilnnr.Hv Ii II
maiiggagaliiig S,1 riakala.ing
PAGKUKUBLI N(; KAALAMAN SA PASYEN'I'E
Afig uris Jfl J.
it rug iiiipc nrniasvi>n flitmaararrrg inapagpipaktianlari ra ilivi it mananatilrng liltirn. I Iuuiili Iti I mahabarigit .ianiiuiiang
ilalahalaiig hihagi rig p:ii aa r,il. Ngirnit biking p:igsusuril d sa batas, maaning surirru rig I .thics at leelinreal Revicw Boards rig Philippine 1 leant I enrci,
at nica aliensv:iiig tnt usti is s.i pagaaral na Ito .rng riig.i diikumcntong gating sa pag iaral. D:iliil dito. hindi nanuir niasisigurado iia nananatilnig lihim
an f univi mg nig.i iln p irma svi in, subalit rnal ilini it a pa rio aug rnaariiig riiaibu nvag si rnga ahciisvai ig it') lvi in s:i b a ri PAGBIBIGAY NG PAIIIN'ruLoT SA PAGSALI SA PAG-AARAI.
-------------------------------------, -- raioig gul.riig,
lug is:t i;iuiiiiiu;iliaii
iv snrnang-,iviin ri,i ni.igitig kal,ilii k./pasveirc
pag-aaral 11a p:i:ii,ig.iiaig TI-FE Nil Tt.'RAL HISTOR}'OFPATIENi'S WITH 50-69% INTERNAL L11R077DARTER 'STENOSIS:
A PHILIPPINE HE4RT CENTER EXPERIENCE' ia isasagawa ni Dr. Kathkeri ( . ( uv Si paglagda k kit sii ]it tang iOi, iia unitawag ira
pahuntrilur si j rags.ili rig pag -aarah pniitniy:ni ki i ia ipirialiwanag rig litis i saakin ig tag:i- salrksik o rig kanilang kasainli,ui sa pag-aaral ang larnim rig
ka sulatanig Ito. I 'lriaturiav:in ko ii n na rrabas:r at n miii tidilian ko rig husti i aug laIi:rn rig ttiipi ,rniasvon na riak:isaad si iirr:in ig ha hagi ng kasulatari na Ito
parunigkol ia pag- aaral.
P:isverite
lestigo
lestigo
Kumuha rig Pair inittilot:
I .agda sit ubabaw rig pangalan
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The Use of Aerosolized Prostacyclin Analogue (Iloprost) in
the Prevention of Post-operative Pulmonary Hypertensive
Crisis Among Children With Left-to-Right Shunts and
Moderate to Severe Pulmonary Artery Hypertension
Ruzenette Felicitas R. Hernandez, MD, Jhuliet J . Balderas, MD
Blandina Trinidad F. Ferrera, MD, Maria Eloisa R. Lazaro, MD
Magdalena J . Lagamayo, MD, Ma. Lourdes SR. Casas, MD
Division of Pediatric cardiology, Philippine Heart center
OBJECTIVES None I I as investigated on aerosolized pulni ilar' vasodilators using prost.LCvill) analogues. This study was therefore conceptualized to determine the effect Of inhalatiunal or aeroolized prustacvelin analogue (Ilopo 151) in the prevention of pustoperative pulmonary hypertensive crisis when given at least 48 hours in the postoperative period. 1'hie specific objectives arc:
(1) to determine the effect of aerosrlized llopror on the ox ygen saturation, systolic and (liastohc HP, tricuspid and pulmonary
regutgitati ins. pulmonary artery pressure. Qp/Qs and pulmonary vascular resistance (RpRs). and (2) to determine the effect
on the following clinical parameters: occurrence of pulmonar y hypertensive crisis, length of hospital stay, duration of
mechanical ventilation, and in-house mortality.
BACKGROUND The natural history of an uncorrected congenital heart disease especially alter two years of age is the development of
pulmonary hypertension. Among left —to-right shunts, when the pre_tiperauve pulmonary arter y pressure rises about twothirds the s y stolic blood pressure, the risk for postoperative pulmonary hypertensive crisis increases and determines the
surgical risk, morbiditv, and niortalitv. Pulmonar y hy pertensive crisis is an episode of acute postoperative deterioration with
acute reduction in oxygen deliver y. Ilic increased pulmonary vascular resistance (RpRs), and increased right ventricular
afterload decreases the cardiac output. This leads to ox y gen desaturation, metabolic acidosis, and a further reduction in
cardiac output leading to bradvcardia, and death. Attempts therefore at pharmacologic vasodilatation of the pulmonary bed
alter surgery is the goal of management. Several drugs have been recommended, including oxygen inhalation, nitric oxide, and
niilnnone.
METHOD This is a randomized double-blind placebo controlled study. '['he study population included pediatric its (0-19 years of
age) with congenital heart disease ((:1 ID) - left-right shunts with moderate to severe pulmonary arterial hypertension
admitted at the Philippine I leart Center from March 2005 to januar y 2006. PA pressure was determined by Doppler
ecliocardiography using pulmonar y acceleration time (P;V1). Patients with PA pressure of at least 60 inmllg anel above were
included in the studv. The need for preoperative hemodvnamic study to determine operability was decided upon by the
attending physician.
Patients were divided into two groups: Group I received ever y 6 hours ac rosolized Ihoprost for 48 hours, and group II was
the control group, given nebulized saline solution. Randomization was done b- using a table of random numbers.
Evaluation of parameters was (lone at 0-hour. 24- hour, and 48-hour postoperativel y. Ihere were 19 patients enrolled in
the study : ten in Group I and nine in Group 11. Aerosolized Iloprost was given at a close of 25 fig. kg mm and was given
at 6-hour interval for 48 hours.
nineteen patients enrolled in the studs'. 58% were males with a 1.4:1 male to female ratio. Mean age was 7.25 + 5.93
RESULTS Of the
months in the Iloprost group and 3,63 ± 5.19 months in the placebo group. Both were comparable in their preoperative
baseline characteristics, with a mean PAP of 68.55 + 10.70 and 60.37 + 12.66 respectively (p >0.05). Ventricular Septal
Defect (VSD) was the most common lesion (59%).
lvcry 6 hours nebuhisatiomi for 48 hours post-operatively did not change 02 saturation nor there was a drop in systolic and
diastolic blood pressures. 1'here was no difference in the tricuspid regurgitation let in both groups, but a significant dropped
in pulmonary regurgitation jet was noted in the Iloprost group 48 hours post-operatively (p 0.040). Pulmonar y artery
pressure analysis showed a more significant drop at the end of 48 hour (p 0.002). Both groups showed a decrease in
pulmonary vascular resistance with a higher drop in the placebo group at 24 hours (p 0.028) and a more significant decrease
at 48 hours in the Iloprost group (p 0.012). Ihere was a decreasing trend in the Qp/Qs ratio from pre-operative levels to
48 hours post-operatively but these were not statisticall y significant. Increasing the sample size is recommended. No
mortality, in both groups with no side effects noted.
CONCLUSION .\erosohized Iloprost given every 6 hours can be an important pharmacologic agent to modify the pulmonary vascular bed in
the immediate postoperatie period to prevent pulmonary hypertensive crisis among children with CIII) who undergo
surgical correction. Ii is suggested that pre-operative acrosohized I lop rost nebulization as preoperative pulmonary vasodilarator
may he started 48 hours preoperatively to significantly drop the P,-\P and pulmonary vascular resistance in the immediate
post-operative period. Once proven, a protocol in the approach of children with ('III) with moderate to severe pulmonary
hypertension should be recommended. This can also increase the number of children who can still he operable despite
moderate to severe PA hypertension.
BACKGROUND OF THE STUDY
Ihe natural history of an uncorrected congenital
heart disease especiall y after two years of age is the
development of pulmonary hypertension. It is an
important determinant in the clinical presentation and
surgical approach of patients with congenital heart
disease and contributes significantl y to morbidity and
mortality in cardiac surgery.
There is no single therapeutic approach that is
uniformly successful for secondar y pulmonary
h y pertension. Fherapv has improved dramatically over
the past several decades, resulting in sustained clinical
and hcmodvnaniic improvement, as well as increased
survival in children. Once pulmonar y hypertension has
been diagnosed, therapeutic efforts should be
simultaneously directed toward the specific treatment
of the inciting causes suspected as well as toward
reduction of pulmonary vascular resistance and
improve right ventricular function b y optimizing
preload and contractility
Conventional medical management of ptilrnotiry
arterial h y pertension can be divided into three
categories: general Supportive care, hyperventilation
and pharmacologic vasodilators. One of the most
successful approaches to reduce pulmonar y artery
pressures is the manipulation of cardio-rcspiratory
interactions to lower pulmonar y vascular resistance.
Therapy directed at reducing pulmonary hypertension
consists of increasing pi 1, decreasing partial pressure
of carbon dioxide in arterial 1)100(1 (Pa('02), increasing
Pa()2 and minimizing intra-thoracic pressures. General
supportive care consists of ox ygen administration to
maintain normocapnia, correction of acid base
abnormalities, and maintenance of normal temperature
and blood pressure. Avoidance or suppression of
stressful stimuli through administration of sedatives,
anesthetics and neuromuscular paral ysis is important.
I lvpervcntilation to produce respiratory alkalosis is the
classic treatment to cause relativel y selective relaxation
of the constricted puhnonarv circulation.
Use of vasodilator drugs or blockers of endogenous
vasoconstrictor release have resulted in the
understanding that no single drug is likely to be found
to treat all the problems in every pulmonary
h y pertensive patient. \"asodilators include alpha
adrenergic antagonists, nitro-vasodilators, beta
adrenergic agonists, prostaglandins and calcium
channel blockers2 . Vasodilators can be administered
either intravenousl y or inhalational. Intravenous
vasodilators can reduce pulmonary vascular resistance
but also have an effect on the s y stemic circulation.
Arterial hypotension is usuall y expected, which results
in the reduction of right coronar y 1)100(1 flow and may
lead to further deterioration of right ventricular
performance'.
Inhaled nitric oxide (NO) is a more selective
pulmonary vasodilator with virtuall y no systemic side
effects. Recentl y, the inhalational use of the longacting prostacvciin analog, Iloprost, has been reported
to offer superior selective pulmonary vasodilatorv
properties relative to nitric oxide inhalation, in primary
pulmonary hvpertension. 'Ihere are series of foreign
studies on the treatment of pulmonary hypertension
using prostacvlin analog, Iloprost, but there is no study
on its usefulness post-operati'ely, on children with
secondary pulmonary h y pertension undergoing
corrective open heart surgery.
lhe ultimate goal in the treatment of patients with
congenital heart disease is corrective surgery. Patients
with moderate to severe pulmonary arter y hypertension
are in a high risk of post-operative mortalit y and
morbidity due to h ypertensive crisis. It is therefore the
aim of this stud y to determine whether inhaled hioprost
can be used for pulmonary h y pertension Postoperatively to prevent hypertensive crisis and mortality.
Should it be proven, this drug may he added to the
usual medications given to patients operated with
pulmonary arter y hypertension secondar y to congenital
heart disease.
REVIEW OF RELATED LITERATURE
Ii a study (lone b y I anger et. al. on ten (10) patients
with pulmonary hypertension secondar y to mitral valve
disease and associated with pulmonary hypertension
Who underwent mitral valve repair or mitral valve
replacement and were given intra-operative inhalation
of long-acting prostacyclin analogue, Iloprost, there
was a significant decrease in mean pulmonar y arterial
pressure from 31.6 ±/-6.6 to 26.1+/'-3.1 mm Hg.
(P=0.01)".
Inhaled Tioprost caused a selective decrease in
pulmonary artery pressure in all patients and an overall
decrease in Rp/Rs from 0.62+/- 0.47 to 0.20+/-0.14
(p<O.OI ). Systemic artery pressure onl y slightly
decreased with aerosolized Iloprost application (p<0.05) according to Hallioglu et. al. in their study .
analogue Iloprost for secondary pulmonary
hypertension among children with left to right shunts.
In the study done b y Rimcnsbcrgcr et. al. on inhaled
nitric oxide (NO) versus aerosolized Iloprost in
secondary pulmonary hypertension, it showed that with
inhaled NO, the pulmonary vascular resistance and
systemic vascular resistance ratio decreased from
0.48+/- 0.38 to 0.27+/- 0.16 (p<0.001). With Iloprost,
it decreased from 0.49 +/- 0.38 to 0.26+/- 0.11
(p <0.05) 6
STUDY SETTING
OBJECTIVES OF THE STUDY
General Objective:
To determine the effect of aerosolizcd Prostacvcin
analogue (Iloprost) in the prevention of pulmonary
hypertensive crisis when given at least 48 hours in the
immediate p )st-operative period.
Specific Objectives:
1 . To compare the effect of inhaled Iloprost postoperatively on the following parameters:
1.1 Oxygen saturation
1.2. Systemic blood pressure
1.3. Diastolic blood pressure
1.4. Tricuspid regurgitation
1.5. Pulmonary regurgitation
1.6. Pulmonary artery pressure by PAT
1.7. Qp/Qs
1.8. Pulmonary vascular resistance
2. To determine its effect as to:
2.1 presence of pulmonary hypertensive crisis
2.2 length of hospital stay
2.3 duration of mechanical ventilation
2.4 in-hospital mortality.
3. To determine its adverse reactions if any among
children with secondary pulmonary hypertension
undergoing cardiopulmonary bypass.
METHODOLOGY
STUDY DESIGN
This is a randomized double blind experimental
placebo controlled study which identifies the effects
of 48-hour post-operative inhalation of prostacycin
This study was conducted in a tertiary hospital,
the Philippine Heart Center, East Avenue, Quezon
City, Philippines.
STUDY POPULATION
The study population included pediatric patients
(Iday to 19 years old) with moderate to severe
pulmonary arterial hypertension secondary to congenital
heart disease (CH1)) admitted at Philippine Heart
Center from March 2005 to January 2006. Pre-operative
pulmonary artery pressure was determined by Doppler
echocardiography using pulmonary acceleration time
(PAT) and was defined as follows: mild pulmonary
arterial hypertension (PAH) PAT of 80 to 100 mscc,
moderate PAl-I 60 to 80 msec and severe PAH < 60
msec. These pediatric patients with CHD and
pulmonary hypertension with or without cardiac
catheterization and was operated, were included in the
study. The need for pre-operative hemodvnamic study
to determine operability was decided upon by the
attending physician.
Patients were divided into two groups. Group I is
the study population who received every 6 hours
aerosolized Iloprost for 48 hours; and Group II is the
control population who received placebo nebulization
every 6 hours for 48 hours. Randonuzation was done
by using a table of random numbers. Acrosolized
Iloprost was added to the usual treatment regimen of
post-operative intensive care of children undergoing
corrective cardiac surgery.
Informed consent was obtained from parents before
patients were included in the study dul y approved by
the institutional ethics committee.
Excluded in the study were the following:
1. patients with mild pulmonary artery hypertension
2. patients with primary pulmonary hypertension
3. patients with cardiom\opathy, mitral or aortic valve
disease
4. patients with uncorrected hemorrhagic disease and
liver disease
5. c y anotic congenital heart disease
A total of nineteen (19) subjects were included in
the study, ten (10) from the Iloprost group and nine (9)
from the control group.
STUDY PROTOCOL
l,elne 21)1 -a-jib (.1 Di and Art,-ri.4 hid (;
5',
- ) I lemodvnamicsni.ii.5',
y
Selection of Stud population
ii
5',
Randi,mtzariiin
(;Roul'
I
Adintiitst rat nit if act is(ilt,eij topriist immediately at the RR and
cc en (. lirs p.s t iipvrahlvely for 4$ h.,urs
III I
Adn,tnistrariiin of aerciscili,ed
placebo itotnediatel at the RR and
eserv Ii lirs post icpetatis'ely for 48 firs
.
.
y
y lt.A
Determination of baseline ( )2 catur;trti in and PAP b
line if available
hek ire tell csnit,ed lit pr. st and ,l.icebc, administration and at IS. 10 and (.1 nicncczes alter administrate in and then e' sri hour for 48 Ir%.
y
Measurement if paeamcrers b 21)b with (ll)S irnmcdi.iteiv pcistocperative,
dose and
24 itrs in,] 48 irs. diet the
dose cit acrocolized I Ioprccst and as the need
arises flit any signs it1 iti perterisive Colas
4.5
8.
-
5',
,\nal so ill dat.i
* Color Flow Dopier Study
DRUG ADMINISTRATION
Iloprost (Tiomedion; ScheringAG, Berlin, Germany
was obtained as an ethanol-buffered solution and was
prepared from a vial of 50ug/0.5 ml. Aerosolized
Iloprost was administered with a dose of 25 ng. kg'.
mm Three (3) ml. of isotonic saline solution was
added to the nebulizing solution. For nebulization, we
used the Optineb ncbulizcr connected to the inspiratory
limb of the ventilator or to a modified Jackson-Rees
system for hag ventilation, and if extubated, we used
the nebulization by face mask. Iloprost was
continuously aerosolized with a flow rate of 6 LPM
for approximately 10 minutes.
1'hc control group received 3 ml. of isotonic saline
solution delivered thru the Optineb nebulizing jet
connected to the ventilator and once extubated, thru
face mask.
MEASUREMENT of PARAMETERS
Doppler echocardiographic measurements was
obtained using a commercially available echo-Doppler
apparatus Acuson XP and Aspen equipped with a 4
MHz, 5 MHz and 7 Ml-lz transducers with the
possibility of performing combined 2-dimensional
echocardiography and continuous wave or single-gated
pulsed wave Doppler echocardiography. Simultaneous
electrocardiogram tracing and Doppler
echocardiographic measurements were obtained at a
recording speed of 1 00mm/sec. In the supine position,
the pliltIlonary valve and the pulmonary artery A)
were visualized from parasternal short axis view using
standard technique at the second or third left parasternal
space. lb obtain the PA flow velocit y wave, the pulsed
wave Doppler sample volume was carefully placed in
the middle of the P\, irrespective of the length of the
PA. Pulmonary artery pressure by pulmonary
acceleration time, tricuspid regurgitation, pulmonary
regurgitation, Qp/Qs and pulmonary vascular
resistance were computed. Pulmonary vascular
resistance was determined by Doppler
echocardiography as the ratio of RVPEP/ VTI. R\TEP
was measured from the beginning of the QRS to the
opening of the valve. The VTJ was obtained in meters
by digitizing the signal envelope with the aid of a
computer program (Figure i)M. Measurements of at least
three cardiac cycles was obtained and averaged.
Fig. I. Doppler Recording of the Pulmonar y Artery
PATIENT CHARACTERISTICS
l)ernographic variables included age, sex, weight,
body surface area. Clinical and laboratory parameters
were systolic blood pressure, oxygen saturation,
echocardiographic parameters: tricuspid and pulmonary
regurgitation jets, pulmonary artery pressure (PAP) by
PAT, Qp/Qs, and pulmonary vascular resistance
PVR). Cardiac catheterization parameters include
mean PA pressure, systolic PA press Lire, pulmonary
vascular resistance PVR), s y stemic vascular resistance
(SVR), Rp/Rs, pulmonary artery oxygen saturation, and
Qp:Qs.
ANALYSIS OF DATA
Statistical analysis was (lone by the Division of
Preventive Cardiolog y. l)ata gathered was analyzed
using the Epi Info.
I re1uencv, percentage, mean, standard deviation
and upper and lower 95% confidence intervals were
calculated from the data.
Independent 1 , —test was used to determine the
mean difference between the placebo and Iloprost
group. Paired 1-test was used to determine the mean
changes within group of the different variables.
Levine's test for equality of variance was likewise
employed to find out homogeneity of variables.
Analy sis of co-variance ANCOVA) was also used to
determine differences between groups with baseline
as covariate in cases of heterogeneity of baseline data.
To determine change within group, \Vilcoxon match
pair sign rank's test was employed. P value of< 0.05
was considered significant.
RESULTS
There were a total of nineteen (19) patients
included in the stud y, diagnosed with congenital heart
disease with left to right shunt with moderate to severe
pulmonary arterial hypertension; ten (10) from the
Iloprost group and nine (9) from the placebo group.
They were admitted at the Philippine Fleart (:enter from
March 2005 to January 2006. Five patients underwent
cardiac catheterization pre-operatively which was not
a factor for randomization.
Of the congenital heart disease with pulmonary
arterial hypertension, ventricular septal defect (VSD)
was the most common lesion comprising eleven (59%)
of the population as seen in Table I. This was followed
by isolated patent ductus arteriosus (PI).\), sixteen
percent (16). liftecn percent had combined lesions
(10% with VSD and PI)A).
Table I. Distribution of Cascs a to Cardiac Lesion
LESION
Group I
ILOPROST
(%)
N
7
(38)
0
(0)
(0)
0
1
(5)
\S1)
PDA
\SD
AVSI)
COMBINEI):
I
VSD,PD.\
:\S1),P[)i\
1
10
TOTAL
(5
(5)
(53)
Group II
PLACEBO
N
(%)
(21)
4
(16)
3
1
(5)
(0)
0
TOTAL
N
Ii
3
1
1
%)
(59)
(16)
(5)
(5)
1
0
9
2
1
19
(10)
(5)
(100)
(5)
(0)
(47)
Iet. PDA- Patc,>t d,cru. .,r nu.\I) ,\trI cr. II ekfect,
V'd ) VeirncuL,r ­ pi a]
- .'>trv>sernincular septal defect
There were eleven (58%) males and eight (42%)
females, with a 1.4: 1 male to female ratio (Table II).
Sex distribution was comparable in both groups.
Table 11. Sex Distribution
Group I
ILOPROST
N %
42
8
M.\1.E
l : IMALI 2
It)
52
TOTAL 10
SEX
Group II
PLACEBO
N
3
16
32
6
9
48
TOTAL
N %
58
11
42
8
100
19
The mean age in the Iloprost group was 7.25 ± 5.93
months as compared to the placebo group of 3.63 ±
5.19 months but the difference was not statistically
significant (Table III). The oldest patient in the Iloprost
group was a case of a seventeen-year old male with
ventricular septal defect and a patent ductus arteriosus.
and a fifteen-year old female with an isolated patent
ducnis arteriosus in the placebo group.
Table III. Age Distribution
VARIABLE Group I
ILOPROST
Mean SD
:\GE (mos.)
7.25±5.93
Group II
PLACEBO
Mean SD
P VALUE
3.63 ± 5.19
0.178
Pre-operative comparison of baseline characteristics
in 'fable IV, showed that pulmonary artery pressure was
comparable on both groups and not statistically
significant. Comparison of pulmonary vascular
resistance in both groups was highest and statistically
significant in the Iloprost group with a p value of 0.014
which may be secondary to older age. Qp/Qs, shunt
gradient, tricuspid regurgitation and pulmonary
regurgitation jets were not statistically significant in
both groups. Mean 02 saturations were 95.05 ± 4.64%
and 97.77 ± 1.78%, and the mean SBP were 99.00 ±
12.87mmHg and 92.22 ± 6.67 mmHg for the Iloprost
and placebo groups respectively.
Table W. Pre_operativc Baseline Characteristics
VARIABLES
PAP by P.VI (mmIh)
I'VR (,,/in)
Group
IILOPROST
Mean
SD
68.55 + 1070
((.15
QPQ'
0615 +
1.92 ±
Shunt Gradient (mrnlig)
38.67
TR jet (rnrnlkO
PR jet (mm! Ig
48.56 ± 19.4
29.83 + 18.33
95.05 ± 4.64
990(1
2.S
(°n)
02 vii.
5151' (mm!
!t
1)!)!' (innil !r(
68.0(1
0. 173
0.014**
0.458 -- ((.08
1.91) ±1.09
36,50 + 19.10
1.04
+ 56
1095
+
P VALUE
Group II
PLACEBO
Mean
SD
60.3 + 12.1*8
0.892
0.801
45.38 ± 27.20
11.780
29.66 + 22.67
97.77 ± 1.78
9222 + 6.67
0.988
60)8) + 00.00
0.178
0A)7
0.166
02- ox y gen; SBP- systolic blood pressure, DBP- diastolic blood
pressure QpQs_ pulmonar y to systemic blood flow, PVRpulmonar y vascular resistance, PAT- pulmonary acceleration time,
PAP- pulmonary artery pressure, TR - Tricuspid regurgitation, PR-.
Pulmonar y regurgitation
Post-operatively, there was a drop in the pulmonary
artery pressure at 0 to 48 hours but was not statistically significant. There was a statistically significant difference in the TR jet immediately post-operatively
between the Iloprost and the placebo group (p 0.027).
The pulmonary regurgitation jet was lower in the Iloprost group post-operatively but the difference was not statistically significant. The pulmonary vascular resistance did not show any change from 0 to 24 hours
but a statistically significant fall was seen at 48 hours
post-operatively (p value 0.039). There was no
significant difference in the pulmonary to systemic flow ratio (Qp/Qs) in both groups post-operatively with a p value of >0.05 at 0, 24 and 48 hours (Fable VII).
of the shunt
((HOUR
24 HOUR
48 HOURS
1I.0PROST PlACEBO ILOPROST PLACEBO ILOPROST PLACEBO
Mean SD Mean SD
610112'0
P\I'hI'.V(
60.0-U'S
I' .1+e
FR 10
(1,19
22.8-19.1
17.5 ± 12.91
MeoSD
Mra,SD
MrnSD
Mru,SD
('77±14,3
)41,,.(3 I
;3'9' 11.$
61.4- 1S,7
(.87
28.3113.91
17.7133
0.637
23.40±120
341±12.7
flhIfl
There were seven patients (37%) and five patients
(26%) with severe pulmonary arterial hypertension in
the Iloprost and Placebo groups respectively. Three
patients (16%)and four patients (21%) in the Iloprost
and Placebo groups respectively had moderate
pulmonary artery hypertension (-Table V).
Table V. Distribution as to Severit y of Pulmonary Artery
Pressure
VARIABLE ILOPROST
N
R\P liv PSI
NiOl )LR.Vll.3
(16)
7
SEVERL
(37)
TOTAl.
10
(53)
PLACEBO
N ("/o
(21)
(26)
(47)
4
3
9
TbIc VI. posI . operaIisc Iicmod'nam,c P,ramriers
02
8151'(nu)I
Di(l'2uu,)18
I' ,.,1.,
SHOCK
iI.OPROSr PLACEBO
SD
M' ­ Si)
91.31(I.S)
'1,7-I,)
.4'(
''''13.4
I')-),)
'.488
67.7-13.')
3.0(1l1.
"8
;-' 1.7 '''''l'
84.0+8.22
0 070
0.02
24 29±I6.5
13.0±5.8
11.14+
19.8=10,6
18.9±11.0
((((66
16,9 (0.7
(.46±0.08
((.901
0.411±11.08
((,42j(I.08
0.207
((30±0,07
0.28±110.1
0,870
((.39±1)07
.42,40,21
((.02
1.45±0.44
I,41jI1,07
(.52±1) II
0.039
1.23111.20
0.191
o.51
1,42±11.49
I)
149
5 9(0
Pulmonary artery pressure showed a significant drop
48 hours post-operatively compared with pre-operative
measurements. Even if there was a higher pulmonary
artery pressure in group I than in group II, a more
significant decrease in PAP was seen at 48 hours with
a p value of 0.002 (Fig. II)
80
70
60
50
• ILOPROST
40
PLACEBO
30
24 HOUR
II.OPROST PLACEBO
Me,,, SD
Me,,n S
00.4+1.21
-.i.
54.5-9.54
19.3±8,70
Fig. II. Changes in PAP Pre-operatively and at 0, 24, 48 hours
between Iloprost and Placebo Groups Post-operatively
Every 6-hour nebulization for 48 hours postoperatively did not change 02 saturation at 0, 24 and
48 hours nor there was a drop in systolic and diastolic
blood pressures during the 48-hour nebulization period
(Table VI).
VARIABLES
I' ,,Iuc
MT,
(mm Hg(
I' V,IIOC
I'VE
(Sc;,? XI)
P ;4,,
(sQs
48 HOURS
ii.OPROS'i' PLACEBO
Mrm Si)
Mr,u, Si)
911.0(L)'
10
1
20
10
0
Pro Op
64)0(0.48
0 hour
24 hi-s
48hrs
8'3-" 1
0.63
POST-OPERATIVE TIME (hrs)
There was a decrease in tricuspid regurgitation jet
in both groups from pre-operarive measurements to
post-operative values but these were not statistically
significant (Fig. III). A statistically significant drop in
the pulmonary regurgitation jet was noted 48 hours
post-operatively in the Iloprost group (p 0.040) (Fig.
IV).
tg \'. Ihangs in Pulmonar y \ ascular Rcsist.incc 1 re-i >IJcraLlvclv and
l >ost-operativcly Between the Iloprost and Placebo Groups
0.7
0.6
0.5
0.4
0.3
Fig. III. Changes in Tricuspid Regurgitation jet Pre-operatively
and at 0, 24, 48 hours between Iloprost and Placebo Groups Postoperatively
ILOPROST
PLACEBO
0.2
0.1
0
60
Pre-OP
0 hour
24 hrs
4hrs
50
40
—.—ILOPROST
30
AI
20
PLACEBO
iix F
0 09 1
10
There was a decreasing trend in pulmonary to svsteniic
flow (Qp/Qs) ratio from pre-operativc levels to 48
hours post-operatively in both groups but these were
not statisticall y significant ( Fig.VI).
lig. VI. Changes in Qp/Qs Pre -opera tivclv and Post-operatively Between
Iloprost and Placebo
2.5
0
I
Pre Op
0 hour
24 hrs
48hrs
2 -
l'OSI'.OPERATIVE TIME (hrs)
Fig. IV. Changes in Pulmonary Regurgitation jet Preoperatively and at 0, 24, 48 hours between Iloprost and Placebo
Groups Post-operatively
•
1.5
-4— ILOPROST
-
PLACEBO
0.5
0
Preop
0 hour
24 hrs
48 hrs
In the Iloprost group, there were still three (30%)
patients with pulmonary, hypertensive crisis and four
(44%) in the placebo. There was no mortalit y in both
groups.
Table VIII. Clinical Outcome of Patients
N
3
30
PLACEBO
N
4
44
2
20
0
0
0
0
1
11
0
0
0
0
0
0
1
1
0
11
ILOPROST
OUTCOME
The pulmonary vascular resistance showed a
statistically significant change with aerosolized Iloprost.
Although group I had a higher PVR compared with
group II, both groups showed a decrease in PVR with
higher drop in the placebo group at 24 hours. There
was a more significant decrease in PVR at 48 hours in
the Iloprost group than in the placebo group (Fig V).
Pulmonary I IPN crisis
MORBIDITY
Residual VSD
Residual \'SD
with Cerebral Pals y
Residual VSD, PD\
with iliB
Intracranial I lcmorrhagc
MORTALITY
I IPN- I Ivpertensive, Cl TB- Complete I Icart Block
224
There was a shorter duration of ventilation in group I
than group II but was not statistically significant. The
length of hospital stay was longer in group II probably
secondary to post-operative morbidity, but a direct
correlation can not be concluded (Table IX)
Table IX. Duration of Ventilatory Support and Hospital Stay
Between the Iloprost and Placebo Groups
VARIABLES
Group I
ILOPROST
Mean SD
465 ±_7.6
Duration of
Ventilation (days)
Length oil lopital 20.89 ± 25.43
stay (days)
Group II
PLACEBO
Mean SD
6.9 ± 8.0
P Value
0.549
30.90 ± 21.66
0.36
DISCUSSION
Pulmonary blood flow increases markedl y after
birth. This is due to the physical expansion of the lungs
with gas or due to the increase in oxygen concentration
to which the vessels are subjected. A fall in pulmonary
vascular resistance ensues reaching adult levels at 6 to
8 weeks after birth '.
In many infants with congenital heart lesions, there is
retardation of the normal maturation of the pulmonary
arterioles. The smooth muscle layer in the arterioles
thins but not to the extent noted normally, and the
time period of the changes is prolonged. The
persistence of the muscle interferes with the normal
decrease in pulmonary vascular resistance. Pulmonary
vascular resistance falls slowl y over the first 3 to 4
months and does not reach the very low levels seen
normally. Pulmonary vascular resistance is maintained
at levels of about 2 to 4 times the normal level.
Pulmonary blood flow increases as resistance falls, but
pulmonary arterial pressure remains high at systemic
levels because in these patients, its level is determined
by the size of the communication between the two
sides of the heart and not by the pulmonar y vascular
resistance
There are three known factors associated with
delayed maturation of the pulmonary arterioles: large
systemic to pulmonary communications, altitude and
increased pulmonar y blood flow. 'dl these have one
feature in common, increased pulmonary arterial
pressure
The subjects of this stud y are patients with
pulmonary arterial hypertension due to increased
pulmonary blood flow and systemic-to-pulmonary
communication, secondary to left-to-right shunt in
patients with congenital heart disease.
The assessment of pulmonary vascular reactivity
plays an important role in the management of patients
with pulmonary hypertension and congenital heart
disease. Pulmonary hypertension (P1-IT) is recognized
as a risk factor for pen-operative and post-operative
morbidit y and mortality in cardiac surgical patients.
Patients who develop moderate to severe
pulmonar y arterial hypertension are prone to develop
an episode of acute post-operative deterioration with
acute reduction in oxygen deliver y. The increased
pulmonary vascular resistance (RpRs) increases right
ventricular afterload and decreases the cardiac output.
As cardiac output decreases, mixed venous saturation
falls and aggravates hypoxic pulmonary
vasoconstriction, thus amplifying the crisis. This leads
to oxygen desaturation, metabolic acidosis, and a
further reduction in cardiac output leading to
bradycardia, and death. The requirements of pulmonary
hypertensive crisis are increased pulmonar y artery
pressures, increased right heart pressures, right
ventricular (RV) d ysfunction, decreased cardiac output,
and decreased oxygen delivery . Prevention therefore
is imperative in these patients.
This study shows that modification of pulmonary
vascular bed with adequate pulmonary vasodilation is
important despite a good surgical technique.
Aerosolized Iloprost showed a decrease in pulmonary
artery pressure up to the 48-hour with a significant drop
in pulmonary vascular resistance. Although there was
no significant drop in the TR jet post-operatively in
both groups, a significant decline in PR jet was noted
48 hours post-operatively in the Iloprost group.
The most significant improvement in the treatment
of severe pulmonary hypertension in recent years has
been the introduction of continuous intravenous
prostacvcin (P(;L) infusion which has been shown to
improve exercise tolerance and survivaP". PGI, was
thought to he a highl y selective pulmonary vasodilator
on the studies in infants with pulmonary hypertension.
Prostacvcin (PCI.,) has been proposed as an alternative
to nitric oxide after the repair of (III). Aerosolized
Iloprost might have advantages over the inhalation of
nitric oxide, such as its lack of toxic reactions (which
require monitoring of NO, and methemoglobin
formation during NO inhalation), and its easy
administration by conventional nebulizcrs, compared
with the more complicated delivery s y stems required
for NO. Possible life threatening rebound phenomena
have been described with inhaled NO but not with
aerosolized PGI, or Iloprost withdrawal. In our study,
no side effects were noted in the Iloprost group, from
initiation to termination of the medication. These
advantages might favor the use of Iloprost for the
treatment of P1-IT.
Aerosolized Iloprost has been shown to induce
selective pulmonary vasodilatation in adults with
pulmonary hy pertension, with a low risk of systemic
side effects. In children, an improvement of pulmonary
hypertension has been demonstrated after long-term
therapy with inhaled Iloprost. It exhibited a favorable
hemodynamic response in pulmonar y arterial
hy pertension patients: pulmonary artery pressure and
pulmonary vascular resistance decreased, CO and
arterial P0, increased, systemic blood pressure
remained stable and caused a significantly greater
increase in cardiac output 3 . We noted a fall in
pulmonary vascular resistance in our study which is
consistent with the findings of Hoeper et. al. The
pulmonary vascular resistance significantly dropped 48
hours after initiation of Iloprost post-operatively.
Fven if pulmonary artery pressure does not drop
significantly despite aerosolized Iloprost administration
within 48 hour post-operatively, our observations are
consistent with the findings of Herrera", who did a
study on 252 patients with acvanotic congenital heart
disease with pulmonar y arterial hypertension at the
Philippine Heart Center from January 2001 to March
2003. A decline in pulmonary artery pressure postoperatively was noted to start 2 weeks to I month after
surgery (p value 0.000). Further decline which were
also statistically significant were noted at 6 months to
1 year (p value 0.008), and I year (p value 0.001) post
cardiac surgery ' This can explain why the pulmonary
artery pressure of the patients of both groups did not
show statistically significant changes 48 hours after
surgical correction.
The use of inhaled nitric oxide has been shown to
he helpful for the assessment of pulmonary reactivity
in selecting patients for surgerv1 In this setting, the
aerosolization of prostacycim might offer a real
alternative to nitric oxide. In children with pulmonary
arterial hypertension and CHID, both iNO and
aerosolized Iloprost are equally effective in selectively
lowering pulmonary vascular resistance'. In the study
of Rimensbcrger et. al.' and several other 'investigators I,
they observed no changes in systemic vascular
resistance or in systemic arterial pressures during
Iloprost inhalation. Furthermore, the y noted an
impressive response to aerosolized Iloprost with
inversion of the intracardiac shunt and further
improvement of Rp/Rs. Our findings are consistent
with the findings of these previous investigators.
Preferential distribution of aerosolized Iloprost to
the best ventilated lung areas which improved
ventilation-perfusion matching, was seen b y an incrcasc
in arterial ox y gen saturation . Same findings were noted
by Hoeper et al.' Aerosolized Iloprost also exerted
beneficial effects on arterial oxygenation, which
probably reflected the more potent effects of Iloprost:
in the pulmonar y vascular bed and the more
pronounced increase of mixed-venous oxygen
saturation. We observed the same findings as Hallioglu
et. a! . Our study noted an increasing trend of oxygen
saturation post-operatively in the Iloprost group
although not statisticall y significant. There was no
significant change in Qp/Qs pre-operatively and postoperatively between the Iloprost and placebo group
(Fig. V I)
Clinical parameter assessment and changes in terms
of need for length of mechanical ventilation, effect on
hospital stay and pulmonary hypertensive crisis were
not significant in both groups. This may be due to the
population. An increase in sample size maybe necessary
to recommend a guideline for the prevention of
pulmonary hypertensive crisis in the immediate postoperative period.
CONCLUSION AND RECOMMENDATION
Aerosolized Iloprost every 6 hours for 48 hours in
the immediate post-operative period can be an
important additive drug in the prevention of acute
pulmonary hypertensive crisis because of its potential
to decrease the pulmonary vascular resistance in the
to 48dI hour even if the pulmonary artery pressure
does not drop significantly.
I
It is however a rccommendatioii that, a tollow up
study on pre-treatment for modification of the
pulmonary vascular bed with pre-operative nebulization
of Iloprost is needed since there were still 30% of
patients who had pulmonary hypertensive crisis despite
post-operative administration of aerosolized Iloprost.
An increase in the number of subjects is necessar y to
attain a significant difference and decrease the variability
within each group.
Once proven, a follow-up research on pre-operative
use of aerosolized Iloprost 48 hours prior to surgery
to prevent pulmonary hypertensive cnsis among children
with CHD undergoing CPB can be done.
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ir
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Center experience. Phil. Heart Center Journal, Jan-Dec
2005;l 1:34-38.
12. Roberts . 1p), Lang P. Bigatcllo I.M. et. al. Inhaled nitric
oxide in congenital heart disease. Circulation.
1993;87:447-453.
13. Olschewski 11, \X'almrath D, Schemnulvr, et. a].
Aerosolized prostacyclin and iloprost in severe
pulmonar y h y pertension. Ann intern Medicine
1996; 124:820-824.
CLINICAL RESEARCH FORM
Patient ID no.
Name
Age:
Sex:
Address:
VSI)
Dx:
Others or Combination
OUTCOME:
MORBI 1)FIY:
Group:________ Placebo _____Iloprost
Birthdatc:
Weight: PDA
ASD
AVSD
Mortality
survived
1-lyperrensive Crisis
Length of hospital stay
Duration of Mechanical Ventilator
Others
Cause of Death:
Side lffects: PARAMETERS
)2 sat
SBP
Qp
Qs
Qp/ Qs
Rp/Rs
PAT
PAP by PAI
Dec. TIME
TRJ
PR
Shunt Grad.
PAP by PA line
PREOPERATIVE
POSTOPERATIVE
24 HOUR
48 HR
CARDIAC CATHETERIZATION PARAMETERS:
[PARAMETERS
NIean l\P
Systolic PAP
\TR
TVR
pRs
)p:Qs
02 saturation
PRE- 02
POST —02
PHILIPPINE HEART CENTER
East Avenue, Quezon City Section of Non —Invasive Cardiology
Department of Pediatric Cardiology
CONSENT FOR INCLUSION IN THE ILOPROST STUDY ON THE POST-OPERATIVE INHALATION IN PULMONARY ARTERY HYPRTENSION SECONDARY TO CONGENITAL HEART DISEASE
Patient
Hosp. NO.
Date
1. 1 hereby consent to the performance of upon myself/ above patient the procedure : Iloprost
adniinist ration.
2. 1 further consent the performance of such additional procedure as stated in the heading as ma y be
considered necessar y or desirable in the judgment of my attending ph ysician, 1)r. Ruzenette Feicitas
R. Hernandez of the above named institution.
3. I attest that the above procedure and trial will be done iii conjunction with the standard procedure.
4. 1 also consent to the procedure for the purpose of better decision making, treatment options, and for
the purpose of advancing medical knowledge.
5. 1 attest that the trial has been fully explained to inc and I understand what will be done to me/ above
patient.
THE UN[)FRSIGNED CERTIFIES THKI' SHE! HE UNDJRSTANDS THE FOREGOING, AND
IS THE PATIENT, OR IS AUTHORIZED BY THE PATIENT TO EXECUTE THE ABOVE AND ACCEPT
ITS TERMS
Signature of Patient
Date
Because the above patient is a minor, or in unable to sign
Consent is given on the patient's behalf by
Signature of Patient's Authorized Agent
Relationship to the Patient Date
Note: In case the patient/responsible party cannot understand and read English, the above must be translated to
him/her in him/her own dialect.
The Effect of Combination of Angiotensin Converting Enzyme
Inhibitor and Angiotensin II Receptor Blocker on the Systolic
Function in Patients with Chronic Heart Failure:
A Meta-Analysis
Jannice Lone Thason, MD, Zarina Lorenzo, MD, Regina Yao, MD,
Marcellus Francis L. Ramirez, MD
University of Santo Thrnas Hospital, Espana, Manila
RESEARCH QUESTION
Is dual blockade with ;\Cl inhibitor (.\(Ei) and Angiotensin Receptor Blocker (:\RB) better than ,CEi alone in
terms of an increase in left ventricular ejection fraction (LVEF) among patients with chronic heart failure (I IF)?
BACKGROUND the efficac y of ACEi in [IF was alread y proven. I lowever, it remains a significant cause of hospitalization among
adult patients and is associated with high mortality. As pharmacologic mechanisms of ACEi and ARB differ, an
improvement in L\'lT can be expected in combining them.
OBJECTIVE
'10 determine the effects of combined therap y of
and .\RB in improving JVFIF among patients with
chronic heart failure.
INCLUSION CRITERIA
SEARCH STRATEGY
Randomized controlled trials comparing mean change in EVEr among plttclitS with chronic ill (El <40 0 "o and
NYI IA ll-lV). treated with an .\CEI-F;\RB and placcho4-A(:Ei.
\Xe searched the MIIDLINE (1996 to January 2006) for studies ill which .\RH was added to .\(l.i ill paticilts
with II E The following search items were used: heart failure, angiotcnsln converting enzyme inhibitor/s.
angiotcnsin 11 receptor type I blocker/s.
STUDY MANEUVERS
Data were analyzed independently. The method and qualit y of the studies were rated using critical appraisal tool on treatment which measures blinding, randomization, withdrawals and drop-outs.
STATISTICAL ANALYSIS
Formal meta-analysis and investigation of heterogeneity among the studies included was conducted using
comprehensive meta-analvsis version 2.2.040.
RESULTS:
live studies with a total of 3328 patients were analyzed (mean age of 63.4 SD 0. IS, 80.3% males). The etiology
of IlF was ischemic in 56.8%. DCM in 30.5%. 60.89 4o belong to NYI-L\ class 11. The mean baseline EF was
26.43% ± 0.87. After a duration of treatment of 6 weeks to 6 months with .CEi and ARB, the Increase in the
LVEF among the patients who received an .-\RB + ACEt was greater than those who were on ACEi + placebo
(p value <0.05).
CONCLUSION
Combination therap y is more effective than ACE inhibitor alone.
INTRODUCTION
Pharmacotherapy for heart failure has advanced considerably in recent years as many clinical trials have
proven the benefit of ACEi and beta-blockers on the morbidity and mortality. However, heart failure remains one of the leading causes of hospitalization among adult patients, mortality among patients with heart failure is high, and the quality of life is low.' The renin-angiotcnSifl system (RAS) has been classically viewed as an endocrine s y stem, comprising
organs that secrete a precursor and various regulatory
enzymes into the circulation. The final product, angiotensin II, is formed when circulating anglotensin converting enzyme (ACF ) cleaves angiotensin I. Angiotensin 11 acts on distant targets. More recently, it was found out that some organs, such as the heart,
to
synthesize all the necessary components fora local RAS.
The identification of RAS components and angiotensin
II receptors in cardiac tissue suggests the existence of
an autocrine/paracrine system that has effects
independent of angiotensin II derived from the
circulatory system. The angiotensin type I (ATI)
receptors present in various peripheral tissues and
organs mediate most of the classic actions of
angiotensin II, including its trophic and hyperplastic
cardiovascular effccts.1
Angiotensin II has many diverse vascular effects
that are mediated through two plasma membrane
receptors. The ATI receptor mediates the majority of
actions of A-Il including vasoconstrictiOn, aldosterone
secretion, vascular smooth muscle growth, and
synthesis of the prothrombotic factor plasnnogen
I
activator inhibitor-i (PM-I). The pathophvsiological
consequences of AT1 receptor activation appear to
promote the formation of atherosclerosis, thrombosis,
and vascular inflammation. Moreover, angiotensin IT
acts via the ATI receptor to produce growth factors
(basic fibroblast growth factor, platelet derived growth
factor, transforming growth factor-B) and extracellular
matrix proteins (collagen, fibronectin, tenascin) that
affect vascular and cardiac hypertrophv and
remodelling.2
Angiotensin converting enz yme inhibitors, which
were initially developed for the treatment of
hypertension, have now become the treatment of choice
for patients with Clii' due to LV s ystolic dysfunction.
Suppression of angiotensin II produced by the RAS,
using an ACEi, results in a reduction of thrombus
formation and surface expression of platelet
glvcoprotein 111)/I1 la following myocardial infarctions.
Studies have also demostrated the effectiveness of
ACEi in the prevention and regression of LVH.
Angiotensin-converting enzyme inhibitors reduce
ventricular and vascular remodelling.
However, previous studies have proven that
persistence of angiotensin II or even an increased in
plasma levels via alternate pathways suggests that longterm ACE-inhibition may onl y partially suppress the
activated renin-angiotensin-aidosterone system.
Angiotensin II receptor blockers may be a better
therapeutic option since it blocks angiotensin II from
all sources without the side effects thought to be due
to nonspecific actions of ACE inhibitors. The
combination of ACE inhibitors and \RB ma y have a
synergistic effect.
Son-ic patients with chronic heart failure who were
receiving diuretics, beta blockers, ACE inhibitors and
digoxin still manifest deterioration of left ventricular
function and worsening of heart failure s ymptoms. This
resulted to deterioration of quality of life and increase
in hospitalizations. With the discover y of persistence
of angiotensin II despite ACE inhibition, and the
addition of an angiotensin receptor blocker will have
a synergistic effect to block the actions of angiotensin
II, the combination of the two was studied and
investigated.
OBJECTIVE
This meta-analvsis aims to determine the effects
of combination therapy with an ACE inhibitor and
angiotcnsin TI type 1 receptor blocker in the left
ventricular ejection fraction.
METHODS
Seareb stratt'y anti siiu/y selection
We searched MEDLINE (1996 to January 2006)
for studies in which an ARB was combined with an
ACE inhibitor in patients with heart failure. We
included the following search terms using both free
text and MESI-1 methods: heart failure, angiotensin
converting enz yme inhibitor/s, angiotensin II receptor
ty pe 1 blocker/s, names of individual ACE inhibitors
and ARBs. We augmented our search by reviewing
reference list of all retrieved articles. Studies that met
the following criteria were included in the study:
randomized controlled trial, studypopulation included
adult patients with moderate to severe heart failure
(defined as ejection fraction of <40%, New York 1 leart
Association Class 11-TV, intervention arm included
simultaneous treatment with an ACI'inhibitor and an
ARB, a comparator arm included treatment with an
ACE inhibitor with or without beta-blocker, digoxin,
diuretics or combination. All of the included studies
reported an improvement in ejection fraction as an
important endpoint. Others investigated on the
improvement of functional class (NYHA),
cardiovascular morbidit y and mortality, number of
hospitalizations, hemodynamic and neurobormonal
changes as their outcomes. Full articles were obtained
from websitcs of specified publications. Articles not
published in English were excluded.
Data Hx/raction
l)ata were anal y zed independently b y 2
investigators (Z.L. and RA). The following data were
abstracted: trial design, sample size, medications used
and improvement of ejection fraction. Differences
over inclusion of studies and/or interpretation of data
were resolved by discussion. The two investigators
rated the method quality of all included studies using
critical appraisal tool on treatment which measures
blinding, randomization, withdrawals and drop-outs.
c;,1te,ia icr evnsiden'ng .cti,dies Icr this rev/en'
RESULTS
Originally published articles of randomized
controlled trials that were reviewed and represented a
parallel design having heart failure patients evidenced
by an ejection fraction of less than 40 6 as subjects
and treated with a combination of ACE inhibitor and
A RB were included in this review
Eight articles were gathered however only 5 articles
were included in this meta-anal sis. Two of the
excluded studies reported on cardiovascular morbidity
and mortality as primar endpoints and failed to
investigate on the ejection fraction. One stud reported
a significant increase in cardiac output but did not
specif the mean change in ejection fraction.
01
y
y
y
y
Ijj)e.l 0/ cit/come iiieasit/rS
The outcome of therap was reported as an increase
in ejection fraction from the baseline ejection fraction
after treatment. Some of the studies checked on the
improvement of quality of life, decrease of end systolic
left ventricular volume and improvement of New York
I leart Association Classification. One stud mentioned
a decrease in hospitalization and cardiovascular
morbidit and mortality.
y
y
Five randomized controlled clinical trials were
included in this meta-analvs 1s. lour studies were
double-blinded placebo controlled trials. One study is
randomized, double blinded and double dummy using
3 parallel groups. One stud did not use a placebo.
Description of the studies included are summarized in
Fable 1.
i
y
y
/1 na/ysis
Improvement of ejection fraction is the outcome
of interest of this meta-analysis. The h pothesis to be
tested was that there is a more significant increase in
ejection fraction among patients with congestive heart
failure treated with a combination of an ACE inhibitor
and an angiotensin receptor blocker than in those
patients receiving ACE inhibitors alone.
In the published trials, data generall were
presented as a pooled summar post-treatment after
ACE-inhibitor, angiotensin II receptor blocker type I,
or combination of ACE and ARB.
Formal meta-analysis and investigation of
heterogencitv among the studies included was
conducted using NCSS-PAS Software program.
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data extraction forms for articles evaluating treatment.
Comparison between completed forms was done.
1'he key data elements gathered were categorized
as follows (1) study characteristics which included
study duration, sample size and methods of
randomization and blinding, (2) clinical outcomes/
efficacy parameters. (3) mean age of population, (4)
male to female ratio, (5) cause of heart failure and (6)
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RAP - nghl alrial pressure PAP - pulmonary artery pressure. CO . cardiac output. SVR - systemic vascular
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Table 3 provides the mean change in LV ejection
traction of the patients under each designated treatment
groups in the 5 studies included. All of the patients had
an increase in ejection fraction.
Figure I. shows that the increase in the ejection fraction
among the patients who received an angiotensin receptor
blocker was greater than those in patients who were on
ACE inhibitor plus placebo. In contrast, the stud y by
Murdoch et. al. showed that the control group had a more
significant increase in the ejection fraction compared to
the treatment group.
J/)?at///efl/ (.haraciensiiis
In the studies included, an angiotensin receptor
blocker is added to an ACE inhibitor in patients with
heart failure. The magnitude of the increase in the ejection
fraction in patients on combined ACE inhibitor and ARB
treatment was compared to that of patients maintained
on ACE inhibitor alone or with other usual drugs for
heart failure e. g. beta-blockers, digoxin or diuretics. In
the stud y by Shu Kasania et. al. a total of 32 patients were
treated with an ACE inhibitor and a loop diuretic. Sixteen
patients were randomized to group A who were given
valsartan in addition to their usual regimen and the
remaining 16 patients (group B) continued their current
regimen. Series of examination were performed before and
6 months after treatment. Two studies used Enalapril
\vhilc the rest used various ACE inhibitors. Tvo of the
studies included used Valsartan. Others used losartan,
Candesartan and Eprosartan. In the RESOLVI) Pilot
Study by McKelvie, et al., a total of 768 were included and
were randomized into 3 groups: 327 received Candesartan,
109 received enalapril and 332 received combination
therap y. Candesartan patients were further randomized to
4, 8, or 16mg dail y. Conbinadoli-thera1)y patients received
candesartan at either 4 or 8 mg daily plus enalapril lOmg
twice dail\ The medications were blindly titrated upward
over 4 to 6 weeks. Krum et. al. included subjects from the
Val-Heft trial who were on ACE. inhibitors but not on
beta- blockers 60.6 0 o and were like\visc given Valsartan
added to background ACE inhibitor therapy. The patients
W ho were included in the stud y by Cocco et. al. were
randomized into 3 parallel subgroups who received
placebo- placebo, enalapril, and enalapril + losartan
respectivel y. The doses of enalapril and losartan were
escalated successively at weekly intervals. The highest dose
of which was chosen according to safet y, tolerance and
cardiac symptoms and it was maintained for six weeks.
1'he -\l)EPT stud y made use of an angiotensm receptor
blocker antagonist, eprosartan, added to their usual ACE
inhibitor therap y that could be enalapril, perindopril,
trandolopril or c1uinapnl. The dose of eprosartan was
increased in every 2-week interval until the target dose
400mg twice dail y was reached. Patients unable to tolerate
doses could have their dose maintained or decreased. There
was no significant difference observed between treatment
groups with regards to their treatment.
TAN 3
.h.n
Ctini.I
ARB • ACE
Study
B±ste 1%)
h
thbor
ACE h iiibitie • placebo
End ofaewn
1Bas#iI
End cdU,iet.qn
,31(a4.5)
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1339t2.t
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Md<eM,M al
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30(±7)
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41(±13)
[341*5)
37j
g
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)in n et al
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302(t97)
26.5(*6.9)
29.2(t9 7)
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21$(i2)
23.71±1.3)
Ejection Fraction at Baseline and End of Treatment
45
40
35
LL
25
• treatment
• treatment End
• control Baseline
• control End
20
t
i
5
:\
:
N
0
(..occ.o
Mc.K
elvie
.Kiiir.i
Kr urn
\lurdoc)i
Studies
Figure 1. The mean change in ejection fraction is greater in patient who received the
combination therapy of ACE inhibitor and angiotensin receptor blocker.
Effect-Equality (Heterogeneity) Test
Outcome
Rows
Measure
Combined Mean Difference
Cochran's
Q
4.285
Prob
OF
Level
4
'0.369
This shows that the test for hetcrogcinitv of the five
trials was not significant with p> 0.05. Studies involved
showed a statisticall y significant benefit towards the use
of combination therapy.
occoet a
Standard
SOd dli?
error
in means
variance
j353
0126
0100
Lover
Iirflt
0515
Upper
unit
U04
Sid dir in medris Td
IeSr
SlIs1I, !or eal.1 51u05
Stu0yname
21
RelaOV e Relative
wi4fl wight
ARB
Z-Value p-Value +ACEI ACEI
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0612
15
lb
Ii 93
952
hIchekI001al
0207
0111
0012
0010
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109
Kasna 01 al
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0 345
0 119
0085
1 438
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18
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7
7
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0195
3748
0530
Murdoch el al
. 1.00
.0.50
Favors ACE!
0.00
0.50
1.00
Fas ors ACEI + ARE
Figure 2. Angiotensin-receptor blocker added to angiotensin converting enzyme blocker improves left ventricular systolic function as shown by a more significant
increase in the LV ejection traction compared to an ACE inhibitor alone.
DISCUSSION
The activation of the renin-angiotensin-aldosterone
system RAAS) plays a key role in the pathogenesis of
chronic heart failure. ACE inhibitors had been proven
to retard progression of heart failure thus were
considered as one of the primar y treatment of heart
failure. Recent studies have shown that angiotensin
receptor blockers also render benefit in the management
of heart failure. According to Hamroff, et. al.
incomplete suppression of the RAAS during long-term
ACE inhibition ma y contribute to symptomatic
deterioration in patients with congestive heart failure.
Recent evidence suggests that AC Ii inhibitors may not
completely block the formation of angiotensin 11. 2 NonACE enz y mes, such as cbvmase, are thought to increase
the conversion of anglotensin I to angiotensin II and,
over time, return angiotensin 11 level to pretreatment
levels, These non-ACE-dependent pathways appear to
be up-regulated with long-term ACE inhibitor use.
Thus, the combination therapy with an angiotensin
receptor blocker added to an ACE inhibitor ma y allow
a more complete blockade of the rcnin-angiotensin
system thereb y provide additional effect in cardiac
remodelling.' However, some clinical trials have shown
an increased risk of development of adverse effects
such as hvperkalemia, increase in creatinine and
hypotension.
Although there were differences in the 5 studies
with the drugs used, patient characteristics, controls,
sample size, duration of follow-up, the studies were
it
similar enough for inclusion into a single n3eta-analysis.
Of the 3328 patients included in the study. 1659
(49.8°/b) patients received :\RB added to an ACE
inhibitor and 1669 (50.2/0) patients were maintained
on ACE inhibitors with or without other conventional
drugs used for heart failure. There was an observed
increase in left ventricular ejection fraction (LVEF) in
both groups but those who received ARB added to
ACT . inhibitors had a more significant increase in LVEF
in four studies. Combining the 5 studies, the
combination of an ACE inhibitor and an ARB is more
effective in increasing the left ventricular ejection
fraction (Cl 95 .',o, p value <0.05). However, the study
by Murdoch et. al. (ADEPT) showed no significant
change in LVEF with eprosartan + ACE inhibitor
therapy with p value 0.968. However, cprosartan was
associated with a significant reduction in diastolic blood
pressure and a trend toward a reduction in systolic blood
pressure compared with placebo. Failure to demonstrate
significant long-term hemodynamic changes may be a
consequence of the continued use of an AC I inhibitor
and other vasodilators rather than inadequate number
of participants. There is no significant change in the
LVEF because the study period ma y be short for LV
remodeling to become apparent. Other possible reasons
are (1) close of eprosartan may not be sufficient and (2)
the high dose of the ACE inhibitor may be used which
made it difficult to document incremental hemodynamic
effect of the addition of an ARB.
The stud y b y Cocco et. al. showed that the
combination of enalapril + losartan is more effective
than enalapril alone in improving myocardial function
both at rest and after stress which was detected after
six weeks of therapy. The positive effect of the
combination is attributable to a more effect antiischemic effect, perhaps reducing the escape
phenomenon observed with monotherapv with ACE
inhibitors.
Results from the Val-Heft showed a significant
increase in LVEl among patients who received
valsartan compared to placebo. This stud y also reported
that mortality was not affected b y valsartan but
morbidit y endpoints were significantl y reduced.
Valsartan reduces hospitalization and slows LV
remodelling in patients who received an ACE inhibitor
who were not maintained on beta-blockers. The
RESOLVD Pilot Stud y likewise proved that the
addition of an ARB (candesartan) to an ACE inhibitor
(enalapril) was more beneficial for preventing left
ventricular remodeling than either candesartan or
cnalapril alone.
The Eorcst ])lot shows that the studies prove the
addition of an angiotensin receptor blocker to a standard
treatment for heart failure in a form of an ACE inhibitor
causes a significant increase in IA" ejection fraction thus
retarding progression of heart failure. A complete
blockade of the renin angiotensin s y stem by combination
therapy renders a beneficial effect in retarding
ventricular remodeling which is considered a main
pathophvsiologv in the development of heart failure.
The meta-anal y sis performed showed significant
beneficial effect of addition of an angiotensin receptor
blocker to an ACE inhibitor in the study population.
However, certain points must be considered such as
variable length of treatment, different types of ACE
inhibitors, different types of ARB, and the doses used
for each treatment arm.
REVIEWER'S CONCLUSION
Based on the studies reviewed, dual inhibition is
more effective than ACE inhibitor alone. The
continuous suppression of the RAAS by the dual effect
of an ARB added to an ACE inhibitor is the main
mechanism that advocates the use of such combination
therapy
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Cohn,). N. and ( . IOgiioiii. A R:iiidoiiiized trial CCI the .lngiotcusiiireceptor blocker valsarun in chronic heart failure. New I :ngland
Journal of Medicine, Vol 345. No. 23. I)ccernber 2001 pp 1667 1675
2. \lai.chio G, et. al. I ffect of the aiign Oensln-converting-enz):ine
inhibitor benaze1,ril on the progression of chronic renal insufficiency.
The ;\ ng tcnsin-( ;onvertiflg- I nzyiiie Inhibition iii Progressive Renal
Insufficiency Study Group. New !ngland Journal of Medicine. Vol
334:939-945. 1996
3 MacKinnon, M. et. al.( oinbination therapy with an angiotensli
rcceptc r blocker and an ACE inhibitor in proteinuric renal disease:
a svstcniatic review of tile efficac y and safet y data. . 1uncrican JOUrrial
of Kidne y 1)iseasesl Vol 48. No. 1: 8-20. 2006
4.
Murdoch 1). R. ci. al. .\ 1)1: P1 :Addition of the Mi receptor
antagonist eprosartan to ACF inhibitor therap y in chronic heart
failure trial: I lcniodvnamic and neurohorrnonal effects, American
I Icart Journal. Vol 141. No.5:800-807. 2001
5. (occo. ci. al. Effects of combined treatment with enalapnl and
losartan on m yocardial function in heart failure. I leart. 88:185-186.
2002.
6.
Kruni. I lenr. Cr. :11.: Effect of valsartan added to background ACE
inhibitor therap y in patients with heart failure: results from Val
I let t. The European Journal of I kart Failure- Vol 6:937-945. 2004.
Kasaina. S., et. al. : Addition of valsartan to an angior&nsinconverting enzyme inhibitor improves cardiac sympathetic nerve
aciitivltv and left ventricular function in patients with congestive
heart failure. 1 he Journal of Nuclear Medicine. Vol 44. No. 6:884890.2003.
8.
Sharma, I)., Buvsc, M. Pitt. 13. and Rucinska, E. \Icta-analvsis of
observed no irtalitv data from all-controlled, double -blind, multipledose studies of iosartaii iii heart failure. .\m • 1 Cardio. Vol. 85, 187i92. 2000.
9.
Pfeffc i, 'ui., Swcdberg. (2.. I leld. P, McMurray, .1 et. al. Effects of
candcrsanian 0 0 mortalit y and morbidit y in patients with chronic
heart failure: the CHARM overall programme. Lancet. Vol 362,
759-771.2003.
10. NlcMurrav,J. Osrcrgren,j. Granger, C. et al. f : ffec t s of candesartami
iii patients with chronic heart failure and reduced left-ventricular
s y stolic function raking angiotensin-coverring enz yme inhibitors:
the Cl l.\RM-Addcd trial.
The Value of Human Heart-Type Cytoplastic Fatty Acid
Binding Protein (H-FABP) as a Marker for the Early
Diagnosis of Acute Coronary Syndrome
Maureen V Valentin, MD, Alan Regin S. Malvar, MD,
Marcellus Francis L. Ramirez, MD, Orlando T. Bugarin, MD,
Milagros E. Yamamoto, MD, Eduardo Vicente S. Caguioa, MD
Ste. Toma$ (i'niz'crsiry ITJos/nta/
BACKGROUND
Ilie human heart type fanv acid-binding protein (ii l:\bI>) is an emerging marker for the diagnosis and
stratification of acute coronary s yndrome ACS). It can be used as an early marker of heart tissue injury.
OBJECIIVE
TO evaluate the usefulness of qualitative H-FABP compared to Troponin 1 in the earl y diagnosis of acute
non ST elevation myocardial infarction (NSIl M 1).
METHODS
The study included 35 consecutive adult patients who presented with clinical features of ACS. Patients
viili ST elevation on electrocardiogram ([CG) and history of muscle In j ury were excluded. FCC and
blood samples were taken for Iroponin I and H-F,\BP. The quantitative lropoiiin I assay was timed at
least 4 hours after the onset of s ymptoms while qualitative II l\Il' was extracted immediatel y on
presentation. The results of the I l-l.\BP were compared with 1 ropoilin I used as the gold standard for
.\NlI using it ciii off value of 0.5 mg/ml.
it
RESULTS
The mean age of the stud y population was 573 13. years; 19 patients C54.3 0 0) were males. Majority had
normal renal function (71%). Among the 35% patients. 11 were positive for II I' -\ UP while 24 were
negative. The minimum time from onset of symptoms to I I-F;\BP testing was 1 hour. The group with
positive Fl FAI3P group (2.193 2.763 vs 0.024 ±_0.018 ng/ml, pl) using a Troponin 1 value of 0.5
ng/mI as it diagnostic cut off for .\MI, the sensitivity and specificity of I l-F.-\ UP was computed at 100/o
and 85 7% respectively, with a positive predictive value of 64% and negative predictive value of 100%.
Receiver operating characteristics curve analysis showed a value of 0.929 (95% confidence interval 0.7888 to
i)957 p value of 0.0001).
1
1
CONCLUSION
liie qualitative whole blood rapid II - I -\ UP test is it useful and accurate test in the early evaluation of
patients with suspected ,-\Ml. It offers the advaiittye of earlier release and detection compared to the
standard Troponin I
INTRODUCTION
Acute tiiy cardial iii farction (:\ Il continues to draw
significant rriortalirv anti morbidity worldwide. To date, the
\\rld Health Organization (WI -b) criteria for the diagnosis
of AMI is being used. l-lowcvcr, continuing researches and
investigations are ongoing because the diagnoslic process is
complex since the majorit y of patients suspected to have
\MI have atypical s ymptoms and nonspecific FCG changes.
'I-Ills is the main reason why biochemical markers of cardiac
injury are included in the diagnostic criteria.
The available cardiac markers include, troponin 1 (TnI).
troponin T (TnT), CKN[B, mvoglobin, I-1-FABP, glycogen phophotylasc isocnzvrne BB (GPBB), high. sensitivit y CRP.
urinary albumin, S- 100 protein and Nl-proBiNP/proBNP.
Ihe cardiac form of InI is a reliable marker of cardiac tissue injury and widel y available. It is more sensitive and significantl y more specific than (:KI's[B. Cardiac 'I'nI can only be detected in patient's blood 3 - 6 hours after onset of
chest pain and reaching peak levels within 16 — 30 hours. Fvidence has shown that early diagnosis and treatment
increases the survival rate and the rapid exclusion of AMI can reduce the number of unnecessary admissions. 'lhercfore,
a cardiac marker in which the blood level go up immediately
after cardiac injury is needed
HEART-TYPE, FATTY-ACID BINDING PROTEIN
'Ihe heart-t ype. fatt y-acid binding protein (I l-F.\BP) is
an emerging diagnostic marker for the early diagnosis of
AMI. It is a low molecular cvtoplasmic protein that is present
in abundance in cardiac myocytes with a concentration of
0.57 mg/g weight of cardiac tissue. It is rapidly released
into the circulation after m yocardial cell damage, and its
plasma level rises as earl y as 3 hours after AMI.
'Ihe application of I I-FABP, especiall y for the early
diagnosis of acute coronary s yndromes, is indicated because
of its rapid release into the plasma after m yocardial injury
and its relativel y low plasma reference concentration.
OBJECTIVE
li.> evaluate the usefulness of heart t ype, fatty-acid
binding protein (H_l'ABP) compared to Troponin I in the
early diagnosis of acute non SI' elevation myocardial
in hirction (NS'lI M1).
METHODS
RESULTS
'I'his is a prospective cohort stud y done in a Tertiary
Care Universit y I lospital (University of Santo Tomas
Hospital) between August I') to September 30, 2006. Ihe
study involved 35 consecutive patients seen at the L'S'!
I lospital with the following inclusion criteria:
1. 18 years old and above
2. presented to the ER with acute coronar y syndrome
(ACS)defined as
a. sudden onset chest pain 30 minutes or longer
and/or
b. sudden onset of dvspnca (angina C1Wvakffl)
The tollo\Vmg were the exclusion criteria:
1. S'! segment elevation as seen on FC(
2. history of recent muscle injury
All patients had a 12 lead lX ; done on initial evaluation,
and blood drawn for both Troponin I and I H\BP . The
blood for I IFABP was extracted inimediatclv on evaluation
with at least 30 minutes interval after onset ot chest pain,
while the blood for 'i'roponin I 'as extracted at least 4 hours
after onset of chest pain. Pour drops 01 the patient's whole
blood (approximately Gt}- lOt) 111, were applied on the test
field of the II-lARI' kit, the CardioDetect med card
(Rcnnesens GmbI I), and the test results were interpreted after
15 minutes according to manufacturer's instructions.
The following clinical date were taken from each patent:
history of h ypertension, hvperlipidemia,, diabetes melhtus,
smoking historx, family histor y of ischemic heart disease,
and previous history of A 'vii.
'1 'he patients were followed up individtiallv. The incidence
of heart failure, arrh ythmia, and death were recorded as well
as the number of days of stay in the intensive care unit and
cardiovascular unit and duration of hospital slay.
The study was done according to the Declaration of
I lelsinki and according to institutional guidelines on research.
Proper informed consent and patient confidentiality were
observed.
Among the 35 subjects, 19 (54.3°) were males and 16
(45.7o) were females. The mean age was 57 + 13 years
T-lvpertension was s_'m in 26 patients (74) and diabetes
melhtus in 13 patients (37). Eighteen patients (51%) had
dvslipidemia and 13 patients (37) gave a history of smoking.
Majority of the cohort had normal renal function with a
mean serum crearininc 1.37 f: 1.16 g/di .. The mean time
period between svmptoni onset and blood drawn for I]FAUP and Till was 6.38 + 5.82 hours and 7.51 + 5.1$ hours
respectivel y. The minimum time interval from the onset of
symptom to I I-FABP testing was I hour, while the minimum
time from symptom onset IC> ' Iroponin 1 examination was 4
hours. The 12 Lead l-CG binclines on admission werc normal
in 13 patients 37°). T-wave inversion was seen in 13 patients
(370 o). Q-waves in patients (17'). and arrh ythmia in 3 patients
($°). (fablel)
'!'here \vere no differences in baseline characterisucs
between patients with positive I I-FABP and those with
higher ' Iroponin 1 levels. 2.193 2.763 ng/mnl, compared to
the group with negative tests, 0.024+0,018 rig/rill, at 1)=ft0l.
(Table 4)
Using a 'I'nl level of > 0.5 ng/ml as the gold standard
for the diagnosis of AM 1, the sensitivity and specificity of
CardioDetect med carol was computed at lOO"n and $5.70/a
respectivelyThe
.
positive predictive value was 64°o and
negative predictive value was 100' ('[',able 2 & 3) Receiver
operating curve anal ysis showed a value of 0.929 (95)o
confidence interval of ().788 to 0,987 and p value of 0.0001).
(Figure 3)
There was no difference in the incidence of heart failure,
arrh ythmia, and death as well as the duration of ICU stay
and hospitalization between the 2 groups.
ANALYSIS OF DATA
The stud y group was divided into those with positive
H F.\BP and negative() Ill "ABP. Clinical parameters and
Troponin 1 were compared and analyzed between the 2
groups, Troponin 1 of 0.50 ng/ml was used as a cut, off for
AMI as indicated b y the Access Cardiac Kit used in USTH.
The sensitivity, specificity, positive l)redhcUve value (PPV,
negative predictive value (NPV) and diagnostic accuracy
(defined as the sum of true positives and true negatives
divided by the total number of patients) were determined
for Cardioi)etect tried card test and iroponin I assays. The
non parametric and parametric variables were likewise
analyzed using the Fisher's exact test and 'I-test respectively.
Receiver operating curve anal ysis was done using iroponin
I as standard.
1+)
DISCUSSION
In several studies, serum H-FABP has been shown to be
a sensitive marker for the detection of AMI. However, the
widespread use of serum 1-1-FABP has been limited b y the
complicated laboratory procedures required for its
determination. Recently, a 1-step in'Imun ochromatograph ic
point of care test, CardioDetect mcd card, which takes only
15 minutes to perform has been introduced. It qualitatively
detects the presence of H-FABP in concentrations >_7ng/
inl in a patient's whole blood using I I-FABP specific
monoclonal antibodies. The monoclonal antibodies are
placed on a precisely defined position on the dipstick (capture
line) When blood containing h-FABP passes through this
capture line, the antibodies bind the h-I 'A BI) molecules, and
a red strip becomes visible. There is also a "control" line that
becomes visible when blood passes through it. The rest is
considered positive, and a diagnosis of AMI is made when
the 2 lines (appearing as red strips) are visible through the
test card window. On the other hand, the presence of a single
"control" line (single red strip) indicates a negative test and
the absence of myocardial infarction. This study evaluated
the diagnostic efficacy of the CardioDetect med card test
kit with Tnt as the standard.
Our date showed that serum H-FABP has sensitivity of
100% and a specificity of 85.7%. The mean time from the
onset on chest pain and extraction of whole blood for I IFABP was 6.38 and that of Tnl was 7.51 hours. Analysis of
the release kinetics of H-FABP revealed that it is released
within 2 hours of s y mptom onset, reaches its peak
concentration within 4-6 hours and returns to its normal basal
levels by 20 hours. "The l-l-FABP appear to he a stable
protein, exhibiting an intracellular turnover with a half-life
of approximately 2 to 3 da y s. In this study it has been shown
that within 6-7 hours after symptom onset, the sensitivity of
H-FABP itt the diagnosis of AM I is 100", o with a specificity
of 85.7% Similarly, in a study by Senio et al., in patients
within 3 hours of symptom onset, sensitivit y and specificity
levels for I1-FABP were 100% and 63% respectively. A stud
by Alhashemi et al., also showed that at more than 4 hours
but 12 hours or less in duration, the sensitivity of
CardioDetect was 100'o Furthermore, the ROC value of
0.929 indicates that I l-FABP is a good and accurate test in
the diagnosis of AMI I 1-FAI3P testing by cardiodetect has
been approved as a diagnostic marker for ACS in European
countries such as German y, France, Italy, Sweden and Finland.
Presently it still awaits US FDA approval.
Unlike the findings of the stud y of Suzuki et al.., which
showed that a positive I l-FABP is an independent predictor
of adverse events within 30 days from the acute event, this
study was not able to prove the prognostic value of HFABP because of the short follow up
CONCLUSION:
The qualitative whole blood rapid lI-FABP test is a useful
and accurate test in the early evaluation of patients with
suspected AMI. It offers the advantage of earlier release and
detection compared to the standard Troponin 1.
REFERENCES
1. Shamiri M,\, Chaudhry K. \rafah M, Owais M, Bashir M,
Human Heart-Type Cytoplasmic Fatty Acid Binding Protein
for the Diagnosis of Acute M yocardial Infarction. Clinical
Evaluation of JI-FABP in Comparison to CK-2\1B and cTn-L
2.Alhashemi JA Diagnostic Accurac y of a Bedside .Qualitalive
Immwiochromatographic Test for Acute Myocardial Infarction.
Ame,ican Journal of Emergent) , Medicine (2006) 24. 149-155.
3. Glatz JFC, Van der Vussc GJ. and Ilerrnens \V Fatty Acidbinding Protein as the Earliest Available Plasma Marker of Acute
'Myocardial Injurv.Journa/eif CiinicalL.egandAxiiy 2002; 25: 167 177.
4. Chan CPY Sanderson JE. Glata j FC, Cheng WS, I lempel ;\,
Renneberg' R. A superior early myocardial infarction marker,
Zeitschnliji'r Kareiiologie 2004; 1 -10.
5.
6.
199, 111:292-294.
7.
8.
9.
10.
STUDY LIMITATIONS
The study was limited b y the small population because
of the limited number of I l-FABP kits. Unlike the other
studies on I l-FABP wherein serial examinations were done,
Ili this stud y there was only one determination, hence the
sensitivity and specificity were evaluated in different time
frames from the onset of chest pain. Other statistical
parameters were not evaluated because this studs' compared
a qualitative variable (II-FABP) and a quantitative variable
Troponin 1). Furthermore, its true prognostic, value was
not adequately tested because of the small sample size and
the short follow up period.
Alhadi HA and Fox KAA. Do we need additional markers of
nlyocvte necrosis. The potential value of heart fatty-acid-binding
protein. Q Med 2004-,9 7": 187- 198. Alhashemi, JA. Diagnostic
accurac y of a bedside qualitative immunochromatographic test
for acute myocardial infarction. Auietcan Journal ojEmirtencJ!
Medicine 2006; 24:149-155.
Glaix jF, Van der Vusse Gj, \Iaessen JG, Ct al. Fatty AcidBinding Protein as Marker of Muscle In jury: Experimental
Finding and Clinical Application. :\cta .-\nacsthcsiol Scand Stipp.
11.
Suzuki M. 1-Ion S. Noma S. and Kobayashi K. Prognostic Value
of a Qualitative 1st for Heart- typeFatt y Acid-Binding Protein
in Patients with Acute Chest Pain: Comparison with Rapid
Iroponin T and Mvoglobin Tests. J/ie America,; Journal of
Medicine August 2003; 115:185-190.
Seino V. Ogata KI . Takano T, Ishu 1, 1 lishida 1-I, et al. Use of
a Whole Blood Rapid Panel Test for Heart-Type Fatt y AcidBinding Protein in Patients with Acute Chest Pain: Comparison
with Rapid Troponin T and Mvoglobiri Test. TheAim'iicanjwirnal
of Medicine August 2003; 115:185-190.
1 Ida K, Nagao K, Uchi anna . 1, Kushiro .1., Relationship
between Heart-Type Fatly Acid-Binding Protein Levels and the
Risk of Death in Patients with Serious Condition on Arrival at
the Emergency Department Internal Medicine Vol 44. No. 10
(October 2005).
Cavils U, Coskun F. Yavuz B, Cifti 0, Sahiner L, ci al heartType, Fatty-Acid Binding Protein Can Be a Diagnostic Marker in
Acute Coronary S y ndromes. Journal of the National Medical
AssociationJulv 2006; 98, 7:106- 1070.
Kiyoshi 1, Nagao K, Uchiyarna . 1. and Kushiro T, Relationship
between Heart-Type Fatty Acid-Binding Protein Levels and the
Risk of Death ill Patients with Serious Condition on Arrival at
the Emergency Department . Inierna/Medicine October 2005; 44,
10:1039-1045.
12. Maurice .\L-\, Ilermens \VT, and GlatzJFC , Fatty acid-binding
protein as plasma markers of tissue injury (.7inica (ji,imica /lcia
2005; 325:15-35.
13. Meng N, Ming M, and Wang N, I [cart fatty acid binding protein
as a marker for postmortem detection of early myocardial
damage. Forensic Science International; 160:11-16.
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