Quantitative comparison of clopidogrel 600mg, prasugrel and

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Quantitative comparison of clopidogrel 600mg, prasugrel and
International Journal of Cardiology 158 (2012) 181–185
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard
Editorial
Quantitative comparison of clopidogrel 600 mg, prasugrel and ticagrelor, against
clopidogrel 300 mg on major adverse cardiovascular events and bleeding in coronary
stenting: Synthesis of CURRENT-OASIS-7, TRITON-TIMI-38 and PLATO☆
Sukhjinder S. Nijjer ⁎, Justin E. Davies, Darrel P. Francis
International Centre for Circulatory Health, Imperial College London, North Wharf Road, London, England, UK
a r t i c l e
i n f o
Article history:
Received 13 November 2011
Accepted 17 December 2011
Available online 10 January 2012
a b s t r a c t
The convention of loading with clopidogrel 300 mg before coronary intervention may be due for change, but
to what?
Newer antiplatelet agents may offer better outcomes, at some financial cost. Disappointingly for decision-making
clinicians, head-to-head comparisons for the newer alternatives are not available. We systematically review and
compare the three alternative strategies: clopidogrel 600 mg, prasugrel and ticagrelor. A total of 14 studies have
compared these strategies with the long-standing convention of 300 mg.
Throughout this analysis, we consistently report incremental costs and consequences using clopidogrel 300 mg
as the reference strategy. Risk ratios for major adverse cardiovascular events at 30 days were 0.74 (95%
confidence interval 0.66–0.82, p = 0.002) for clopidogrel 600 mg, 0.78 (0.69–0.89; p b 0.001) for prasugrel and
0.88 (0.77–1.00; p = 0.045) for ticagrelor. All-cause mortality risk ratios were 0.87 (0.74–1.03) with clopidogrel
600 mg, 0.95 (0.78–1.16) with prasugrel and 0.78 (0.69–0.89) with ticagrelor. TIMI major bleeding has risk ratio
0.92 (0.74–1.16; p = 0.85) with clopidogrel 600 mg, 1.32 (1.03–1.16; p = 0.03) with prasugrel and 1.25 (1.03–
1.53; p = 0.03) with ticagrelor. Incremental cost for the first year was £0.32 (US$0.50, €0.40) with clopidogrel
600 mg, £608 (US$977, €709) with prasugrel and £665 (US$1068, €775) with ticagrelor.
All three strategies have shown a similar reduction in MACE at 30 days by comparison to clopidogrel 300 mg. All
three strategies offer progressive benefit, most marked with Ticagrelor. Whether this is worth both the risk of
non-compliance with twice-a-day dosing in real-life patients lacking the same motivation as their trialvolunteer counterparts, and the 2000-fold difference in incremental cost, is the remaining matter for debate.
© 2011 Elsevier Ireland Ltd. All rights reserved.
Conventional antiplatelet strategy prior to coronary intervention,
particularly in acute coronary syndrome, is to give loading doses of
clopidogrel 300 mg followed by 75 mg daily in addition to aspirin,
originated using dose-ranging studies in healthy volunteers [1]. There
are now three new competing strategies: clopidogrel 600 mg followed
by 75 mg daily, prasugrel 60 mg followed by 10 mg daily, and finally
ticagrelor 180 mg followed by 90 mg twice-a-day. Each strategy has
been compared to the conventional approach of clopidogrel 300 mg/
75 mg and not head-to-head. In this editorial, we systematically review
the literature to provide summary information on how each of these 3
☆ Statements: all three authors declare there is no relationship with industry regarding
this submission. Authorship: all three authors have contributed significantly to the
submitted work. All authors have read and approved the manuscript.
⁎ Corresponding author. Tel.: 44 207 594 3442.
E-mail address: [email protected] (S.S. Nijjer).
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2011.12.046
strategies compares with the traditional strategy. This may be
particularly important as costs may be very different.
Clopidogrel 300 mg/75 mg is potentially limited because, as a
prodrug, clopidogrel requires two-step hepatic enzyme activation so
the antiplatelet effect is only fully achieved at 24 h [2]. Wide interindividual variability in enzyme processing due to variants of the
cytochrome system has been reported but has questionable clinical
significance [3].
Clopidogrel 600 mg/75 mg could offer advantages over 300 mg/
75 mg by achieving adequate antiplatelet effect earlier and perhaps
overcoming gastrointestinal absorption issues. Observational data
and small randomised studies support the notion of improved
outcomes seen with higher loading dose strategy [4–11].
Prasugrel, a third generation thienopyridine, although still a
prodrug, requires only one-step hepatic metabolism before irreversibly
inhibiting platelets. It has proved a more potent antiplatelet agent [12].
Ticagrelor, a novel pyrimidine, targets P2Y12 receptors to cause
reversible anti-platelet inhibition without a reliance on hepatic
182
Editorial
metabolism. Plasma levels are maintained for 12 h, necessitating a
twice-a-day regimen. Compliance has been good in well-motivated
trial volunteers [13].
a statistically significant reduction in MACE at 30 days, possibly
hindered by many patients having early clopidogrel exposure [13]. A
clear reduction in MACE is seen at 1 year in both all comers and in
the subgroup undergoing invasive treatment (Table 1).
1. Systematic review
1.2. All cause mortality
1.1. MACE
Major adverse cardiovascular events at 30 days on all three new
strategies are shown in Table 1. Whilst TRITON-TIMI-38 and PLATO
report outcomes at the equivalent of 1 year, few clopidogrel 600 mg
studies do so [5,7]. The largest clopidogrel 600 mg study is
CURRENT-OASIS-7, a multi-centre trial featuring 25,086 ACS patients
intended for early PCI randomised to 600 mg loading, 150 mg up to
day 7 then 75 mg ongoing [14,15]. Outcomes were reported at
30 days; the impact of the clopidogrel 150 mg given for 6 days on
the outcome cannot be separated from impact of the initial 600 mg
loading dose. We used the angioplasty subgroup for this study,
which is aimed at assisting decision-making by interventionists.
Prasugrel was assessed by TRITON-TIMI-38, a large multi-centre ACS
study featuring 13,608 moderate-to-high risk ACS patients, randomised to prasugrel 60 mg/10 mg or clopidogrel 300 mg/10 mg once
coronary anatomy had been determined by angiography [16,17].
Ticagrelor was assessed in PLATO, a multi-centre study featuring
18,624 ACS patients randomised to ticagrelor 180 mg/90 mg bd
(twice-a-day) versus clopidogrel 300 mg/75 mg. 19.6% patients in
the clopidogrel arm and 13.7% of the ticagrelor arm had been given
clopidogrel 600–675 mg within 24 h before or after randomisation
[13,18].
Clopidogrel 600 mg showed a benefit over 300 mg loading in a total
of 28,307 patients (Table 1); meta-analysis of those patients undergoing PCI shows an OR 0.74 (0.66–0.82, p b 0.00001) in favour of 600 mg
(Fig. 1). This is similar to another meta-analysis which suggested a
24% relative risk reduction in MACE in ACS [19]. Prasugrel in TRITONTIMI-38 showed reduction in MACE at 30 days and 15 months,
predominantly driven by a reduction in type 1 and 4 myocardial
infarctions (Table 1) [17,20]. Ticagrelor in PLATO did not demonstrate
All cause mortality was assessed to avoid the impact of differing
definitions and biochemical (non-clinical) myocardial infarctions. In
28,333 patients, clopidogrel 600 mg did not give clear statistical
benefit (OR 0.87, 0.74–1.03, p = 0.10 Fig. 1B), though a trend to
benefit is seen. Death at 12 months was only reported by Choi et al.
and not by Mangiacapra et al. and therefore not meta-analysed.
TRITON-TIMI-38 found that prasugrel gave no difference in death at
15 months (HR 0.95, 0.78–1.16, p = 0.64) [17]. PLATO showed
ticagrelor reduced all cause death (ARR 1.4%, HR 0.78, 0.69–0.89,
p b 0.001) [13].
1.3. Bleeding
Bleeding rates are variably reported. We focused on the stringent
TIMI-defined major bleeding rates to avoid difficulties with noncomparable study definitions of bleeding and variable reporting of
GUSTO-bleeding. Table 2 summarises the available bleeding data
from the clopidogrel 600 mg studies, TRITON and PLATO. Bleeding
was also not statistically different between the two clopidogrel
dosing strategies (OR 0.92, 0.74–1.16, p = 0.0.49; Fig. 1C). Both
prasugrel (HR 1.32, 1.03–1.68, p = 0.03) and ticagrelor (HR 1.25,
1.03–1.53, p = 0.03) significantly increased TIMI major bleeding
(Table 2), and clopidogrel 600 mg did not.
1.4. Cost analysis and best estimates of outcome effects of the 3 strategies
Fig. 2 shows the current 3 strategies side-by-side, in the context of
the traditional 300 mg loading strategy. The point estimates of the risk
reductions from the 3 new strategies are similar (Fig. 2A). Bleeding
Table 1
Major adverse cardiovascular events (MACE) as reported in studies comparing standard clopidogrel loading (300 mg) versus alternatives, specifically clopidogrel 600 mg, prasugrel
or ticagrelor which are shown under italicized headings. ns, not stated in original publication.
Study
Alternative to standard clopidogrel
Standard clopidogrel loading (300 mg)
Total
n
%
Total
n
%
126
146
34
77
3146
73
2158
8560
12,520
109
103
1217
5
7
2
8
91
1
93
330
522
7
6
92
4
5
5.9
10.3
2.9
1.4
4.3
3.9
4.2
6.4
5.8
7.6
129
146
35
42
959
98
1153
8703
12,566
98
98
1447
15
18
4
10
50
11
81
392
557
16
15
111
Clopidogrel 600 mg, MACE at 1 year
2010
Mangiacapra et al.
2011
Choi et al.
157
1217
26
155
17
12.7
98
1447
Prasugrel
2007
6813
643
–
9.9
–
9333
864
443
569
9.8
4.8
9
Clopidogrel
2005
2006
2006
2008
2008
2008
2009
2010
2010
2010
2011
2011
600 mg, MACE at 30 days
ARMYDA-2
Cuisset et al.
ALBION (300 mg vs 600 mg)
Abuzahra et al.
Bonello et al.
Jung et al.
HORIZONS-AMI
CURRENT-OASIS 7 (PCI)
CURRENT-OASIS 7 (All)
ARMYDA-4 RELOAD
ARMYDA-6MI
Choi et al.
TRITON-TIMI-38 (15 months)
TRITON-TIMI-38 (30 days)
Ticagrelor
2009
PLATO (12 months)
PLATO (30 days)
PLATO (Invasive Only, 12 months)
6732
HR
95% CI
p value
12
12
11.4
23.8
5.2
11.2
7
4.5
4.4
16.3
15
7.7
ns
ns
ns
ns
ns
ns
ns
0.86
0.94
0.35
ns
ns
ns
ns
ns
ns
ns
ns
ns
0.74–0.99
0.83–1.06
0.12–0.96
ns
ns
0.041
0.02
ns
0.04
b 0.001
0.013
b 0.001
0.039
0.3
0.041
0.049
0.977
26
198
27
13.7
0.62
0.38–1.00
0.05
0.473
6795
781
–
12.1
–
0.81
0.78
0.73–0.90
0.69–0.89
b 0.001
b 0.001
9291
1014
502
668
11.7
5.4
10.7
0.84
0.88
0.84
0.77–0.92
0.77–1.00
0.75–0.94
b 0.001
0.045
0.0025
6676
Editorial
183
Fig. 1. Meta-analysis of (A) major adverse cardiovascular events (MACE). (B) All-cause mortality and (C) TIMI-defined major bleeding, at one month in studies assessing a loading
dose of clopidogrel 600 mg versus 300 mg in acute coronary syndromes.
complications appear to be not significantly greater for clopidogrel
600 mg but are greater for the newer agents (Fig. 2B).
In incremental cost, the strategies differ greatly. The clopidogrel
600 mg strategy adds +£0.32 (US$0.50, €0.40) over and above the
traditional loading strategy. It is typical to stop clopidogrel at 1 year
and therefore no further cost is incurred. Both prasugrel and ticagrelor
add significant additional cost over and above (+£608 (US$977,
€709) and £665 (US$1068, €775) respectively; Fig. 2C). The analysis
assumes that these agents, too, are stopped at one year: if administration continues, the cost difference widens further.
The authors of this manuscript have certified that they comply
with the Principles of Ethical Publishing in the International Journal
of Cardiology [21].
between the new strategies will be smaller than between one of them
and clopidogrel 300 mg. The likelihood that the ultimately-reported
difference may be 2 or 3 times smaller than that of the landmark trials
against 300 mg makes such trials unattractive to corporations who
hold clinical trial purse-strings. Second, to detect a difference onethird as large requires a study 9 times as large, with attendant very
large costs. Third, the large size and/or prolonged duration of such a
trial, starting from this late stage in the patent lifespan of each of
the two new drugs, would leave commercial sponsors with little or
no remaining duration of commercial monopoly. With headline
figures less superficially impressive, recruitment vastly more difficult,
and time to return investment severely curtailed, commercial trials
with these endpoints are triply unlikely.
2. Don't let patients wait for head-to-head randomised trials
3. Conclusions
It is unwise to await head-to-head trials on every question [22]:
they may not materialise for a long time, or ever. First, the difference
The three new competing strategies all have merit with reduction in
MACE compared to clopidogrel 300 mg/75 mg, at some incremental
184
Editorial
Table 2
Major bleeding events reported in studies comparing clopidogrel 600 mg loading dose, prasugrel or ticagrelor with clopidogrel 300 mg in patients with acute coronary syndromes.
TIMI — thrombolysis in myocardial infarction criteria; GUSTO-global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries. ns – not stated in
original publication.
Study
Clopidogrel 600 mg
ARMYDA-2
Cuisset et al. 2006
ALBION (300 vs 600)
ALBION (300 vs 900)
Abuzahra et al. 2008
Bonello et al. 2008
Jung et al. 2008
HORIZONS-AMI
HORIZONS-AMI
HORIZONS-AMI
CURRENT-OASIS 7 (PCI)
CURRENT-OASIS 7 (PCI)
CURRENT-OASIS 7
CURRENT-OASIS 7
ARMYDA-4 RELOAD
ARMYDA-6MI
Choi et al. 2011
Overall for TIMI
Bleeding
definition
Alternative to standard clopidogrel
Standard clopidogrel loading (300 mg)
Total
n
Total
n
%
TIMI
Study-defined
GUSTO
GUSTO
TIMI
Study-defined
Study-defined
Study-defined
TIMI
GUSTO
Study-defined
TIMI
Study-defined
TIMI
TIMI
TIMI
Study-defined
126
146
34
34
77
3146
73
2158
2158
2158
8560
8560
12,520
12,520
252
103
1217
0
0
0
0
1
24
2
132
78
78
139
81
313
210
0
2
5
129
146
35
35
42
959
98
1153
1153
1153
8703
8703
12,566
12,566
251
98
1447
0
0
0
0
1
13
1
108
53
62
99
72
255
168
0
2
6
Prasugrel
TRITON-TIMI-38 (15 months) TIMI
6813
146
Ticagrelor
PLATO (12 months)
TIMI
9333
%
2.4
221
cost and with a tendency to increased bleeding. Patients are undergoing
treatment today: interventionists cannot await head-to-head trials that
may never arrive or even begin.
The point estimates of reduction in MACE are similar in the 3 new
strategies, although that of ticagrelor is numerically the largest. This
benefit was found with a 19% of the control arm having had clopidogrel
600 mg, providing a tantalising glimmer of head-to-head comparison.
However, bleeding is significantly increased with both prasugrel and
ticagrelor. Finally, the additional financial cost is much larger for
prasugrel and ticagrelor than for clopidogrel 600 mg.
The best option may depend on circumstances. For healthcare
systems without significant budgetary limitations, and in patients
with good compliance with twice-daily medication, in whom the
significant increase in bleeding is not a concern, ticagrelor is the
best option. However, the clopidogrel 600 mg option also offers
significant reduction in MACE, requires only once-daily dosing, and
has an incremental cost smaller by a factor of 2000.
0
0
0
0
2.7
0.8
2.7
6.1
3.6
3.6
1.6
1
2.5
1.7
0
1.9
0.4
6795
2.8
[7]
[8]
[9]
[10]
[11]
[12]
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Fig. 2. A. The relative risk reduction in major adverse cardiovascular events relative to
usual care of clopidogrel 300 mg loading dose with 75 mg daily. B. The relative risk
increase or decrease for TIMI major bleeding compared to clopidogrel 300 mg loading
dose and 75 mg daily. C. Additional financial costs per year of alternative strategies
over usual care of clopidogrel 300 mg and 75 mg daily for 1 year; prices quoted in
English pounds sterling using British National Formulary quoted prices for proprietary
clopidogrel, Effient® (prasugrel) and Brilique® (ticagrelor) with equivalent prices in
US dollars ($) and Euro (€) according to the exchange rate November 2011. Error
bars show 95% confidence intervals.

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