News from GARFIELD - Thrombosis Research Institute

News from GARFIELD:
Vital Real-World Insights into
Blood Clot Management
ESC Congress 2013
Amsterdam
3 September 2013
www.tri-london.ac.uk
News from GARFIELD:
Vital Real-World Insights into
Blood Clot Management
Professor the Lord Kakkar
Thrombosis Research Institute and University
College London, UK
www.tri-london.ac.uk
Disclosures
Research Support/P.I.
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai
Employee
N/A
Consultant
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai,
Novartis, Adventrix, Daiichi Sankyo, Shire
Major Stockholder
N/A
Speakers Bureau
N/A
Honoraria
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai, GSK
Scientific Advisory Board
Bayer HealthCare, Sanofi-Aventis, Boehringer
Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai,
Novartis, Daiichi Sankyo
www.tri-london.ac.uk
VTE: incidence and clinical impact
• EU member states
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640,000 symptomatic deep vein thromboses (DVT)
383,000 pulmonary emboli (PE)
VTE-related deaths were estimated at 480,000 annually:
• 34,450 (7%) diagnosed with VTE and treated
• 163,050 (34%) estimated to be sudden fatal PE
• 281,000 (59%) followed undetected PE

UK: annual death rate from VTE is estimated just over 0.1% i.e.
60,000 deaths annually in the UK(3)
• United States
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Up to 900,000 VTEs annually(1)
3rd most common CV illness after ACS and stroke(2)
Around 300,000 deaths annually
• Uncertainty persists on VTE incidence and burden
1. Heit JA. The epidemiology of VTE in the community. Arter Tromb Vasc Biol. 2008: 28:370-372,
2. Goldhaber SZ. Pulmonary embolism thrombolysis: A clarion call for international collaboration. J Am
Coll Cardiol. 1992, 19: (2): 246-247.
3. McManus RA, Fitzmaurice D, Murray E, et al; Thromboembolism. Clin Evid . 2009 Mar 9; 2009.
We still have unanswered questions in this
disease area
•
Focus in RCTs is safety, efficacy, type of treatment,
certain HEOR aspects
• Practical treatment aspects can not be answered in
RCTs
• Treatment duration in RCTs is defined, however it is
known that persistence in a real life setting can be
low
• RCTs show treatment regimens seem to be shorter
than recommended guidelines
• Real-world clinical data is needed to confirm this
dynamic and understand why this occurs
www.tri-london.ac.uk
The Treatment of Venous Thrombosis:
A Need for Real-World Evidence
Professor Jeffrey Weitz
McMaster University, Ontario, Canada
www.tri-london.ac.uk
Disclosures
• Dr. Weitz has served as a consultant and has
received honoraria from Boehringer-Ingelheim,
Bayer, Janssen, BMS, Pfizer, Merck, Daiichi
Sankyo, and Portola
www.tri-london.ac.uk
Burden of Venous Thromboembolism
Common disease (1-2 cases per 1000 persons)
Incidence increases with age
Recurrence rate of 30% at 10 years
www.tri-london.ac.uk
Impact of Venous Thromboembolism
• In patients with pulmonary embolism, up to
– 25% present with sudden death
– 15-20% die within 3 months
• In patients with deep-vein thrombosis, up to
– 60% develop post-thrombotic syndrome
– 3-4% develop venous ulcers at 10-20 years
www.tri-london.ac.uk
Venous Thromboembolism recurrence
• Up to 25% of VTEs occur in patients with previous VTE
• Estimated cumulative risk of recurrence in unprovoked VTE
– 10% at 1 year
– 15-20 % at 3 years
– 25% at 5 and 30% at 10 years
• Morbidity and mortality increase with recurrence
– Recurrent PE is associated with a 15% mortality rate
– Recurrent DVT carries about 2% mortality rate (1, 2)
1. Frederick A. Spencer. JAMA and Archives Journals (2008, February 25). Patients who develop blood
clots at risk of recurrence within three years.
2. Dorothy M. Adcock. Recurrence of thromboembolism: determining risk. Clinical Haemostasis Review;
Vol 19: 1, 2005.
Venous Thromboembolism complications:
Post-thrombotic syndrome
• Despite progress in DVT diagnosis and treatment,
PTS incidence is 20-60% within 1-2 years (4, 5)
• PTS has a substantial impact on Quality of Life
(QoL)
• PTS represents a substantial economic burden
• Despite substantial morbidity arising from PTS,
prevention is hindered by lack of attention and
limitations of available therapeutic options for
preventing and treating PTS (12)
4. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic
syndrome. Arch Intern Med 2004; 164: 17-26.
5. Ashrani AA, Heit JA. Incidence and cost burden of PTS. J Thromb Thromolysis 2009; 28: 465-476.
12. Raymond LW. Getting a leg up on the postthrombotic syndrome. Chest 2003; 123:327-330.
Venous Thromboembolism complications:
Chronic thromboembolic pulmonary hypertension
• The incidence of CTPH is not well documented
• Prospective 2 year follow-up data show:
– Cumulative incidence of symptomatic CTPH of 1% at 6
months, 3.1% at one year, and 3.8% at two years
– Circulatory/respiratory-related patient-month costs are
$2,496 (24)
18. Vittorio Pengo et al. N Engl J Med; 2004: 350: 2257-2264.
24. Noam Y. Kirson et al. Chest October 2010 vol. 138 no. 4 supp 375A.
(18)
Venous Thromboembolism: Implications for
therapy
• Appropriate thromboprophylaxis is critical
• Well-controlled anticoagulation for the
appropriate duration is essential for patients with
established venous thromboembolism
• Prophylaxis and treatment are simplified with
new oral anticoagulants
www.tri-london.ac.uk
The Price of Venous Thrombosis and
Cost-Effectiveness of Blood Clot Management
Dr Lorenzo Mantovani
University of Naples Federico II, Italy
www.tri-london.ac.uk
Disclosures
• Research funding from
– Bayer Research, Pfizer, and BMS (in the field of
Thrombosis) and Bayer, Boehringer- Ingelheim
(outside the field of Thrombosis)
• Speaker’s fees from
– BMS Boehringer-Ingelheim (In the field of
Thrombosis), Pfizer (outside the field of Thrombosis)
• Advisory Board fees from
– Bayer, Daiichi Sankyo (in the field of Thrombosis) and
Pfizer (outside the field of Thrombosis)
www.tri-london.ac.uk
Clinical significance
• Pulmonary embolism has a high fatality rate:
– 4.2% in hospital
– 13.8% at 90 days after hospital discharge
• 25.7% of patients recently hospitalized before
pulmonary embolism diagnosis
• Hospitalization costs associated with treating
pulmonary embolism average $8764 per patient
www.tri-london.ac.uk
Patient demographics are related to economic
costs
www.tri-london.ac.uk
Economic costs (1)
www.tri-london.ac.uk
Economic costs (2)
www.tri-london.ac.uk
Economic costs (3)
• 25,000 annual deaths in England
from hospital-contracted VTE
– More than breast cancer, AIDS and road
traffic accidents combined
– More than 25x deaths from MRSA
• UK annual cost of post-surgical
VTE £204.7-£222.8 million
– Office of Healthcare Economics, 1993
• Total direct and indirect costs of
VTE management £640 million
– House of Commons Health Select Committee, 2005
www.tri-london.ac.uk
Cost Effectiveness of Prevention
www.tri-london.ac.uk
Cost Effectiveness of Treatment
www.tri-london.ac.uk
Conclusions and the future
• VTEs are costly events, affecting people predominantly in
their working age
• Effective and safe prevention of VTE is dominant or costeffective
• Effective and safe treatment of VTE and prevention of
recurrent DVT/PE is dominant or cost effective
• (Prospective) Evidence generation on
– Treatment variability and organizational issues
– Patients’ relevant outcomes, including HRQoL and indirect
costs
www.tri-london.ac.uk
Arterial Thrombosis Management:
Insights from GARFIELD-AF
Professor Alexander G. G. Turpie
McMaster University, Hamilton, ON, Canada
www.tri-london.ac.uk
Disclosures
• Research Support
None
• Employee
None
• Consultant and/or Honoraria
Bayer HealthCare, Boehringer-Ingelheim, Bristol-Myers
Squibb, Johnson and Johnson, Sanofi-Aventis, Takeda, Portola
• Stockholder
None
• Speakers Bureau
Pfizer, GSK
• Scientific Advisory Board
Bayer HealthCare, Johnson and Johnson,
www.tri-london.ac.uk
Atrial fibrillation:
The most common cardiac dysrhythmia
Atrial
fibrillation
www.tri-london.ac.uk
GARFIELD context:
The burden of stroke in atrial fibrillation
Stroke is responsible for 10%
of deaths worldwide
Non-valvular AF is responsible
for 50% of cardioembolic stroke
www.tri-london.ac.uk
GARFIELD context:
The atrial fibrillation treatment paradox
Anticoagulation reduces stroke
risk for patients with AF
Anticoagulation is consistently
under-utilised in patients with AF
% VKA
www.tri-london.ac.uk
GARFIELD context:
Developments in the field of anticoagulation
NOAC superior
www.tri-london.ac.uk
Warfarin superior
GARFIELD mission:
Describing and clarifying AF and anticoagulation
GARFIELD will enhance understanding of the burden of
thromboembolic stroke and identify opportunities for the
incorporation of innovations designed to improve safety,
outcomes and utilization of healthcare resources.
Its unique design and methodology will provide representative,
real-world insights, and will clarify AF treatments and outcomes
for patients, clinicians and healthcare providers as they evolve
over time.
GARFIELD will be governed by the highest academic and ethical
standards in the generation, dissemination, and communication
of its research findings.
www.tri-london.ac.uk
GARFIELD methodology:
Novel approach to outcomes research
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Independent academic research initiative
34 countries
Sites representative of national AF care settings
Randomized site selection
5 sequential prospective cohorts
55,000 patients with AF
Newly-diagnosed patients
Unselected eligible patients enrolled consecutively
Long-term follow-up (minimum of 2 years)
Extensive monitoring (20% of CRFs)
www.tri-london.ac.uk
GARFIELD methodology:
Representative investigators randomly selected to participate
Sites representative of national AF care settings
• Network of National Coordinating Investigators
• Site list selected according to distribution of AF care settings in each
country
Randomized site selection
• Sites from each section of national care setting distribution randomly
selected to participate
www.tri-london.ac.uk
GARFIELD methodology:
Unselected, prospective patients enrolled consecutively
Inclusion criteria
• Males and females aged 18 years and over
• Written informed consent
• New diagnosis of non-valvular atrial fibrillation (diagnosed within the
last 6 weeks) with at least one additional investigator-determined
risk factor for stroke
Non-inclusion criteria
• No further follow-up envisaged or possible
• Transient AF secondary to a reversible cause
• Recruited in a controlled clinical trials
www.tri-london.ac.uk
GARFIELD success:
Representation of global AF population
Current status:
Cohort 1
Cohort 2 & 3
25000
20000
First data presented:
10,618 patients describing the
end of the VKA-only era
11,707 prospective patients
recruited in 30 countries
First patient in:
December 2009
5000
Cohort 2 complete:
Baseline data describing
global treatment patterns
15000
10000
Cohort 1 complete:
24,000 patients
Preliminary follow-up data:
Cohort 3 initiation:
First description of outcomes
according to treatment
More than 220 prospective
patients enrolled per week
Patients 0
www.tri-london.ac.uk
GARFIELD insights from Cohort 1:
New guidelines, new treatments, old problems
Antithrombotic treatment
according to CHA2DS2-VASc score
Preliminary outcomes at 12
months according to treatment
www.tri-london.ac.uk
Closing remarks
GARFIELD investigator network represents AF
care as it is provided throughout individual
healthcare systems
GARFIELD patient population describes
representative AF treatment and outcomes in
everyday clinical practice
www.tri-london.ac.uk
Announcing What’s Next:
The Future of GARFIELD
Professor the Lord Kakkar
Thrombosis Research Institute and University
College London, UK
www.tri-london.ac.uk
GARFIELD VTE: Global prospective registry
• 10,000 patients
• 25 countries
• Purpose:
– To explore acute and long term management and
outcomes in patients with symptomatic VTEs, treated
in a real-world setting
www.tri-london.ac.uk
Funding
The GARFIELD VTE Registry is supported by an
unrestricted research grant from Bayer HealthCare
www.tri-london.ac.uk
GARFIELD VTE: Logistics
• Global Scientific Steering Committee members:
– Walter Ageno (Italy), Pantep Angchaisuksiri (Thailand), Henri
Bounameaux (Switzerland), Joern Dalsgaard-Nielsen (Denmark),
Martin Van Eickels (Germany), Samuel Goldhaber (US), Sylvia
Haas (Germany), Ajay Kakkar (UK), Lorenzo Mantovani (Italy),
Frank Misselwitz (Germany), Paolo Prandoni (Italy), Sebastian
Schellong (Germany), Alexander Turpie (Canada), Jeff Weitz
(Canada)
• Timelines:
– FPI Q1/2014
– LPFV Q2/2015
– LPLV Q2/2018
www.tri-london.ac.uk
GARFIELD VTE: Study Objectives
• Treatment duration
• Adherence to guidelines
• Difference between compounds
• Reasons for treatment cessation (both Patient and Health Care
Professional)
• Incidence of complications
• VTE recurrence, CTEPH, PTS, major bleeding, other bleeding,
Cardiovascular events, mortality
• Practical aspects
• Switching from and to novel anticoagulants
• Bleeding management
• HEOR
• Health care resource use
• PROMs
www.tri-london.ac.uk
GARFIELD VTE - Design
Patients with acute
VTE and indication
for anticoagulation
Patients treated with standard therapy
or direct oral anticoagulants
Duration of treatment according to
physician’s decision
N=10,000
Baseline Visit (day 1):
Baseline demographics
Underlying diseases
Current episode of VTE
Follow up visits on treatment (quarterly):
Efficacy/Safety
HEOR
Incidence of complications
Practical treatment aspects
Follow up visits after end of treatment (2x year): Incidence of complications
www.tri-london.ac.uk
Follow-up for 36
months from
VTE diagnosis
(irrespective of
therapy duration)
GARFIELD VTE: Endpoints (1/3)
• Symptomatic venous thromboembolic events
including DVT, non-fatal and fatal PE
• Prevalence and severity of post thrombotic
syndrome (PTS, Villalta Scale)
• Prevalence and severity of chronic
thromboembolic pulmonary hypertension
(CTPH)
www.tri-london.ac.uk
GARFIELD VTE: Endpoints (2/3)
• Cerebrovascular events defined as stroke including
– Primary ischaemic stroke
– Primary intracerebral haemorrhage
– Secondary haemorrhagic ischaemic stroke
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•
•
•
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Transient ischemic attacks (TIAs)
Systemic embolisation
Acute coronary syndromes
All cause mortality
Bleeding events
– Frequency
– Location
– Severity
www.tri-london.ac.uk
GARFIELD VTE: Endpoints (3/3)
• Therapy persistence (rate of discontinuation, duration of
time on therapy, reasons for discontinuation)
• Hospitalisation (inpatient, outpatient, and emergency
room)
• Need for urgent venous and arterial revascularization
• Days of working time lost / productivity lost
• QoL (VEINES-QoL questionnaire)
• For patients treated with VKA additionally:
– Frequency and timing of monitoring required in maintaining
therapeutic anticoagulation
– INR recordings in relation to therapeutic range
– Outcomes in relation to INR fluctuation
www.tri-london.ac.uk
GARFIELD VTE: Unique Methodology
• Global prospective registry
– Minimum 10,000 patients
– 25 countries
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500 randomly selected representative sites
Sites will enrol consecutive eligible patients
Follow up of minimum 3 years
Long term prospective review of recurrent VTE,
PTS, CTPH, bleeding
www.tri-london.ac.uk
Can new oral anticoagulants address this
challenge?
• Address a true clinical need?
 High risk populations
• Achieve meaningful clinical outcomes?
 Mortality impact
• Demonstrate consistent safety?
 Bleeding/non-bleeding
• Ensure maximum utility?
 Persistence and adherence
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