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RationaleRationale for RA for RAAAS blockade S blockade in in
– Telmisartan added to standard antiplatelet therapy versus standard antiplatelet therapy alone
– ER-DP + ASA* compared with Clopidogrel
► Diuretic, -blocker and/or calcium channel blocker as needed to control blood pressure
► Treatment period up to 4 years
► The world’s largest secondary stroke prevention trial
– 15,500 patients at around 600 centres in 32 countries
* Extended-release dipyridamole + aspirin
Study design – 2 x 2 factorial
Clopidogrel (75 mg) qd
Extended-release dipyridamole (200 mg)
+ ASA (25 mg) bid
Telmisartan (80 mg) qd Placebo qd
n = 7,750n = 7,750TOTAL
n = 15,500
Telmisartan+
ER-DP + ASA
n = 3,875
Telmisartan+
ER-DP + ASA
n = 3,875
Placebo+
ER-DP + ASA
n = 3,875
Placebo+
ER-DP + ASA
n = 3,875
Telmisartan+
Clopidogrel
n = 3,875
Telmisartan+
Clopidogrel
n = 3,875
Placebo+
Clopidogrel
n = 3,875
Placebo+
Clopidogrel
n = 3,875
ER-DP = Extended-release dipyridamole
Telmisartan summary
► An effective antihypertensive
► With once-daily morning dosing, provides efficacy even in the risky, early morning hours due to long duration of action
► Provides long-acting, insurmountable blockade of AT1 receptor
– Associated with target-organ protection
► Crosses the blood–brain barrier
ER-DP + ASA*
► 6,602 patients with transient ischaemic attack or stroke within preceding 3 months
► Treated for 2 years with either:
– Placebo
– ASA (50 mg daily) alone
– ER-DP (400 mg daily) alone
– Combination ER-DP + ASA
► 2 x 2 factorial design
► Primary endpoints: stroke, death and stroke/death composite
Diener et al. J Neurological Sci 1996;143:1–13.
European Stroke Prevention Study 2 (ESPS-2)
* Extended-release dipyridamole + aspirin
ER-DP + ASA*
► ER-DP+ASA is twice as effective for secondary stroke prevention as either ASA or ER-DP alone
Diener et al. J Neurological Sci 1996;143:1–13.
ER-DP + ASA vs Placebo 37.0% <0.001
ER-DP vs Placebo 16.3% 0.039
ASA vs Placebo 18.1% 0.013
ER-DP + ASA vs ASA 23.1% 0.006
European Stroke Prevention Study 2 (ESPS-2)
Pairwise comparisons Relative risk p valuereduction
* Extended-release dipyridamole + aspirin
Antiplatelet summary
► Extended-release dipyridamole, Clopidogrel and ASA have complementary mechanisms of action
► The combination of ER-DP plus ASA is more effective than the components in preventing second stroke
► Adding ASA to Clopidogrel increases the risk of adverse events without increasing efficacy
Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
Inclusion criteria
► Age ≥55 years AND ischaemic stroke within 90 days prior to study entry
OR
► Age >50 years AND ischaemic stroke within 120 days prior to study entry AND at least two of the following risk factors:
– Diabetes mellitus– Hypertension (SBP 140 or DBP 90 mmHg)– Smoker at time of qualifying stroke– Obesity (BMI >30)– Vascular damage (stroke, myocardial infarction, or peripheral artery
disease) prior to qualifying stroke– End-organ damage (retinopathy, left-ventricular hypertrophy or
microalbuminuria).
Main exclusion criteria
► Haemorrhagic stroke
► Unstable angina
► Patients bedridden, with dementia or unable to give informed consent
► Carotid endarterectomy
► History of thrombocytopenia
Primary and secondary outcomes
Primary outcome
► Time to recurrent stroke (target is 2,280 strokes)
Secondary outcomes
► Vascular events
– composite of time to first stroke, myocardial infarction or vascular death
► Vascular events or congestive heart failure
► New-onset diabetes
Tertiary outcomes
► Stroke or major haemorrhagic event
► Major haemorrhagic events
► Minor haemorrhagic events
► Other designated vascular events
► Death
► New or worsening congestive heart failure
► Thrombotic thrombocytopenic purpura
► Neutropenia
Patient follow-up
► Baseline visit and on discharge from hospital or Day 7 (whichever soonest)
► Visits at Month 1, Month 3 and Month 6
► Visits every 6 months thereafter
► Telephone contact every 3 months
Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
Global trial
Europe17 countries
Africa and Middle East2 countries
Asia8 countries
South America1 country
North America3 countries
Australia
32 countries, 600 study centres
Academicrepresentatives
Sponsorrepresentatives
(non-voting)
Sponsor
DSMB
Adjudication &AssessmentCommitteeEurope
CML/NCEuropeCML/NC
North Am.CML/NC
North Am.CML/NC
South Am.CML/NC
South Am.CML/NC
AfricaCML/NCAfricaCML/NC
AsiaCML/NCAsia
CML/NC
Steering Committee
Trial Management Committee
Publications Committee
DSMB = Data and Safety Monitoring Board; CML = Local Clinical Monitor for country; NC = National Co-ordinator for country
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Study organization
Telmisartan
Beyondblood pressure
2003–2006 2007 and beyond
Protection inProtection inthe early the early
morning/24-hour morning/24-hour efficacyefficacy
Life saving
Efficacy vs Efficacy vs ACE inhibitorsACE inhibitors
and other ARBsand other ARBs
Heart Heart protection/protection/
LVH reductionLVH reduction
Renoprotection Renoprotection in diabeticsin diabetics
Antihypertensive Antihypertensive efficacy in efficacy in
special patient special patient populationspopulations
Phase III and IV programme rationale
Major Phase IV trials of Telmisartan
In high-risk individuals
Blood pressure
Stroke endpoint
15,500 patients for up to 4 years
History of stroke
Normo- and hypertensives
Stroke is the primary endpoint
31,546 patients for up to 5.5 years
History of stroke or recent ischaemic attack, coronary artery disease, peripheral vascular disease, diabetes mellitus with target-organ damage
Normo- and hypertensives
Stroke is part of the primary combined endpoint
Outcome trials of Telmisartan
Enrollment by country
Country N Country N Country N
Argentina 534 Hong Kong 250 South Africa 79
Australia 276 India 1620 South Korea 626
Austria 277 Ireland 30 Spain 130
Belgium 418 Israel 449 Sweden 503
Brazil 300 Italy 419 Taiwan 926
Canada 1549 Japan 210 Thailand 219
China 2130 Malaysia 112 The Netherlands 485
Denmark 231 Mexico 222 Turkey 62
Finland 216 Norway 152 UK 502
France 125 Portugal 280 Ukraine 560
Germany 1287 Russia 1353 USA 3408
Greece 30 Singapore 363
Total number of Countries or Regions = 35 (20 in ESA)
Total number of Randomized Patients = 20,333
PRoFESS Enrollment - Italy
PRoFESS EnrollmentCountry = Italy
Goal N=660 in two yearsReduced goal N=400 by 31 March 2006
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Nu
mb
er o
f P
atie
nts
Italy
Italy Original Projection
Italy Adapted Projection
Italy Projection with Extended Enrollment
419 pts
Enrollment End = 31 May 2006
Goal 400
Thank You!!
.. to all our investigators and study coordinators
060717
Our goal of 20,000 patients from 720 sites in 35 countries was achieved 2 days early.
How does PRoFESS compare with similar antiplatelet trials?