Copyleft Clinical Trial Results. You Must Redistribute Slides PRoFESS ® Trial Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS ® )

PRoFESS ® Trial Presented at the 17 th European Stroke Conference (ESC) in Nice, France Presented by Dr. Ralph Sacco, Dr. Salim Yusuf, Dr. Hans-Christof Diener Trial PRoFESS ® Trial Copyleft Clinical Trial Results. You Must Redistribute Slides

Trial: Background PRoFESS ® Trial: Background Elevated blood pressure is a significant risk factor for stroke and recurrent stroke.Elevated blood pressure is a significant risk factor for stroke and recurrent stroke. The ESP2 trial showed that extended-release dipyridamle (ER-DP) + Aspirin combination therapy is beneficial in the reduction of secondary strokes.The ESP2 trial showed that extended-release dipyridamle (ER-DP) + Aspirin combination therapy is beneficial in the reduction of secondary strokes. The PRoFESS ® trial aimed to 1) show that aspirin combined with ER- DP is superior to Clopidogrel in preventing stroke recurrence and 2) evaluate the relationship between blood pressure lowering and stroke recurrence via treatment with Telmisartan vs. placebo.The PRoFESS ® trial aimed to 1) show that aspirin combined with ER- DP is superior to Clopidogrel in preventing stroke recurrence and 2) evaluate the relationship between blood pressure lowering and stroke recurrence via treatment with Telmisartan vs. placebo. Cerebrovascular Dis. 2007; 23/ESC 2008

ER-DP + Aspirin +Telmisartan n= 5,000 Trial: Study Design PRoFESS ® Trial: Study Design Clopidogrel+ Telmisartan Telmisartan n= 5,000 ER-DP + Aspirin +Placebon=5,000 20,332 patients > 50 years with at least ischemic stroke* (see inclusion criteria) Double-blind. Placebo-controlled. Simultaneous randomization. Doses: (200 mg ER-DP + 25 mg Aspirin) 2x/day, 80 mg Telmisartan, 75 mg Clopidogrel 1x/day  Primary Endpoint: rate of first recurrent stroke  Secondary Endpoints: stroke, MI, vascular death, rate of new diabetes mellitus  Tertiary Endpoints: major hemorrhagic event, all deaths, new or worsening congestive heart failure 2.5 yrs. mean follow-up 2.5 yrs. mean follow-up R Copyleft Clinical Trial Results. You Must Redistribute Slides Clopidogrel+Placebon=5,000 Cerebrovascular Dis. 2007; 23/ESC 2008

Trial: Inclusion Criteria PRoFESS ® Trial: Inclusion Criteria Age ≥ 55 years and ischemic stroke within 90 days prior to study entryAge ≥ 55 years and ischemic stroke within 90 days prior to study entry Age years and/or with stroke and at least 2 of the following risk factors:Age years and/or with stroke and at least 2 of the following risk factors: –Vascular disease (stroke, MI, or peripheral artery disease) prior to qualifying stroke –Hypertension (SBP ≥ 140 or DBP ≥ 90 mm Hg) –Diabetes mellitus –Obesity (BMI > 30) –Smoker at time of qualifying stroke –End-organ damage (retinopathy, left-ventricular hypertrophy, or microalbuminuria) Neurologically and clinically stableNeurologically and clinically stable Cerebrovascular Dis. 2007; 23/ESC 2008 Copyleft Clinical Trial Results. You Must Redistribute Slides

Trial: Exclusion Criteria PRoFESS ® Trial: Exclusion Criteria Hemorrhagic strokeHemorrhagic stroke Congestive heart failure or unstable anginaCongestive heart failure or unstable angina Pre-stroke history of dementia requiring institutional carePre-stroke history of dementia requiring institutional care Inability to give informed consentInability to give informed consent Modified Rankin Scale > 4Modified Rankin Scale > 4 Hypersensitivity to any of the study drugsHypersensitivity to any of the study drugs Hepatic and renal insufficiencyHepatic and renal insufficiency History of thrombocytopeniaHistory of thrombocytopenia Uncontrolled hypertension or ongoing treatment with an ARBUncontrolled hypertension or ongoing treatment with an ARB Required or planned continued treatment with antithrombotics or anticoagulantsRequired or planned continued treatment with antithrombotics or anticoagulants Cerebrovascular Dis. 2007; 23/ESC 2008 Copyleft Clinical Trial Results. You Must Redistribute Slides

Characteristic Mean age 66.1  8.6 yrs Female36.0% Median time from index event to randomization 15 days Patients randomized within 10 days 39.9% Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Ethnic Group %European/Caucasian57.3 Chinese18.0 South Asian 8.4 Japanese1.1 Malay0.6 Other Asian 4.6 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Ethnic Group % Black African/African American 4.0 Native Latin 4.5 Caribbean/Hispanic0.3 Arab, Persian 0.2 Other0.8 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Modified Rankin Scale % No symptoms at all (0) 14.1 No significant disability (1) 37.3 Slight disability (2) 25.0 Moderate-severe disability (3-5) 23.7 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

TOAST% Large-artery atherosclerosis 28.5 Cardioembolism1.8 Small-artery occlusion 52.1 Other determined aetiology 2.0 Undetermined aetiology 15.5 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Medical History %Hypertension73.8 Diabetes mellitus 28.1 Hyperlipidemia46.6 Ischemic coronary artery disease 16.2 Previous MI 6.7 Congestive heart failure 2.6 Atrial fibrillation 2.6 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Medical History % Valve disease 1.7 Prior TIA 8.6 Previous stroke (before index event) 18.3 Occlusive peripheral arterial disease 2.9 Deep vein thrombosis 1.5 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Risk Factor % Current smoker 21.2 Former smoker 36.2 Regular alcohol consumer (> 1 drink/week) 35.4 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Concomitant Medication % ACE inhibitors 36.8 Statins47.2 Fibrates1.7 Calcium channel blockers 24.2 ARBs5.2 Betablockers20.7 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Concomitant Medication % Loop diuretics 3.2 Thiazide diuretics 17.1 Potassium-sparing diuretics 1.5 Insulin5.6 Oral hypoglycemic drugs 18.6 Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Physical Examination Physical Examination Mean blood pressure 144/84 mm Hg Mean body mass index 26.8 Mean waist circumference 96.6 cm Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides *n = 20,332 for all baseline values Cerebrovascular Dis. 2007; 23/ESC 2008

Mini Mental State Examination class % < Trial: Baseline Characteristics PRoFESS ® Trial: Baseline Characteristics Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

The rate of first recurrent stroke was similar between the combination therapy and the single antiplatelet agent treatment groups.The rate of first recurrent stroke was similar between the combination therapy and the single antiplatelet agent treatment groups. HR 1.01HR % CI % CI Stroke recurrence (%) Stroke recurrence (%) Trial: Primary Endpoint PRoFESS ® Trial: Primary Endpoint n = 10,000 p = Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Trial: Primary Endpoint PRoFESS ® Trial: Primary Endpoint Type of first recurrent stroke ER-DP + Aspirin (n = 10,000) Clopidogrel (n = 10,000) (n = 10,000) Ischemic, no. (%) 780 (7.7) 805 (7.9) Hemorrhagic, no. (%) 83 (0.8) 45 (0.4) Other/unknown, no. (%) 52 (0.5) 48 (0.5) Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Telmisartan demonstrated no significant benefit over placebo in the rate of recurrent stroke.Telmisartan demonstrated no significant benefit over placebo in the rate of recurrent stroke. Lowering blood pressure with Telmisartan for 2.5 years after a stroke does not significantly reduce the rate of stroke.Lowering blood pressure with Telmisartan for 2.5 years after a stroke does not significantly reduce the rate of stroke. HR 0.95HR % CI % CI Stroke recurrence (%) Stroke recurrence (%) Trial: Primary Endpoint PRoFESS ® Trial: Primary Endpoint n = 10,000 n = 10,000 p = 0.23 p = 0.23 Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides There was no significant difference in the rates of recurrent stroke between the Telmisartan and placebo groups in the first 6 months of the trial.There was no significant difference in the rates of recurrent stroke between the Telmisartan and placebo groups in the first 6 months of the trial. HR 1.07HR % CI % CI Stroke recurrence (%) Stroke recurrence (%) Trial: Primary Endpoint Exploratory Analysis PRoFESS ® Trial: Primary Endpoint Exploratory Analysis n = 10,000 n = 10,000 p = 0.38 p = 0.38 Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Beyond 6 months, Telmisartan was associated with a lower stroke recurrence rate.Beyond 6 months, Telmisartan was associated with a lower stroke recurrence rate. HR 0.88HR % CI % CI Stroke recurrence (%) Stroke recurrence (%) Trial: Primary Endpoint Exploratory Analysis PRoFESS ® Trial: Primary Endpoint Exploratory Analysis n = 10,000 n = 10,000 p = p = Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Secondary Endpoint PRoFESS ® Trial: Secondary Endpoint There was no difference in the rate of secondary endpoint between the two groups.There was no difference in the rate of secondary endpoint between the two groups. HR 0.99HR % CI % CI Stroke, MI or vascular death (%) p = 0.83 n = 10,000 Clopidogrel ER-DP + Aspirin Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Secondary Endpoint PRoFESS ® Trial: Secondary Endpoint There was no significant difference in the occurrence of major vascular events (stroke, MI, vascular death, new or worsening heart failure) between the two groups.There was no significant difference in the occurrence of major vascular events (stroke, MI, vascular death, new or worsening heart failure) between the two groups. HR 0.94HR % CI % CI Major vascular events (%) p = 0.11 n = 10,000 PlaceboTelmisartan Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Secondary Endpoint PRoFESS ® Trial: Secondary Endpoint There was no significant difference in the rate of new diabetes mellitus between the two groups.There was no significant difference in the rate of new diabetes mellitus between the two groups. HR 0.82HR % CI % CI Rate of new diabetes mellitus (%) p = 0.10 n = 10,000 PlaceboTelmisartan Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Secondary Endpoint Exploratory Analysis PRoFESS ® Trial: Secondary Endpoint Exploratory Analysis There was no significant difference in the occurrence of major vascular events between the two groups during the first 6 months of the the trial.There was no significant difference in the occurrence of major vascular events between the two groups during the first 6 months of the the trial. HR 1.10HR % CI % CI Rate of major vascular event (%) p = 0.14 n = 10,000 PlaceboTelmisartan Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Secondary Endpoint Exploratory Analysis PRoFESS ® Trial: Secondary Endpoint Exploratory Analysis Beyond 6 months, the rate of major vascular events was lower in the Telmisartan group.Beyond 6 months, the rate of major vascular events was lower in the Telmisartan group. HR 0.87HR % CI % CI Rate of major vascular event (%) p = n = 10,000 PlaceboTelmisartan Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: 2º and 3º Outcomes PRoFESS ® Trial: 2º and 3º Outcomes End point ER-DP + Aspirin (n = 10,000) No. (%) Clopidogrel (n = 10,000) (n = 10,000) No. (%) Hazard ratio (95% CI) PMI 178 (1.7) 197 (1.9) 0.90 ( ) Death 739 (7.3) 756 (7.4) 0.97 ( ) New or worsening CHF 144 (1.4) 182 (1.8) 0.78 ( ) Major hemorrhagic event 419 (4.1) 365 (3.6) 1.15 ( ) Life-threatening hemorrhagic event 128 (1.3) 116 (1.1) -- Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Benefit/Risk Analysis PRoFESS ® Trial: Benefit/Risk Analysis There was no significant difference in the benefit-risk ratio between the two groups.There was no significant difference in the benefit-risk ratio between the two groups. HR 1.03HR % CI % CI Stroke recurrence or major hemorrhage (%) p = 0.50 n = 10,000 Clopidogrel ER-DP + Aspirin Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Limitations PRoFESS ® Trial: Limitations The duration of follow up should be extended for an accurate assessment of the long term effects of both the blood pressure lowering and antiplatelet therapies on the rate of recurrent stroke. The duration of follow up should be extended for an accurate assessment of the long term effects of both the blood pressure lowering and antiplatelet therapies on the rate of recurrent stroke. Cerebrovascular Dis. 2007; 23/ESC 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides Trial: Summary PRoFESS ® Trial: Summary ER-DP/Aspirin combination therapy is not superior to Clopidogrel in reducing stroke recurrence rate.ER-DP/Aspirin combination therapy is not superior to Clopidogrel in reducing stroke recurrence rate. Lowering blood pressure for 2.5 years after a stroke does not significantly reduce the rate of recurrent stroke or other major vascular events compared to placebo.Lowering blood pressure for 2.5 years after a stroke does not significantly reduce the rate of recurrent stroke or other major vascular events compared to placebo. Cerebrovascular Dis. 2007; 23/ESC 2008