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

Copyleft Clinical Trial Results. You Must Redistribute Slides

PRoFESS® TrialPRoFESS® Trial

Prevention Regimen For Prevention Regimen For Effectively avoiding Second Effectively avoiding Second

Strokes (PRoFESSStrokes (PRoFESS®®))

PRoFESSPRoFESS®® Trial TrialPRoFESSPRoFESS®® Trial Trial

Presented at the 17Presented at the 17thth European Stroke European Stroke Conference (ESC) in Nice, FranceConference (ESC) in Nice, France

Presented by Dr. Ralph Sacco, Dr. Salim Presented by Dr. Ralph Sacco, Dr. Salim Yusuf, Dr. Hans-Christof Diener Yusuf, Dr. Hans-Christof Diener

PRoFESS® Trial Trial



PRoFESS® Trial: Background Trial: BackgroundPRoFESS® Trial: Background Trial: Background

• Elevated blood pressure is a significant risk factor for stroke and Elevated blood pressure is a significant risk factor for stroke and recurrent stroke.recurrent stroke.

• The ESP2 trial showed that extended-release dipyridamle (ER-DP) + The ESP2 trial showed that extended-release dipyridamle (ER-DP) + Aspirin combination therapy is beneficial in the reduction of secondary Aspirin combination therapy is beneficial in the reduction of secondary strokes. strokes.

• The PRoFESSThe PRoFESS®® trial aimed to 1) show that aspirin combined with ER- trial aimed to 1) show that aspirin combined with ER-DP is superior to Clopidogrel in preventing stroke recurrence and 2) DP is superior to Clopidogrel in preventing stroke recurrence and 2) evaluate the relationship between blood pressure lowering and stroke evaluate the relationship between blood pressure lowering and stroke recurrence via treatment with Telmisartan vs. placebo.recurrence via treatment with Telmisartan vs. placebo.

Cerebrovascular Dis. 2007; 23/ESC 2008Cerebrovascular Dis. 2007; 23/ESC 2008

ER-DP + AspirinER-DP + Aspirin+ +

TelmisartanTelmisartan

n= 5,000n= 5,000

PRoFESS® Trial: Study Design Trial: Study DesignPRoFESS® Trial: Study Design Trial: Study Design

Clopidogrel Clopidogrel ++

TelmisartanTelmisartan

n= 5,000n= 5,000

ER-DP + AspirinER-DP + Aspirin++

PlaceboPlacebo

n=5,000n=5,000

20,332 patients 20,332 patients >> 50 years with at least ischemic stroke* (see inclusion criteria) 50 years with at least ischemic stroke* (see inclusion criteria) Double-blind. Placebo-controlled. Simultaneous randomization.Double-blind. Placebo-controlled. Simultaneous randomization.

Doses: (200 mg ER-DP + 25 mg Aspirin) 2x/day, 80 mg Telmisartan, 75 mg Clopidogrel 1x/dayDoses: (200 mg ER-DP + 25 mg Aspirin) 2x/day, 80 mg Telmisartan, 75 mg Clopidogrel 1x/day

Primary Endpoint: rate of first recurrent strokePrimary Endpoint: rate of first recurrent stroke Secondary Endpoints: stroke, MI, vascular death, rate of new diabetes mellitusSecondary Endpoints: stroke, MI, vascular death, rate of new diabetes mellitus Tertiary Endpoints: major hemorrhagic event, all deaths, new or worsening Tertiary Endpoints: major hemorrhagic event, all deaths, new or worsening

congestive heart failurecongestive heart failure

2.5 yrs. mean follow-up2.5 yrs. mean follow-up

RR


Clopidogrel Clopidogrel + +

PlaceboPlacebo

n=5,000n=5,000


PRoFESS® Trial: Inclusion Criteria Trial: Inclusion CriteriaPRoFESS® Trial: Inclusion Criteria 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 50-54 years and/or 90-120 with stroke and at least 2 of the Age 50-54 years and/or 90-120 with stroke and at least 2 of the following risk factors:following risk factors:

– Vascular disease (stroke, MI, or peripheral artery disease) prior to Vascular disease (stroke, MI, or peripheral artery disease) prior to qualifying strokequalifying stroke

– Hypertension (SBP ≥ 140 or DBP ≥ 90 mm Hg)Hypertension (SBP ≥ 140 or DBP ≥ 90 mm Hg)

– Diabetes mellitusDiabetes mellitus

– Obesity (BMI > 30) Obesity (BMI > 30)

– Smoker at time of qualifying strokeSmoker at time of qualifying stroke

– End-organ damage (retinopathy, left-ventricular hypertrophy, or End-organ damage (retinopathy, left-ventricular hypertrophy, or microalbuminuria)microalbuminuria)

• Neurologically and clinically stableNeurologically and clinically stable

Cerebrovascular Dis. 2007; 23/ESC 2008Cerebrovascular Dis. 2007; 23/ESC 2008Copyleft Clinical Trial Results. You Must Redistribute Slides

PRoFESS® Trial: Exclusion Criteria Trial: Exclusion CriteriaPRoFESS® Trial: Exclusion Criteria 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 Required or planned continued treatment with antithrombotics or anticoagulantsor anticoagulants

Cerebrovascular Dis. 2007; 23/ESC 2008Cerebrovascular Dis. 2007; 23/ESC 2008Copyleft Clinical Trial Results. You Must Redistribute Slides

CharacteristicCharacteristic

Mean ageMean age 66.1 66.1 8.6 8.6 yrsyrs

FemaleFemale 36.0%36.0%

Median time from index event to randomizationMedian time from index event to randomization 15 days15 days

Patients randomized within 10 daysPatients randomized within 10 days 39.9%39.9%

PRoFESS® Trial: Baseline Characteristics Trial: Baseline CharacteristicsPRoFESS® Trial: Baseline Characteristics Trial: Baseline Characteristics

Copyleft Clinical Trial Results. You Must Redistribute Slides Cerebrovascular Dis. 2007; 23/ESC 2008Cerebrovascular Dis. 2007; 23/ESC 2008

Ethnic GroupEthnic Group %%

European/CaucasianEuropean/Caucasian 57.357.3

ChineseChinese 18.018.0

South AsianSouth Asian 8.48.4

JapaneseJapanese 1.11.1

MalayMalay 0.60.6

Other AsianOther Asian 4.64.6



Ethnic GroupEthnic Group %%

Black African/African AmericanBlack African/African American 4.04.0

Native LatinNative Latin 4.54.5

Caribbean/HispanicCaribbean/Hispanic 0.30.3

Arab, PersianArab, Persian 0.20.2

OtherOther 0.80.8



Modified Rankin ScaleModified Rankin Scale %%

No symptoms at all (0)No symptoms at all (0) 14.114.1

No significant disability (1)No significant disability (1) 37.337.3

Slight disability (2)Slight disability (2) 25.025.0

Moderate-severe disability (3-5)Moderate-severe disability (3-5) 23.723.7



TOASTTOAST %%

Large-artery atherosclerosisLarge-artery atherosclerosis 28.528.5

CardioembolismCardioembolism 1.81.8

Small-artery occlusionSmall-artery occlusion 52.152.1

Other determined aetiologyOther determined aetiology 2.02.0

Undetermined aetiologyUndetermined aetiology 15.515.5



Medical HistoryMedical History %%

HypertensionHypertension 73.873.8

Diabetes mellitusDiabetes mellitus 28.128.1

HyperlipidemiaHyperlipidemia 46.646.6

Ischemic coronary artery diseaseIschemic coronary artery disease 16.216.2

Previous MIPrevious MI 6.76.7

Congestive heart failureCongestive heart failure 2.62.6

Atrial fibrillationAtrial fibrillation 2.62.6



Medical HistoryMedical History %%

Valve diseaseValve disease 1.71.7

Prior TIAPrior TIA 8.68.6

Previous stroke (before index event)Previous stroke (before index event) 18.318.3

Occlusive peripheral arterial diseaseOcclusive peripheral arterial disease 2.92.9

Deep vein thrombosisDeep vein thrombosis 1.51.5



Risk FactorRisk Factor %%

Current smokerCurrent smoker 21.221.2

Former smokerFormer smoker 36.236.2

Regular alcohol consumer (> 1 drink/week)Regular alcohol consumer (> 1 drink/week) 35.435.4



Concomitant MedicationConcomitant Medication %%

ACE inhibitorsACE inhibitors 36.836.8

StatinsStatins 47.247.2

FibratesFibrates 1.71.7

Calcium channel blockersCalcium channel blockers 24.224.2

ARBsARBs 5.25.2

BetablockersBetablockers 20.720.7



Concomitant MedicationConcomitant Medication %%

Loop diureticsLoop diuretics 3.23.2

Thiazide diureticsThiazide diuretics 17.117.1

Potassium-sparing diureticsPotassium-sparing diuretics 1.51.5

InsulinInsulin 5.65.6

Oral hypoglycemic drugsOral hypoglycemic drugs 18.618.6



Physical Physical ExaminationExamination

Mean blood pressureMean blood pressure 144/84 mm Hg144/84 mm Hg

Mean body mass indexMean body mass index 26.826.8

Mean waist circumferenceMean waist circumference 96.6 cm96.6 cm



*n = 20,332 for all baseline values*n = 20,332 for all baseline values


Mini Mental State Examination classMini Mental State Examination class %%

< 25< 25 17.417.4

25-2725-27 21.121.1

2828 13.313.3

2929 19.119.1

3030 29.129.1



9.0% 8.8%

0%

5%

10%

ER-DP + Aspirin Clopidogrel

• The rate of first The rate of first recurrent stroke was recurrent stroke was similar between the similar between the combination therapy combination therapy and the single and the single antiplatelet agent antiplatelet agent treatment groups.treatment groups.

• HR 1.01HR 1.01

• 95% CI 0.92-1.1195% CI 0.92-1.11 Str

oke

recu

rren

ce (

%)

Str

oke

recu

rren

ce (

%)

PRoFESS® Trial: Primary Endpoint Trial: Primary EndpointPRoFESS® Trial: Primary Endpoint Trial: Primary Endpoint

n = 10,000n = 10,000 n = 10,000n = 10,000

p = 0.783 p = 0.783


PRoFESS® Trial: Primary Endpoint Trial: Primary Endpoint

Type of first recurrent Type of first recurrent strokestroke

ER-DP + AspirinER-DP + Aspirin(n = 10,000)(n = 10,000)

ClopidogrelClopidogrel (n = 10,000)(n = 10,000)

Ischemic, no. (%)Ischemic, no. (%) 780 (7.7)780 (7.7) 805 (7.9)805 (7.9)

Hemorrhagic, no. (%)Hemorrhagic, no. (%) 83 (0.8)83 (0.8) 45 (0.4)45 (0.4)

Other/unknown, no. (%)Other/unknown, no. (%) 52 (0.5)52 (0.5) 48 (0.5)48 (0.5)



8.7% 9.2%

0%

5%

10%

Telmisartan Placebo

• Telmisartan Telmisartan demonstrated no demonstrated no significant benefit over significant benefit over placebo in the rate of placebo in the rate of recurrent stroke.recurrent stroke.

• Lowering blood pressure Lowering blood pressure with Telmisartan for 2.5 with Telmisartan for 2.5 years after a stroke does years after a stroke does not significantly reduce not significantly reduce the rate of stroke. the rate of stroke.

• HR 0.95HR 0.95

• 95% CI 0.86-1.0495% CI 0.86-1.04

Str

oke

recu

rren

ce (

%)

Str

oke

recu

rren

ce (

%)

PRoFESS® Trial: Primary Endpoint Trial: Primary EndpointPRoFESS® Trial: Primary Endpoint Trial: Primary Endpoint

n = 10,000n = 10,000 n = 10,000n = 10,000

p = 0.23 p = 0.23



3.4% 3.2%

0%

1%

2%

3%

4%

5%

Telmisartan Placebo

• There was no There was no significant difference significant difference in the rates of in the rates of recurrent stroke recurrent stroke between the between the Telmisartan and Telmisartan and placebo groups in the placebo groups in the first 6 months of the first 6 months of the trial. trial.

• HR 1.07HR 1.07

• 95% CI 0.92-1.2595% CI 0.92-1.25

Str

oke

recu

rren

ce (

%)

Str

oke

recu

rren

ce (

%)

PRoFESS® Trial: Primary Endpoint Exploratory Trial: Primary Endpoint Exploratory AnalysisAnalysis


n = 10,000n = 10,000 n = 10,000n = 10,000

p = 0.38 p = 0.38



5.3%6.0%

0%1%2%3%4%5%6%

Telmisartan Placebo

• Beyond 6 months, Beyond 6 months, Telmisartan was Telmisartan was associated with a associated with a lower stroke lower stroke recurrence rate.recurrence rate.

• HR 0.88HR 0.88

• 95% CI 0.78-0.9995% CI 0.78-0.99

Str

oke

recu

rren

ce (

%)

Str

oke

recu

rren

ce (

%)



n = 10,000n = 10,000 n = 10,000n = 10,000

p = 0.029 p = 0.029



PRoFESS® Trial: Secondary Endpoint Trial: Secondary Endpoint PRoFESS® Trial: Secondary Endpoint Trial: Secondary Endpoint

• There was no There was no difference in the rate difference in the rate of secondary of secondary endpoint between endpoint between the two groups.the two groups.

• HR 0.99HR 0.99

• 95% CI 0.92-1.0795% CI 0.92-1.07

13.1% 13.1%

0%

3%

6%

9%

12%

15%

Str

oke,

MI o

r va

scul

ar d

eath

(%

)S

trok

e, M

I or

vasc

ular

dea

th (

%) p = 0.83 p = 0.83

n = 10,000n = 10,000 n = 10,000n = 10,000

ClopidogrelClopidogrelER-DP + AspirinER-DP + Aspirin




• There was no There was no significant difference significant difference in the occurrence of in the occurrence of major vascular major vascular events (stroke, MI, events (stroke, MI, vascular death, new vascular death, new or worsening heart or worsening heart failure) between the failure) between the two groups.two groups.

• HR 0.94HR 0.94

• 95% CI 0.87-1.0195% CI 0.87-1.01

13.5%14.4%

0%

3%

6%

9%

12%

15%

Maj

or v

ascu

lar

even

ts

(%)

Maj

or v

ascu

lar

even

ts

(%)

p = 0.11p = 0.11

n = 10,000n = 10,000 n = 10,000n = 10,000

PlaceboPlaceboTelmisartanTelmisartan




• There was no There was no significant difference significant difference in the rate of new in the rate of new diabetes mellitus diabetes mellitus between the two between the two groups.groups.

• HR 0.82HR 0.82

• 95% CI 0.65-1.0495% CI 0.65-1.04

1.3%1.5%

0%

1%

2%

Rat

e of

new

dia

bete

s m

ellit

us

(%)

Rat

e of

new

dia

bete

s m

ellit

us

(%)

p = 0.10p = 0.10

n = 10,000n = 10,000 n = 10,000n = 10,000




PRoFESS® Trial: Secondary Endpoint Exploratory Trial: Secondary Endpoint Exploratory AnalysisAnalysis


• There was no There was no significant difference significant difference in the occurrence of in the occurrence of major vascular major vascular events between the events between the two groups during two groups during the first 6 months of the first 6 months of the the trial.the the trial.

• HR 1.10HR 1.10

• 95% CI 0.97-1.2695% CI 0.97-1.26

4.7%4.3%

0%

1%

2%

3%

4%

5%

Rat

e of

maj

or v

ascu

lar

even

t (

%)

Rat

e of

maj

or v

ascu

lar

even

t (

%)

p = 0.14p = 0.14

n = 10,000n = 10,000 n = 10,000n = 10,000






• Beyond 6 months, Beyond 6 months, the rate of major the rate of major vascular events was vascular events was lower in the lower in the Telmisartan group. Telmisartan group.

• HR 0.87HR 0.87

• 95% CI 0.80-0.9595% CI 0.80-0.95

8.8%10.1%

0%

3%

6%

9%

12%

Rat

e of

maj

or v

ascu

lar

even

t (

%)

Rat

e of

maj

or v

ascu

lar

even

t (

%)

p = 0.0029p = 0.0029

n = 10,000n = 10,000 n = 10,000n = 10,000




PRoFESS® Trial: 2º and 3º Outcomes Trial: 2º and 3º Outcomes

End pointEnd pointER-DP + AspirinER-DP + Aspirin

(n = 10,000)(n = 10,000)No. (%)No. (%)

ClopidogrelClopidogrel (n = 10,000)(n = 10,000)

No. (%)No. (%)

Hazard ratio Hazard ratio (95% CI)(95% CI)

PP

MIMI 178 (1.7)178 (1.7) 197 (1.9)197 (1.9) 0.90 (0.73-1.10)0.90 (0.73-1.10) 0.28460.2846

DeathDeath 739 (7.3)739 (7.3) 756 (7.4)756 (7.4) 0.97 (0.87-1.07)0.97 (0.87-1.07) 0.51120.5112

New or worsening CHFNew or worsening CHF 144 (1.4)144 (1.4) 182 (1.8)182 (1.8) 0.78 (0.62-0.96)0.78 (0.62-0.96) 0.0220.022

Major hemorrhagic Major hemorrhagic eventevent 419 (4.1)419 (4.1) 365 (3.6)365 (3.6) 1.15 (1.00-1.32)1.15 (1.00-1.32) 0.0570.057

Life-threatening Life-threatening hemorrhagic eventhemorrhagic event 128 (1.3)128 (1.3) 116 (1.1)116 (1.1) -- --



PRoFESS® Trial: Benefit/Risk Analysis Trial: Benefit/Risk Analysis PRoFESS® Trial: Benefit/Risk Analysis Trial: Benefit/Risk Analysis

• There was no There was no significant difference significant difference in the benefit-risk in the benefit-risk ratio between the ratio between the two groups.two groups.

• HR 1.03HR 1.03

• 95% CI 0.95-1.1195% CI 0.95-1.11

11.7% 11.4%

0%

5%

10%

15%

Str

oke

recu

rren

ce o

r m

ajor

hem

orrh

age

(%)

Str

oke

recu

rren

ce o

r m

ajor

hem

orrh

age

(%)

p = 0.50p = 0.50

n = 10,000n = 10,000 n = 10,000n = 10,000

ClopidogrelClopidogrelER-DP + AspirinER-DP + Aspirin



PRoFESS® Trial: LimitationsTrial: LimitationsPRoFESS® Trial: LimitationsTrial: Limitations

The duration of follow up should be The duration of follow up should be extended for an accurate assessment of extended for an accurate assessment of the long term effects of both the blood the long term effects of both the blood pressure lowering and antiplatelet pressure lowering and antiplatelet therapies on the rate of recurrent stroke.therapies on the rate of recurrent stroke.



PRoFESS® Trial: Summary Trial: SummaryPRoFESS® Trial: Summary Trial: Summary

• ER-DP/Aspirin combination therapy is not ER-DP/Aspirin combination therapy is not superior to Clopidogrel in reducing stroke superior to Clopidogrel in reducing stroke recurrence rate. recurrence rate.

• Lowering blood pressure for 2.5 years after a Lowering blood pressure for 2.5 years after a stroke does not significantly reduce the rate stroke does not significantly reduce the rate of recurrent stroke or other major vascular of recurrent stroke or other major vascular events compared to placebo.events compared to placebo.


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