progress perindopril protection against recurrent stroke study progress collaborative group...

PROGRESS

PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE

STUDY

PROGRESS Collaborative Group

Institute for International Health

www.ilh.org/progress

PROGRESS. Lancet 2001;358:1033-41.PROGRESS. Lancet 2001;358:1033-41.

Global burden of stroke

5 million stroke deaths each year 2nd leading cause of death worldwide >15 million non-fatal strokes each year >50 million stroke/TIA survivors alive 1 in 5 survivors suffer another stroke

within 5 years

Secondary prevention of stroke

For patients with ischaemic stroke or TIA Antiplatelet therapy Carotid endartarectomy for patients with

symptomatic carotid stenosis Anticoagulant therapy for patients with atrial

fibrillation

For patients with haemorrhagic stroke No proven treatment

Lancet 2001: Randomised trial of perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient sheamic attack Progress Collaborative Group. Lancet 2001;358:1033-41

PROGRESS

Aim

To determine the balance of benefits and risks conferred by an ACE inhibitor (perindopril) based blood pressure lowering regimen among patients with a history of cerebrovascular disease and a wide range of blood pressure at entry


Cerebral blood flow autoregulation Cerebral blood flow autoregulation during chronic hypertensionduring chronic hypertension

2001000

50

100

Hypertension

Normotension

Cerebral blood flow(mL/min/100 g)

Mean arterial pressure (mm Hg)

Perindopril does not reduce cerebral Perindopril does not reduce cerebral blood flow after a strokeblood flow after a stroke11

Dyker AG et al. Stroke. 1997;28:580-583.

Significant BP control No adverse effect on cerebral blood flow

Time since administration of drug

Diastolic blood pressure

110110

100100

9090

8080

7070

mm

Hg

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 2424

HoursC

m/s

ec

Mean flow velocity (middle cerebral artery)

00 11 22 33 44 55 66 77 88 99 101011111212 2424 22

Time since administration of drug

6060

4040

2020

00Hours Weeks

Perindopril 4 mg

Placebo

Perindopril maintains ICA flow in stroke Perindopril maintains ICA flow in stroke patients with carotid occlusionpatients with carotid occlusion

Lees KR et al. Stroke. 2001;32:473-478.

ICA flow maintained

24h

-30

-20

-10

0

10

20

30

40

50

BS 2.5h 5.5h 7.5h 14dChang

e f

rom

BS

(%

)

Perindopril 4 mg

Placebo

MABP reduced

P=0.017

2.5h 5.5h 7.5h 24h 14dBS

MA

BP (

mm

Hg

)

Perindopril 4 mg is safe to initiate Perindopril 4 mg is safe to initiate

in stroke patientsin stroke patients

Perindopril 4 mg is safe to initiate Perindopril 4 mg is safe to initiate

in stroke patientsin stroke patients

Design

Investigator initiated and conducted Randomised, placebo controlled 4-week open run-in phase on active

perindopril before randomisation Central, computer based randomisation 4 years double-blind treatment

- Recruitment began 1996

- Follow-up ended 2001


PROGRESS Collaborative GroupPROGRESS Collaborative Group

Japan33 centers

Australia16 centers

New Zealand9 centers

Italy17 centers

France24 centers

Sweden23 centers

Belgium2 centers

UK and Ireland23 centers

China26 centers

10 countries172 centers

Patients

In past five years:

- cerebral haemorrhage

- ischaemic stroke

- stroke of unknown type

- TIA or amaurosis fugax No major disability No entry blood pressure criteria


Double blind treatments

Perindopril (4mg) plus indapamide* (2.5mg)

or Matching placebo(s) Against a background of standard care,

including other blood pressure lowering therapy

*unless definite indication or contraindication to diuretic


Trial Profile

7121 patientsregistered

6105 patientsrandomised

484 ineligible532 withdrew

3051 assigned active

3054 assigned placebo

3049 vital status known

3053 vital status known


Study outcomes

Primary

- Total stroke Secondary

- Fatal or disabling stroke

- Major vascular events (non-fatal stroke, non fatal MI, vascular death)

- Dementia (DSM IV) & cognitive function

- Disability and dependency


Baseline characteristics

DemographicFemale sex (%) 30 30Age (years) 64 64 Blood pressureSystolic (mmHg) 147 147Diastolic (mmHg) 86 86Hypertension (%) 48 48

Cerebrovascular historyCerebral haemorrhage (%) 11 11Cerebral infarction (%) 71 71Stroke type unknown (%) 4 5TIA/amaurosis fugax (%) 23 23

Active (n=3051) Placebo (n=3054)


Adherence during follow-up All participants

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42 48

Follow-up (mo)

Ad

he

ren

ce

PlaceboActive

Average adherenceActive* 87%Placebo 88%P=0.07

* Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan)

Reference: Lancet. 2001;358:1033-1041.

Blood pressure differencesAll participants

activeplacebo


0

20

40

60

80

100

120

140

160

B R 1 3 6 9 12 18 24 30 36 42 48 54

Month of follow up

Blo

od

pre

ssu

re (

mm

Hg

)

Mean BP difference

9.0/4.0 mmHg

StrokeAll participants

placebo

active

0 1 2 3 4

Follow up time (years)

Pro

port

ion

with

eve

nt

0.2

0.15

0.1

0.05

28% risk reduction

95%CI 17-38%

p<0.0001


Stroke by medical historyAll participants

Strokes Favours Favours Hazard ratioActive Placebo active placebo (95%CI)

Hypertensive 163 235 0.67 (0.55-0.81)

Not hypertensive 144 185 0.78 (0.63-0.97)

Diabetes 48 65 0.67 (0.46-0.98)

No diabetes 259 355 0.72 (0.62-0.85)

Cerebral infarction 236 307 0.76 (0.64-0.90)

Cerebral haemor. 28 49 0.52 (0.33-0.83)

TIA/amaurosis 33 49 0.66 (0.42-1.02)

Total 307 420 0.72 (0.62-0.83)

0.5 1.0 2.0 Hazard ratio


Stroke by Baseline Blood PressureActive:perindopril 4mg -indapamide 2,5 mg

0.4 1.0 2.0 Hazard ratio

Eventsactive placebo

Favoursactive

Favoursplacebo

Hazard ratio(95% CI)

SBP > 160SBP 140-159SBP <140

57 10654 8739 62

DBP > 95DBP 85-94DBP < 85

27 68 65 99 58 88

150 255Total

0.53 (0.38-0.73)0.59 (0.42-0.84)0.61 (0.41-0.91)

0.38 (0.24-0.59)0.64 (0.47-0.88)0.63 (0.45-0.88

0.57 (0.46-0.70)


Results on cardiac outcomeResults on cardiac outcome

Follow-up time (y)

Pro

port

ion

with

eve

nt

0.05

0.10

0.15

0.20

0.25

1 2 3 4

26% risk reduction(95% CI 16-33%)

P<0.0001

Placebo

Active

Major vascular events

PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.

Major vascular events All participants

Events Active Placebo

Favorsactive

Favorsplacebo

Hazard ratio(95%CI)

Vascular death

Nonfatal MI

Nonfatal stroke

Total

0.4 1.0 2.0Hazard Ratio

181

60

275

458

198

96

380

604

0.91 (0.75-1.12)

0.62 (0.45-0.86)

0.71 (0.61-0.83)

0.74 (0.66-0.84)

PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.

26% risk reduction95% CI 6-42%P value = 0.016

Placebo

Active

Follow-up time (y)

Pro

port

ion

with

eve

nt

0.01

0.02

0.03

0.04

0.05

0.06

1 2 3 4

Major coronary eventsMajor coronary events(CHD death or nonfatal myocardial infarction)(CHD death or nonfatal myocardial infarction)

Eur Heart J 2003: 24:475-84.Eur Heart J 2003: 24:475-84.

Heart failureHeart failure(Death, hospitalization, or discontinuation)(Death, hospitalization, or discontinuation)

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4

Placebo

Active

26% risk reduction(95%CI 5-42%)P value = 0.01

Follow-up time (y)

Pro

port

ion

with

eve

nt

Eur Heart J 2003: 24:475-84.Eur Heart J 2003: 24:475-84.

Other anti-HT drug

No anti-HT drug

Aspirin or other AP

No antiplatelet drug

Total

Events Active Placebo

Favorsactive

Favorsplacebo

229

229

347

111

458

333

271

430

174

604

33% (20 to 43%)

19% (4 to 32%)

23% (11 to 33%)

36% (19 to 50%)

26% (16 to 34%)

0.5 2.0Hazard ratio

1.0

Risk reduction(95%CI)

Major vascular eventsMajor vascular events by treatment at baselineby treatment at baseline

Stroke 2004; 35: 116-121Stroke 2004; 35: 116-121

Results on dementia and cognitive Results on dementia and cognitive decline outcomedecline outcome

Results on dementia and cognitive Results on dementia and cognitive decline outcomedecline outcome

Stroke and dementiaStroke and dementia

Stroke is the leading cause of disability in adults1

Cerebrovascular disease is the second most common cause of dementia2

Vascular dementia is one of the rare preventable dementias3

One sixth of stroke patients have previous dementia4

1. Barba R et al. Previous and incident dementia as risk factors for mortality in stroke patients. Stroke. 2002;33:1993-1998.2. Leys D et al. Epidemiology of vascular dementia. Hemostasis. 1998;28:134-150.3. Hachinski V. Preventable senility: a call for action against the vascular dementias. Lancet. 1992;340:654-648.4. Barba R et al. Prestroke dementia. Cerebrosvasc Dis. 2001;11:216-224.

Major types of dementiaMajor types of dementia

Alzheimer’s disease 53.7% Vascular dementia 15.8%1

– single or multiple infarcts2

– small-vessel disease2 – hypoperfusion2

– hemorrhage2

1. Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9.2. Gold G. Les démences vasculaires. Med Hyg. 2002;60:1165-1167.

The cumulative incidence of The cumulative incidence of dementia after strokedementia after stroke

0

5

10

15

20

25

Incidence of dementia (%)

7%

10%

15%

23%

Timel (y)1 3 5 10

Incident of stroke increase the risk of dementia by 140%

Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9.

Prevalence of vascular dementia in men Prevalence of vascular dementia in men and women in Europeanand women in European countriescountries

Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9.

0

2

4

6

65-69 70-74 75-79 80-84 85-89 90+

WomenMen

Age (y)

Cas

es/1

00 o

f p

op

ula

tio

n

Risk factors for vascular dementiaRisk factors for vascular dementia

Hypertension

Cigarette-smoking

Diabetes mellitus

Atrial fibrillation

Cardiac disease

Carotid stenosis

Hyperlipidemia

Antihypertensive treatment reduces Antihypertensive treatment reduces

the incidence of dementiathe incidence of dementia11

1. Forette F et al. Lancet. 1998;352:1347-1351.

1000 hypertensivepatients treated

for 5 years

19 cases of dementiaprevented

MSBP

173.4 MSBP

151.7Dementia

21 casesDementia

11 cases

P<0.001

P<0.05

2222ApoE4 allele carrier (%)

1515MMSE < 26 (%)

29 (27-30)29 (27-30)Median MMSE score

3939Asian (%)

3030Female (%)

64 (10)64 (10)Age, y (SD)

Baseline characteristicsBaseline characteristics

Active Placebo(n = 3051) (n = 3054)

• 6105 patients with stroke or TIA• FU 3.9 years• MMSE / Screening for dementia each year

Reference: Arch Int Med. In press.

Dementia

1. ScreeningMMSE <26Questions about dementiaMMSE missing

2. DiagnosisSpecialist in each center; DSM-IV criteriaDiagnosis reviewed centrally

Cognitive decline = drop of 3pts or more of MMSE during FU

Cognitive outcomesCognitive outcomes


Cognitive outcomesCognitive outcomes (ctd.) (ctd.)

Dementia– 1580 patients screened positive during FU

– Expert assessment for 98%

– 410 patients demented

– 108 preceded by a recurrent stroke

Cognitive decline

610 patients (25 per 1000 PY)


Effect of treatment on dementiaEffect of treatment on dementia

Dementia

Post-stroke

Without stroke

Total

Events Active* Placebo

Favorsactive

Favorsplacebo


43

150

193

65

152

217

34% (3 to 55%)

1% (-24 to 22%)

12% (-8 to 28%)

0.5 2.0 Odds ratio

1.0

* Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan)Reference: Arch Int Med. In press.

With stroke

Without stroke

Total

Events Active* Placebo

Favorsactive

Favorsplacebo


48

228

276

86

248

334

45% (21 to 61%)

9% (-10 to 84%)

19% (4 to 32%)

Effect of treatment on cognitive declineEffect of treatment on cognitive decline

Cognitive decline

0.5 2.0 Odds ratio

1.0

* Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan)Reference: Arch Int Med. In press.

Barthel scale – activities of daily living

Results on Disability

4 year treatment result in avoidance of 1 case of long term disability for every 30 (95%CI, 19 to 79) patients

Stroke 2003; 34: 2333-2338Stroke 2003; 34: 2333-2338Active : perindopril 4 mg ± indapamide 2,5 mg

PROGRESS establishes the benefits of perindopril-based therapy among patients with cerebrovascular disease for the prevention of: Stroke Coronary heart disease Congestive heart failure Total major vascular events Cognitive decline Disability

Summary of Benefits

RRR CVA/TIA RRR major coronary events

NNT om 1 CV event te voor-komen in 5 jaar

Onderzoek

Aspirine 23% 17% 57 ATC1

Perindopril + indapamide

43% 35% 11 PROGRESS2

Simvastatine2 2% (NS) 23% 32 HPS3

1.1. Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86

2.2. PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84

3.3. HPS. Lancet 2004:363;757-67HPS. Lancet 2004:363;757-67

Evidence based prevention in patients with history of cerebrovascular disease

sticares

sticares

EUROPA is the only study to examine the effect of an ACE inhibitor in all patients with coronary artery disease irrespective of cardiac function and irrespective of the presence or absence of a high risk profile for CADIn this long-term trial of approx 4 years trial the effect of perindopril on cardiovasular mortality and/or non-fatal MI and/or cardiac arrest with successful resuscitation is studied.

Cardiac protection partly BP-independent

Risk reduction

Coronary events

Expected 16% 1

BP-reduction

(10-12 / 5-6 mmHg)

PROGRESS 35%2

BP-reduction

(10-12 / 5-6 mmHg)

1 Collins R et al. Lancet 1990;335:827-38, Expected on diuretic and beta-blocker regime1 Collins R et al. Lancet 1990;335:827-38, Expected on diuretic and beta-blocker regime2. PROGRESS Coll. Eur Heart J (2003) 24, 475-842. PROGRESS Coll. Eur Heart J (2003) 24, 475-84

12.218 patientswith stable coronary artery disease

(no heart failure)Treated with perindopril or placebo

EUROPA. Lancet 2003; 362: 782-788.EUROPA. Lancet 2003; 362: 782-788.

Primary endpoint

% CV death, MI or cardiac arrest% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebo

p = 0.0003p = 0.0003

RRR: 20%RRR: 20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55


Blood pressure reduction alone cannot explain

perindopril’s effects in EUROPA

perindoprilperindoprilplaceboplacebo

RRR 20%RRR 20% RRR 18%RRR 18%

SBP decreaseSBP decreaseduring run-in during run-in

No SBP decreaseNo SBP decreaseduring run-induring run-in

0%

2%

4%

6%

8%

10%

12%

42634263

43034303

18411841

18041804

Incidence ofprimary events

EUROPA. Presented ESC 2004.EUROPA. Presented ESC 2004.

Summary of results

In EUROPA, the largest and longest trial in stableIn EUROPA, the largest and longest trial in stable

documented CAD patients, perindopril 8 mg/ddocumented CAD patients, perindopril 8 mg/d

significantly reduced:significantly reduced:

CV mortality + non fatal MI + cardiac arrest:CV mortality + non fatal MI + cardiac arrest: 20%20% CV mortality and non fatal MI:CV mortality and non fatal MI: 19%19% Fatal + non fatal MI:Fatal + non fatal MI: 24%24% Heart failure:Heart failure: 39%39%


Summary of results

Benefits with perindopril:Benefits with perindopril:

occurred on top of recommended therapy occurred on top of recommended therapy (platelet inhibitors, lipid lowering drugs, (platelet inhibitors, lipid lowering drugs, -blockers)-blockers)

consistent across predefined sub-groupsconsistent across predefined sub-groups

“Perindopril should be considered for chronic

therapy in all patients with coronary disease”

EUROPA investigators: The Lancet 2003


EUROPA and PROGRESS :

Consistent resultsConsistent results

Clear benefits for the many Clear benefits for the many

(hypertensive) patients with established (hypertensive) patients with established

cerebrovascular and/or coronary diseasecerebrovascular and/or coronary disease


References

• PROGRESS. Lancet 2001;358:1033-41. PROGRESS. Lancet 2001;358:1033-41. Stroke 2003; 34: 2333-2338. Stroke 2003; 34: 2333-2338. Eur Heart J 2003: Eur Heart J 2003: 24:475-84. Arch Intern Med 2003; 162: 1069-1075. Stroke 2004; 35: 116-211. 24:475-84. Arch Intern Med 2003; 162: 1069-1075. Stroke 2004; 35: 116-211.

• EUROPA. Lancet 2003; 362: 782-788.EUROPA. Lancet 2003; 362: 782-788.

• Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86

• HPS. Lancet 2004:363;757-67HPS. Lancet 2004:363;757-67

progress perindopril protection against recurrent stroke study progress collaborative group...

Documents

based bloodpressure

stroke deaths

previous stroke

stroke patientslancet

cerebral blood flowtime

active perindopril

wide range of blood

ace inhibitor perindopril