IDPS

IDPS

The value of reducing The value of reducing blood pressure in the blood pressure in the

secondary prevention of secondary prevention of strokestroke

BackgroundBackground

IDPS

BACKGROUND:BACKGROUND: Blood pressure and secondary stroke Blood pressure and secondary stroke

incidenceincidence

4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

7575 8080 8585 9090 9595

Usual diastolic BP (mm Hg)Usual diastolic BP (mm Hg)

Relative risk Relative risk ofof

strokestroke 4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

Relative risk Relative risk ofof

strokestroke

Usual systolic BP (mm Hg)Usual systolic BP (mm Hg)

120120 130130 140140 150150 160160 170170

UKTIA 2435 patientsUKTIA 2435 patients

IDPS

Main results on stroke, Main results on stroke, cardiac events, dementia, cardiac events, dementia,

and cognitive functionand cognitive function

IDPS

AIMAIM

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 pressures at entry.

IDPS

In the past 5 years: cerebral hemorrhage

ischemic stroke

stroke of unknown type

TIA or amaurosis fugax

No major disability

No entry blood pressure criteria

Selection criteriaSelection criteria

IDPS

On top of their previous medication On top of their previous medication (including other BP-(including other BP-lowering agents)lowering agents)

ACERTIL 4 mg ACERTIL 4 mg ±± indapamide* indapamide* (2 or 2.5 mg)(2 or 2.5 mg)

Matching placebo(s)Matching placebo(s)

ACERTIL, ACERTIL ACERTIL, ACERTIL 2 mg 4 mg2 mg 4 mg

NB; mono or bi therapy at the discretion of the physician

MethodologyMethodology

IDPS

Primary Total strokeTotal stroke

Secondary Fatal or disabling stroke

Major vascular events (nonfatal stroke,

nonfatal MI, vascular death)

Dementia (DSM IV) and cognitive function

Disability and dependency

Study outcomesStudy outcomes

IDPS

Japan33

centers

Australia16 centers

New Zealand9 centers

Italy17

centers

France24

centers

Sweden23 centers

Belgium2

centers

UK and Ireland

23 centers

China26

centers

10 10 countriescountries172 centers172 centers

IDPS

Patient flowPatient flow

484 484 ineligibleineligible532 532 withdrewwithdrew

3051 3051 assigned assigned

activeactive

3054 assigned3054 assignedplaceboplacebo

61056105 patients patients randomizedrandomized

7121 pati7121 patients ents rregisteredegistered

3049 vital 3049 vital status knownstatus known

3053 vital 3053 vital status knownstatus known

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

IDPS

Demographics Female sex (%) 30 30 Age (y) 64 64 Asian ethnicity (%) 39 39

Blood pressure Systolic (mm Hg) 147 147 Diastolic (mm Hg) 86 86 Hypertension (%) 48 48

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

Baseline characteristicsBaseline characteristics

Active*Active* PlaceboPlacebo(n = 3051)(n = 3051) (n = 3054) (n = 3054)

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

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

IDPS

† SBP 160 mm Hg or DBP 90 mm HgReference: Lancet . 2001;358:1033-1041.

Characteristic

Coversyl armPlacebo

Other medical history (%)

Current smoker 20 20

Diabetes 13 12

Coronary heart disease 16 16

Blood pressure and hypertension status

Mean systolic blood pressure, mm Hg (SD)

147 (19)

147 (19)

M

ean diastolic blood pressure, mm Hg (SD)

86 (11)

86 (11)

Hypertension (%)

†

48

48

Antihypertensive therapy (%)

50

51

Baseline characteristicsBaseline characteristics

IDPS

Adherence during follow-upAdherence during follow-up

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42 48Follow-up (mo)

Ad

he

ren

ce

PlaceboActive

Average adherenceAverage adherence

Active* 87%Active* 87%

Placebo 88%Placebo 88%

PP=0.07 =0.07

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

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

IDPS

Safety and tolerabilitySafety and tolerability

ACERTIL-based therapy was very well tolerated:

Similar rate of withdrawalrate of withdrawal

• from activeactive therapy and placebo

• in hypertensivehypertensive and nonhypertensive patients

Few withdrawals for hypotension or cough

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

IDPS

Blood pressure differences Blood pressure differences All participantsAll participants

60

80

100

120

140

160

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

Follow-up (mo)

Blo

od

pre

ssu

re (

mm

Hg

)

Mean BP differenceMean BP difference

9.09.0//4.0 mm Hg4.0 mm HgActive *

Placebo

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

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

IDPS

Mean BP reductionsMean BP reductions

HypertensiveNonhypertensive

CombinationSingle drug

All participants

SBP (SE)SBP (SE) DBP (SE) DBP (SE)

9.7 (0.4) 4.0 (0.3) 8.4 (0.4) 4.1 (0.2)

11.8 (0.4) 4.8 (0.3) 5.2 (0.4) 2.8 (0.3)

9.0 (0.3) 4.0 (0.2)

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

IDPS

Results on stroke Results on stroke outcomesoutcomes

IDPS

Follow-up time (y)

Pro

port

ion

wit

h e

ven

t Placebo

Active*

0.20

0.15

0.10

0.05

0.000 1 2 3 4

28% 28% risk risk reductionreduction

95% CI 17 - 38%

PP<0.0001<0.0001

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

StrokeStrokeAll participantsAll participants

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

IDPS

Stroke severity and subtypeStroke severity and subtypeAll participantsAll participants

0.62 (0.48-0.80)

0.74 (0.61-0.90)

0.76 (0.65-0.90)

0.50 (0.33-0.74)

0.82 (0.55-1.24)

0.72 (0.62-0.83)

0.5 2.0 Hazard ratio

1.0

Strokes Active* Placebo

93

179

246

37

42

307

149

238

319

74

51

420

Favorsactive

Favorsplacebo

Hazard ratio

(95%CI)

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

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

• Fatal/disabling

• Other stroke

• Cerebral infarction

• Cerebral hemorrhage

• Stroke type unknown

• Total

IDPS

Stroke by medical historyStroke by medical historyAll participantsAll participants

Hypertensive 163 235

Not hypertensive 144 185

Diabetes 48 65

No diabetes 259 355

Cerebral infarction 236 307

Cerebral hemorrhage 28 49

TIA/amaurosis 33 49

Total 307 420

Hazard ratio(95%CI)

Hazard ratio0.5 2.01.0

Strokes Active* Placebo

Favorsactive

Favorsplacebo

0.67 (0.55-0.81)0.73 (0.58-0.92)

0.67 (0.46-0.98)0.72 (0.62-0.85)

0.76 (0.64-0.90)0.52 (0.33-0.83)0.66 (0.42-1.02)

0.72 (0.62-0.83)

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

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

IDPS

IndicationsIndications

Treatment Treatment should be consideredshould be considered for for patients with cerebrovascular disease, patients with cerebrovascular disease, irrespective ofirrespective of::

Type of stroke or TIA Initial BP (hypertensive or nonhypertensive) Other drugs and treatments Region/ ethnicity Age and gender

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

IDPS

ResultsResults onon

cardiac outcomescardiac outcomes

IDPS

Major vascular eventsMajor vascular events All participants

Hazard ratio(95%CI)

Vascular death

Nonfatal MI

Nonfatal stroke

TotalTotal

Hazard Ratio

Events Active* Placebo

Favorsactive

Favorsplacebo

0.4 1.0 2.0

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)

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

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

IDPS

Major vascular eventsMajor vascular events

Follow-up time (y)PROGRESS Coll. Group Eur Heart J. 2003 24: 475-484

1 2 3 4

*

Pro

port

ion w

ith e

vent

0.05

0.10

0.15

0.20

0.2526%26% risk reduction

(95% CI 16-33%)PP<0.0001<0.0001

PlaceboActive*

IDPS

Follow-up time (y)•Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg •(or 2 mg in Japan)

26%26% risk reduction

95% CI 6-42%PP = 0.01 = 0.0166

PlaceboActiveP

roport

ion w

ith e

vent

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)

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

IDPS

0.00

0.05

0.10

0 1 2 3 4

21% risk reduction21% risk reduction(95%CI 6-33%)P value = 0.008

Follow-up time (y)

Pro

port

ion w

ith e

vent

Placebo

Active

Total coronary eventsTotal coronary events(CHD death, nonfatal MI,

coronary revascularization, unstable angina,

IDPS

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

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

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4

Placebo

Active

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

Follow-up time (y)

Pro

port

ion

with

eve

nt

*

Reference: Eur Heart J. In press.

*

IDPS

Comments and perspectivesComments and perspectives

IDPS

Why the difference betweensingle-drug therapysingle-drug therapy (ACERTIL

alone) and combination therapycombination therapy(ACERTIL plus indapamide)?

IssueIssue

IDPS

Combination therapy (12/5 mm Hg) Combination therapy (12/5 mm Hg) and single-drug therapy (5/3 mm Hg) and single-drug therapy (5/3 mm Hg)

Hazard ratio

Combination

Single drug

Total

Combination

Single drug

TotalTotal

Stroke

Major vascular events

Events Active* Placebo

Favorsactive

Favorsplacebo

Risk reduction(95%CI)

0.5 2.01.0

150157307

231

227

458

255165420

367

237

604

43% (30 43% (30 to 54%) to 54%)

5% (-19 to 23%)5% (-19 to 23%)

28% (17 to 38%)28% (17 to 38%)

40% (29 to 49%)40% (29 to 49%)

4% (-15 to 20%)4% (-15 to 20%)

26% (16 to 26% (16 to

34%)34%)Tests for homogeneity (combination vs single drug): both < 0.001

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

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

IDPS

DemographicDemographic Female sex (%) 29 3232 Age (years)* 63 6565 Asian ethnicity (%) 38 3939

Blood pressureBlood pressure Systolic (mm Hg)* 149 144144 Diastolic (mm Hg)* 87 8484 Hypertension (%)* 54 4040

Baseline characteristicsBaseline characteristics

Combination therapyCombination therapySingle drug Single drug therapytherapy (n = 3544) (n = 3544) (n = 2561)(n = 2561)

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

IDPS

IssueIssue

• Study not designed to detectdesigned to detect

• Study not powered to detectpowered to detect / Number of

subjects too small

• Effect not proven or disproven (Wide CI)

• Differences in patients’ baseline characteristics

Why no detectable effect with ACERTIL alone?Why no detectable effect with ACERTIL alone?

IDPS

Is it safe to lower Is it safe to lower blood pressure, post-blood pressure, post-

stroke, stroke, especially in normotensive especially in normotensive

subjects?subjects?

IssueIssue

IDPS

Adherence during follow-upAdherence during follow-up

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42 48Follow-up (mo)

Ad

he

ren

ce

PlaceboActive

Average adherenceAverage adherence

Active* 87%Active* 87%

Placebo 88%Placebo 88%

PP=0.07 =0.07

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

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

IDPS

Results on Results on dementia and dementia and

cognitive decline cognitive decline outcomeoutcome

IDPS

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

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.

IDPS

Major types of dementiaMajor types of dementia

• Alzheimer’s disease Alzheimer’s disease 53.7%53.7%

• Vascular dementiaVascular dementia 15.8%15.8%11

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.

IDPS

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.

IDPS

Prevalence of vascular dementia in men Prevalence of vascular dementia in men and women in European countriesand women in European countries

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)

Cases/1

00 o

f p

op

ula

tion

IDPS

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

PROGRESS Coll Group Arch Int Med. 2003; 163:1069-1075

IDPS

DementiaDementia1. Screening

MMSE <26Questions about dementiaMMSE missing

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

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

Cognitive outcomesCognitive outcomes

Reference: Arch Int Med. In press.

IDPS

Cognitive outcomes (ctd.)Cognitive outcomes (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)

Reference: Arch Int Med. In press.

IDPS

Effect of treatment on dementiaEffect of treatment on dementia

Post-stroke

Without stroke

Dementia

Total

Events Active* Placebo

Favorsactive

Favorsplacebo

Risk reduction(95%CI)

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.

IDPS

With stroke

Without stroke

Total

48

228

276

86

248

334

45% (21 to 61%)

9% (-10 to 84%)

19% (4 to 32%)

Effect of treatment on cognitive Effect of treatment on cognitive declinedecline

Events Active* Placebo

Favorsactive

Favorsplacebo

Risk reduction(95%CI)

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.

IDPS

ConclusionConclusionConclusionConclusion

• 28%28% reduction in the all strokes

• 50% 50% reduction in the risk of hemorrhagic stroke

• 25%25% reduction in the risk of cerebral ischemia

Reference: Lancet . 2001;358:1033-1041

IDPS

• 26%26% reduction in the risk of major cardiovascular events

• 26%26% reduction in the risk of major coronary events

• 33%33% reduction in myocardial infarction

• All benefits achieved against a background of standard care that included antiplatelet and antihypertensive therapy

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

ConclusionConclusionConclusionConclusion

IDPS

Recommendations for initiationRecommendations for initiation

Acute strokeAcute strokeInitiate treatment at the time of discharge orpost-discharge follow up

History of stroke or TIAHistory of stroke or TIAPrimary care physician to initiate treatment at the patient’s next visit

IDPS

ACERTIL offers optimal ACERTIL offers optimal

cardiovascular protectioncardiovascular protection

in all hypertensive patientsin all hypertensive patients