rationale for raas blockade

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Rationale Rationale for RA for RA A A S blockade S blockade in in secondary stroke prevention secondary stroke prevention P P revention revention R R egimen egimen F F or or E E ffectively avoiding ffectively avoiding S S econd econd S S trokes trokes

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Page 1: Rationale For Raas Blockade

RationaleRationale for RA for RAAAS blockade S blockade in in

secondary stroke preventionsecondary stroke prevention

RationaleRationale for RA for RAAAS blockade S blockade in in

secondary stroke preventionsecondary stroke prevention

PPrevention revention RRegimen egimen FFor or EEffectively avoiding ffectively avoiding SSecond econd SStrokestrokes

Page 2: Rationale For Raas Blockade

American Stroke Association,’06 I-A-tp dopo la fase iperacuta

I-A-efficacia diuretici ±ACE- I

II-B-tp sia ipertesi che normotesi

II-B-target tp individualizzato

(almeno riduzione 10/5 mmHg)

II-C-tener conto comorbidità

SPREAD ‘05

B – trattamento ipertesi

in fase post acuta

B – efficacia ACE- I,

Diuretici,

Ca-antagonisti

Linee guida disponibili sul trattamento antipertensivo nella prevenzione secondaria dell’ictus

Page 3: Rationale For Raas Blockade

Revisione sistematica di 7 RCT in soggetti con precedente ictus: 15527 soggetti (Rashid et al, 2003)

Studio LIFE, ’02 losartan + idroclortiazide vs atenololo+ idroclortiazide, sottogruppo 728 soggetti (segmento prev. secondaria)

Studio MOSES, ‘05 eprosartan vs nitrendipina, 1405 soggetti

►Carter, ’70 Thiazide diureticmg_methyldopa(750 mg); control 99 pts

►HSCGS, ‘74 Deserpidine 1 mg and methylclothiazide 10 mg; placebo

452 pts

►Dutch TIA, ‘93 Atenolol (50 g);placebo 1473 pts

►TEST, ‘95 Atenolol ? mg; placebo 720 pts

►PATS,’95 Indapamide (2.5 mg); placebo 5665 pts Due terzi

dei dati

riconducibili

ai trial PAT e PROGRESS

►PROGRESS, 01

Perindopril 4 mg;placebo

Perindopril 4 mg _ indapamide 2.5mg; double-placebo

2561 pts

3544 pts

►HOPE, ‘00

►segmento prev. secondaria

Ramipril; placebo 1013 pts

Fonti di informazione nella stesura delle linee guida nella prevenzione secondaria dell’ictus attraverso l’uso di antipertensivi

Page 4: Rationale For Raas Blockade

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

Page 5: Rationale For Raas Blockade

Risk factors for stroke

0 1 2 3 4 5 6 7 8 9 10

Hyperlipidaemia 27%

Smoking 27%

Obesity 18%

Inactivity 27%

Carotid stenosis 4%

Hypertension 35%

Relative risk

Percentages indicate

prevalence

2%Atrial fibrillation

Alberts. Curr Med Res Opin 2003;19:438–441

Risk vs prevalence

Page 6: Rationale For Raas Blockade

High blood pressure increasesthe risk of stroke

70 80 90 100 110

4.0

2.0

1.0

0.5

0.25

Usual DBP (mmHg)

Rela

tive r

isk

of

stro

ke

Law et al. Health Technol Assess 2003;7:1–106DBP=diastolic blood pressure

Page 7: Rationale For Raas Blockade

Effect of reducing blood pressure on risk of stroke

► Relative reduction in risk from a 5 mmHg decrease in DBP

-60

-50

-40

-30

-20

-10

0

Ris

k re

duct

ion (

%)

No history ofCVD

Previous stroke

Law et al. Health Technol Assess 2003;7:1–106.

No history of CVD

Previous stroke

High blood pressureAverage blood pressure

CVD=cardiovascular disease

Page 8: Rationale For Raas Blockade

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

Page 9: Rationale For Raas Blockade

Potential benefits of angiotensin receptor blockers

Neuronal/Glial Sensitivity to ischaemia

Stroke volumeInflammation

Regenerative mechanisms

Vascular/Haemodynamic Endothelial factors

AtherosclerosisThrombosis

Brain perfusion

CardiacAtrial fibrillation

Stroke:risk andoutcome

Modified after Unger Th. 2003

Page 10: Rationale For Raas Blockade

Angiotensin blockade in stroke risk reduction

► Angiotensin receptor blockers (ARBs) reduce blood pressure by interrupting the renin–angiotensin–aldosterone system (RAAS)

► Angiotensin AT1 receptor blockade may also provide stroke protection beyond blood pressure lowering

– Clinical and non-clinical studies show that ARBs reduce factors associated with increased risk of stroke

Fournier et al. J Am Coll Cardiol 2004;43:1343–1347.

Page 11: Rationale For Raas Blockade

Angiotensin II

Angiotensin II

Death

Glomerular filtration rateProteinuria/albuminuriaGlomerulosclerosis

Aldosterone release

Renal failure

LVHFibrosisRemodellingApoptosis

VasoconstrictionVascular hypertrophyEndothelial dysfunctionAtherosclerosis

Stroke

HypertensionThrombosis

ArrhythmiaHeart failureMI

AT1

receptor

Vascularremodelling

Direct and indirect effects in target-organ damage

Page 12: Rationale For Raas Blockade

Renin–angiotensin system in the brain

AT1-receptor mediated

► Blood pressure control

► Vasopressin secretion

► Sympathetic modulation

► ACTH secretion

► Thirst

► Oxidative stress

► Endothelial dysfunction

► Pathological remodelling

AT2-receptor mediated

► Neuroplasticity?

► Regeneration?

► Apoptosis?

AT1/AT2 receptors

► Protection against stroke?

► Protection against post-stroke events?

Modified after Unger Th. 2003.

Page 13: Rationale For Raas Blockade

0

10

20

30

40

50

Non-fatal stroke All stroke All stroke

Reduct

ion in r

ela

tive

risk

of

stro

ke

ARBs reduce risk of first stroke

► 4,964 hypertensives for mean 3.7 years

► Blood pressure reduction (SBP/DBP mmHg) was 21.7/10.8 and 18.5/9.2 in the Candesartan and placebo arms, respectively

All patients Patients with ISH

Lithell et al. J Hypertens 2003;21:875–886.Papademetriou et al. Presented at the American Heart Association Annual Meeting, 10 November 2003.

p = 0.04p = ns

p = 0.05

SCOPE study: Candesartan vs placebo

Page 14: Rationale For Raas Blockade

ARBs reduce risk of first stroke

► 9,193 hypertensives for mean 4.8 years

► Blood pressure reduction (SBP/DBP mmHg) was 30/17 and 29/17 in the Losartan and Atenolol arms, respectively

Favoursatenolol

Favourslosartan

Primarycompositeendpoint

Cardiovascularmortality

Stroke Myocardialinfarction

Dahlöf et al. Lancet 2002;359:995–1003

LIFE study: Losartan vs AtenololA

dju

sted h

aza

rd r

ati

o

(95

% C

I)

0.6

0.8

1.0

1.2

1.4

Page 15: Rationale For Raas Blockade

Preventing second stroke

► Meta-analysis of 7 randomized clinical trials

► Much of the inter-class differences are due to blood pressure reduction

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Odds

rati

o

-agonists ACE inhibitors

Rashid et al. Stroke 2003;34:2741–2749.

Diuretics Diuretics +ACE inhibitors

Effect of different antihypertensive classes

Page 16: Rationale For Raas Blockade

Preventing second stroke

0

5

10

15

20

25

30

35

40

45

50 Non-hypertensives

Hypertensives

Reduct

ion in r

ela

tive

risk

of

recu

rrent

stro

ke (

%)

Blood pressure reduction (SBP/DBP, mmHg) 5/3 12/5

Perindopril 4 mg alone

(n = 1,281)

Perindopril 4 mg + Indapamide 2.5 mg

(n = 1,770)

PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.

p = ns

p = ns

p < 0.05p < 0.05

PROGRESS: Perindopril +/- Indapamide

Page 17: Rationale For Raas Blockade

Preventing second stroke

0

2

4

6

8

10

12

14

16

18

Cerebrovacular Cardiovascular Total

Eve

nt

rate

per

10

0 p

atie

nt-

year

s

NitrendipineEprosartan

Schrader. Presented at XXVI ESC, 30 August 2004, Munich, Germany

*

*

* P<0.05 vs Nitrendipine† Includes recurrent events

MOSES: Candesartan vs Nitrendipine

† † †

Page 18: Rationale For Raas Blockade

ARBs – safety post-stroke

► 342 patients with ischaemic stroke and high blood pressure

► Candesartan cilexetil 4 mg/day or placebo for 7 days post-stroke

► Followed by Candesartan cilexetil and other antihypertensive treatment as required for 1 year

► Trial stopped early due to an imbalance in endpoints

► Cumulative 12-month mortality and number of vascular events significantly favoured candesartan (OR 0.48, 95% CI 0.25–0.90)

Schrader et al. Stroke 2003;34:1699–1703.

ACCESS study

Page 19: Rationale For Raas Blockade

Antiplatelets in reducing the risk of stroke

► Antiplatelet agents reduce the risk of thrombosis, a major cause of stroke

► Three antiplatelet agents are commonly used

– Acetylsalicylic acid (ASA, Aspirin)

– Extended-release dipyridamole (ER-DP), usually combined with ASA

– Clopidogrel

► Each has a different mechanism of action

O’Rourke et al. JAMC 2004;170:1123–1133

Page 20: Rationale For Raas Blockade

ER-DP*: Mode of action beyond platelet inhibition

Platelet inhibition/thrombinreceptor reduction

Eisert. in Platelets (Academic Press) 2002:803–815; Aktas. Stroke 2003;34:764–769.Eisert. Am J Therapeutics. 2001;8:443–449; Biaggioni J Investig Med. 2003;51:S370.

Malinin. HeartDrug 2002;2:93–104; Weyrich et al. Abstract P134. ESC 2003.

►Additive to NO increase ►Anti-inflammatory►Antioxidant►Cell membrane protection

►Antiproliferative►Tissue conditioning

Additional effects atthe vessel wall:

Antithromboticproperties

* Extended-release dipyridamole

Page 21: Rationale For Raas Blockade

Summary: current therapeutic evidence

► Hypertension is a major risk factor for stroke

► The risk of stroke is highest in the early morning, at a time when blood pressure surges

► Antihypertensive therapy reduces the risk of first and second stroke

► ARBs likely to have beneficial effects beyond reducing blood pressure (based on MOSES)

► Antiplatelet agents reduce the risk of stroke

Page 22: Rationale For Raas Blockade

Unanswered clinical questions

► Do ARBs reduce the risk of second stroke?

– Are ARBs effective in patients with normal blood pressure?

► Should hypertension be treated in the acute phase of stroke?

– Which antihypertensive should be used to treat hypertension after stroke?

► Are ARBs cerebroprotective?

► Which is superior in second stroke: ER-DP + ASA* or Clopidogrel?

Muir. BMJ 2004;328:–297–298.Albers, Amarenco. Stroke 2001;32:2948–2949.* Extended-release dipyridamole + aspirin

Page 23: Rationale For Raas Blockade

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

Page 24: Rationale For Raas Blockade

The study

► Two primary analyses:

– 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

Page 25: Rationale For Raas Blockade

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

Page 26: Rationale For Raas Blockade

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

Page 27: Rationale For Raas Blockade

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

Page 28: Rationale For Raas Blockade

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

Page 29: Rationale For Raas Blockade

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

Page 30: Rationale For Raas Blockade

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

Page 31: Rationale For Raas Blockade

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).

Page 32: Rationale For Raas Blockade

Main exclusion criteria

► Haemorrhagic stroke

► Unstable angina

► Patients bedridden, with dementia or unable to give informed consent

► Carotid endarterectomy

► History of thrombocytopenia

Page 33: Rationale For Raas Blockade

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

Page 34: Rationale For Raas Blockade

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

Page 35: Rationale For Raas Blockade

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

Page 36: Rationale For Raas Blockade

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

Page 37: Rationale For Raas Blockade

Global trial

Europe17 countries

Africa and Middle East2 countries

Asia8 countries

South America1 country

North America3 countries

Australia

32 countries, 600 study centres

Page 38: Rationale For Raas Blockade

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

Page 39: Rationale For Raas Blockade

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

Page 40: Rationale For Raas Blockade

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

Page 41: Rationale For Raas Blockade

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

Page 42: Rationale For Raas Blockade

PRoFESS Enrollment - Italy

PRoFESS EnrollmentCountry = Italy

Goal N=660 in two yearsReduced goal N=400 by 31 March 2006

0

100

200

300

400

500

600

700

11/1

/200

3

12/1

/200

3

1/1/

2004

2/1/

2004

3/1/

2004

4/1/

2004

5/1/

2004

6/1/

2004

7/1/

2004

8/1/

2004

9/1/

2004

10/1

/200

4

11/1

/200

4

12/1

/200

4

1/1/

2005

2/1/

2005

3/1/

2005

4/1/

2005

5/1/

2005

6/1/

2005

7/1/

2005

8/1/

2005

9/1/

2005

10/1

/200

5

11/1

/200

5

12/1

/200

5

1/1/

2006

2/1/

2006

3/1/

2006

4/1/

2006

5/1/

2006

6/1/

2006

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

Page 43: Rationale For Raas Blockade

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.

Page 44: Rationale For Raas Blockade

How does PRoFESS compare with similar antiplatelet trials?

Trial No. patients Mean follow-up

(months) Study drug

termination for any reason (%)

ESPS 2,500 24 30 ESPS-2 6,602 24 26 MATCH 7,599 18 CAPRIE 19,185 19 21 ESPRIT - DP+ASA -ASA

1363 1376

42 42

34 13

PRoFESS <20,000 11 15.9

8

20,333 16

Page 45: Rationale For Raas Blockade

Strategies that PRoFESS sites use to successfully rechallenge patients:

95%

40%35% 35%

20%

80%

0%

20%

40%

60%

80%

100%

Frequentcommunication

Highlightbenefits of

participation

Prevention:(discuss side

effects/efficacy)

Titrate med’s Family support Establish trustrelationship

Per

cen

t

Page 46: Rationale For Raas Blockade

Focus on rechallenging patients

Total n pt ever off drug

n (%)

successfully rechallenged

n (%)

Global 18,983 5,273

28%

1,642

31%

AAJ 5,904 1,899

32%

529

28%

ESA 7,186 2,093

29%

717

34%

Asia 5,893 1,281

22%

396

31%

31% of patients BACK ON MED’S

Page 47: Rationale For Raas Blockade

Message: A patient can always rechallenge!

As long as it is medically acceptable

• Irrespective of how much time has passed

• Irrespective of the number of times that the patient has discontinued the study med

31% of patients have already successfully rechallenged!

Page 48: Rationale For Raas Blockade

How does PRoFESS compare with similar antiplatelet trials?

Trial Mean follow-up (months)

LTFU %

ESPS 24 0.3 ESPS-2 24 0.6 MATCH 18 4.0 CAPRIE 19 0.2 ESPRIT 42 4.0 PRoFESS – missed 2 consecutive visits

11

4.0%

4.2

Page 49: Rationale For Raas Blockade

N. Randomizzati in Italia

Page 50: Rationale For Raas Blockade

Proportion of patients who have missed two consecutive visits, ESA Region

0%

5%

10%

15%

20%

Austri

a

Belgium

Denmar

k

Finlan

d

Franc

e

Germ

any

Greec

e

Irelan

d

Israel

Italy

Nether

lands

Norway

Portu

gal

Russia

S Afri

caSpa

in

Sweden

Turke

y

Ukrain

eUK

Page 51: Rationale For Raas Blockade

Proportion of patients who have missed their last visit and two consecutive visits, ESA region

0%

5%

10%

15%

20%

Austri

a

Belgium

Denmar

k

Finlan

d

Franc

e

Germ

any

Greec

e

Irelan

d

Israel

Italy

Nether

lands

Norway

Portu

gal

Russia

S Afri

caSpa

in

Sweden

Turke

y

Ukrain

eUK

Page 52: Rationale For Raas Blockade

Summary

► Compliance and Retention rates vary:

– Across regions

– Across countries within regions, and

– Across sites within countries

THEREFORE WE HAVE AN OPPORTUNITY!

► It is never too late to rechallenge study medication

► All sites will be asked to make contact with POTENTIALLY lost patients

► Compliance and Retention are important both to the patients, and to the PRoFESS Trial

Page 53: Rationale For Raas Blockade

AREE GRIGIE

• Effetti specifici sui sottotipi patogenetici di ictus

• Selezione del target terapeutico in tutta la popolazione e nei soggetti anziani

• Epoca di inizio del trattamento

• Atteggiamento nella ostruzione carotidea

• Comorbilità cardiaca & renale

ed antipertensivi

ONTARGETARBs vs ACE-I vs combinazioneProtezione cardiovascolare in soggetti ad alto rischio

•Recidive di ictus•Anziani•Comorbilità

PROFESSTelmisartan nella prevenzione secondaria dell`ictus ischemico

•Sottotipi di ictus (TOAST)•Epoca di inizio del trattamento•Anziani •Comorbilità

Trattamento antipertensivo nella prevenzione secondaria