rationale for raas blockade

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  • 1. Rationalefor RA A S blockade insecondary stroke prevention P reventionR egimenF orE ffectively avoidingS econdS trokes

2.

  • 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 comorbidit
  • 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 dellictus 3.

  • Revisione sistematica di 7 RCT in soggetti con precedente ictus: 15527 soggetti
  • (Rashid et al, 2003)
    • StudioLIFE , 02losartan + idroclortiazide vs atenololo+ idroclortiazide, sottogruppo 728 soggetti
    • (segmento prev. secondaria)
    • StudioMOSES , 05 eprosartan vs nitrendipina, 1405 soggetti

Fonti di informazione nella stesura delle linee guida nella prevenzione secondaria dellictus attraverso luso di antipertensivi 720 pts Atenolol ? mg; placebo

  • TEST ,95

1013 pts Ramipril; placebo

  • HOPE , 00
  • segmento prev. secondaria

2561 pts 3544 pts Perindopril 4 mg;placebo Perindopril 4 mg_ indapamide 2.5mg; double-placebo

  • PROGRESS ,01

Due terzidei dati riconducibiliai trial PAT e PROGRESS 5665 pts Indapamide (2.5 mg); placebo

  • PATS , 95

1473 pts Atenolol (50g);placebo

  • Dutch TIA ,93

452 pts Deserpidine 1 mg and methylclothiazide 10 mg; placebo

  • HSCGS ,74

99 pts Thiazide diureticmg_methyldopa(750 mg); control

  • Carter ,70

4. 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

5. Risk factors for stroke Hyperlipidaemia 27% Smoking 27% Obesity 18% Inactivity 27% Carotid stenosis 4% Hypertension 35% Relative risk Percentagesindicateprevalence 2% Atrial fibrillation Alberts.Curr Med Res Opin2003;19:438441 Risk vs prevalence 6. High blood pressure increases the risk of stroke 70 80 90 100 110 4.0 2.0 1.0 0.5 0.25 Usual DBP (mmHg) Relative risk of stroke Lawet al.Health Technol Assess2003;7:1106 DBP=diastolic blood pressure 7. Effect of reducing blood pressure on risk of stroke

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

No history of CVD Previous stroke Lawet al.Health Technol Assess2003;7:1106. No history ofCVD Previous stroke High blood pressure Average blood pressure CVD=cardiovascular disease 8. 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

9. Potential benefits of angiotensin receptor blockers Neuronal/Glial Sensitivity to ischaemia Stroke volume Inflammation Regenerative mechanisms Vascular/ Haemodynamic Endothelial factorsAtherosclerosis Thrombosis Brain perfusion Cardiac Atrial fibrillation Stroke: risk and outcome Modified after Unger Th. 2003 10. Angiotensin blockade in stroke risk reduction

  • Angiotensin receptor blockers (ARBs) reduce blood pressure by interrupting the reninangiotensinaldosterone system (RAAS)
  • Angiotensin AT 1receptor 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 Cardiol2004;43:13431347. 11. Angiotensin II Angiotensin II Death Glomerular filtration rate Proteinuria/albuminuria Glomerulosclerosis Aldosterone release Renal failure LVH Fibrosis Remode l ling Apoptosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Stroke Hypertension Thrombosis Arrhythmia Heart failure MI AT 1 receptor Vascular r emode l ling Direct and indirect effects intarget- organ damage 12. Reninangiotensin system in the brain

  • AT 1 -receptor mediated
  • Blood pressure control
  • Vasopressin secretion
  • Sympathetic modulation
  • ACTH secretion
  • Thirst
  • Oxidative stress
  • Endothelial dysfunction
  • Pathological remodelling
  • AT 2 -receptor mediated
  • Neuroplasticity?
  • Regeneration?
  • Apoptosis?
  • AT 1 /AT 2receptors
  • Protection against stroke?
  • Protection againstpost-stroke events?

Modified after Unger Th. 2003. 13. 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 Hypertens2003;21:875 886. Papademetriou et al. Presented at the American Heart Association Annual Meeting, 10 November 2003. p = 0.04 p = ns p = 0.05 SCOPE study: Candesartan vs placebo 14. 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

Favours atenolol Favours losartan Primary composite endpoint Cardiovascular mortality Stroke Myocardial infarction Dahl fet al.Lancet2002;359:9951003 LIFE study: Losartan vs Atenolol Adjusted hazard ratio(95% CI) 0.6 0.8 1.0 1.2 1.4 15. Preventing second stroke

  • Meta-analysis of 7 randomized clinical trials
  • Much of the inter-class differences are due to blood pressure reduction

-agonists ACE inhibitors Rashidet al.Stroke2003;34:27412749. Diuretics Diuretics + ACE inhibitors Effect of different antihypertensive classes 16. Preventing second stroke Reduction in relative riskof recurrent stroke (%) PROGRESS Collaborative Group.Lancet2001;358:10331041. p = ns p = ns p < 0.05 p < 0.05 PROGRESS: Perindopril +/- Indapamide 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) 17. Preventing second strokeSchrader. Presented at XXVI ESC, 30 August 2004, Munich, Germany * * * P30)

    • Vascular damage (stroke, myocardial infarction, or peripheral artery disease) prior to qualifying stroke
    • End-organ damage (retinopathy, left-ventricular hypertrophy or microalbuminuria).

32. Main exclusion criteria

  • Haemorrhagic stroke
  • Unstable angina
  • Patients bedridden, with dementia or unable to give informed consent
  • Carotid endarterectomy
  • History of thrombocytopenia

33. 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 infarctionor vascular death
  • Vascular events or congestive heart failure
  • New-onset diabetes

34. Tertiary outcomes

  • Stroke or majorhaemorrhagic event
  • Major haemorrhagic events
  • Minor haemorrhagic events
  • Other designated vascular events
  • Death
  • New or worsening congestive heart failure
  • Thrombotic thrombocytopenic purpura
  • Neutropenia

35. Patient follow-up

  • Baseline visit and ondischarge from hospitalor Day 7(whichever soonest)
  • Visits atMonth 1, Month 3 and Month 6
  • Visits every 6 monthsthere after
  • Telephone contact every 3 months

36. Content

  • Stroke: the scope of the problem
    • Incidence
    • Consequences
    • Risk factors
  • study: therapeutic rationale
    • Angiotensin receptor blockade
    • Antiplatelet therapy
  • The study