Rationale For Raas Blockade
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Rationale For Raas Blockade

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Rationale For Raas Blockade Rationale For Raas Blockade Presentation Transcript

  • Rationale for RA A S blockade in secondary stroke prevention P revention R egimen F or E ffectively avoiding S econd S trokes
    • 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
    • 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
    Fonti di informazione nella stesura delle linee guida nella prevenzione secondaria dell’ictus attraverso l’uso 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 terzi dei dati riconducibili ai trial PAT e PROGRESS 5665 pts Indapamide (2.5 mg); placebo
    • PATS , ’95
    1473 pts Atenolol (50 g);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
  • 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
  • Risk factors for stroke 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
  • 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 Law et al. Health Technol Assess 2003;7:1–106 DBP=diastolic blood pressure
  • 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 Law et al. Health Technol Assess 2003;7:1–106. No history of CVD Previous stroke High blood pressure Average blood pressure CVD=cardiovascular disease
  • 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
  • Potential benefits of angiotensin receptor blockers Neuronal/Glial Sensitivity to ischaemia Stroke volume Inflammation Regenerative mechanisms Vascular/ Haemodynamic Endothelial factors Atherosclerosis Thrombosis Brain perfusion Cardiac Atrial fibrillation Stroke: risk and outcome Modified after Unger Th. 2003
  • Angiotensin blockade in stroke risk reduction
    • Angiotensin receptor blockers (ARBs) reduce blood pressure by interrupting the renin–angiotensin–aldosterone system (RAAS)
    • Angiotensin AT 1 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.
  • 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 in target- organ damage
  • Renin–angiotensin 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 2 receptors
    • Protection against stroke?
    • Protection against post-stroke events?
    Modified after Unger Th. 2003.
  • 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 = 0.04 p = ns p = 0.05 SCOPE study: Candesartan vs placebo
  • 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 öf et al. Lancet 2002;359:995–1003 LIFE study: Losartan vs Atenolol Adjusted hazard ratio (95% CI) 0.6 0.8 1.0 1.2 1.4
  • 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 Rashid et al. Stroke 2003;34:2741–2749. Diuretics Diuretics + ACE inhibitors Effect of different antihypertensive classes
  • Preventing second stroke Reduction in relative risk of recurrent stroke (%) PROGRESS Collaborative Group. Lancet 2001;358:1033–1041. 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)
  • Preventing second stroke Schrader. Presented at XXVI ESC, 30 August 2004, Munich, Germany * * * P<0.05 vs Nitrendipine † Includes recurrent events MOSES: Candesartan vs Nitrendipine † † †
  • 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
  • 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
  • ER-DP*: Mode of action beyond platelet inhibition Platelet inhibition/thrombin receptor 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 at the vessel wall: * Extended-release dipyridamole Antithrombotic properties
  • 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
  • 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
  • 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
  • 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
  • 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 = 7,750 n = 7,750 TOTAL n = 15,500 Telmisartan + ER-DP + ASA n = 3,875 Placebo + ER-DP + ASA n = 3,875 Telmisartan + Clopidogrel n = 3,875 Placebo + Clopidogrel n = 3,875 ER-DP = Extended-release dipyridamole
  • 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 AT 1 receptor
      • Associated with target-organ protection
    • Crosses the blood–brain barrier
  • 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
  • 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 value reduction * Extended-release dipyridamole + aspirin
  • 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
  • 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
  • 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).
  • Main exclusion criteria
    • Haemorrhagic stroke
    • Unstable angina
    • Patients bedridden, with dementia or unable to give informed consent
    • Carotid endarterectomy
    • History of thrombocytopenia
  • 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
  • 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
  • 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 there after
    • Telephone contact every 3 months
  • 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
  • Global trial Europe 17 countries Africa and Middle East 2 countries Asia 8 countries South America 1 country North America 3 countries Australia 32 countries, 600 study centres
  • Study organization Academic representatives Sponsor representatives (non-voting) Sponsor DSMB Adjudication & Assessment Committee Europe CML/NC North Am. CML/NC South Am. CML/NC Africa CML/NC Asia 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 1 Site 2 Site 3 Site 4 etc Site 1 Site 2 Site 3 Site 4 etc Site 1 Site 2 Site 3 Site 4 etc Site 1 Site 2 Site 3 Site 4 etc Site 1 Site 2 Site 3 Site 4 etc
  • Telmisartan Beyond blood pressure 2003–2006 2007 and beyond Protection in the early morning/24-hour efficacy Life saving Efficacy vs ACE inhibitors and other ARBs Heart protection/ LVH reduction Renoprotection in diabetics Antihypertensive efficacy in special patient populations Phase III and IV programme rationale
  • Outcome trials of Telmisartan 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
  • Enrollment by country Total number of Countries or Regions = 35 (20 in ESA) Total number of Randomized Patients = 20,333 363 Singapore 30 Greece 3408 USA 1353 Russia 1287 Germany 560 Ukraine 280 Portugal 125 France 502 UK 152 Norway 216 Finland 62 Turkey 222 Mexico 231 Denmark 485 The Netherlands 112 Malaysia 2130 China 219 Thailand 210 Japan 1549 Canada 926 Taiwan 419 Italy 300 Brazil 503 Sweden 449 Israel 418 Belgium 130 Spain 30 Ireland 277 Austria 626 South Korea 1620 India 276 Australia 79 South Africa 250 Hong Kong 534 Argentina N Country N Country N Country
  • PRoFESS Enrollment - Italy Enrollment End = 31 May 2006 Goal 400
  • 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.
  • How does PRoFESS compare with similar antiplatelet trials? 8 20,333 16
  • Strategies that PRoFESS sites use to successfully rechallenge patients:
  • Focus on rechallenging patients 31% of patients BACK ON MED’S 717 34% 2,093 29% 7,186 ESA 396 31% 1,281 22% 5,893 Asia 529 28% 1,899 32% 5,904 AAJ 1,642 31% 5,273 28% 18,983 Global successfully rechallenged n (%) pt ever off drug n (%) Total n
  • 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!
  • How does PRoFESS compare with similar antiplatelet trials? 4.2
  • N. Randomizzati in Italia
  • Proportion of patients who have missed two consecutive visits, ESA Region
  • Proportion of patients who have missed their last visit and two consecutive visits, ESA region
  • 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
    • 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
    • ONTARGET
      • ARBs vs ACE-I vs combinazione
      • Protezione cardiovascolare in soggetti
      • ad alto rischio
        • Recidive di ictus
        • Anziani
        • Comorbilità
      • PROFESS
      • Telmisartan nella prevenzione
      • secondaria dell ` ictus ischemico
        • Sottotipi di ictus (TOAST)
        • Epoca di inizio del trattamento
        • Anziani
        • Comorbilità
    Trattamento antipertensivo nella prevenzione secondaria