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Reducing CV Events such as MI and Stroke in CV High-Risk patients

Reducing CV Events such as MI and Stroke in CV High-Risk patients. Role of angiotensin II in cardiovascular disease. Angiotensin II is central to cardiovascular disease progression. Myocardial infarction and stroke. Remodelling. Atherosclerosis and left ventricular hypertrophy.

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Reducing CV Events such as MI and Stroke in CV High-Risk patients

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  1. Reducing CV Events such as MI and Stroke in CV High-Risk patients

  2. Role of angiotensin II in cardiovascular disease

  3. Angiotensin II is central to cardiovascular disease progression Myocardial infarction and stroke Remodelling Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death Angiotensin II Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952 Images reproduced with kind permission of Professor Böhm

  4. Effect of RAS blockade

  5. Renin-angiotensin system (RAS) blockade reduces CV disease progression Inhibition of angiotensin II via RAS blockade directly reduces atherosclerosis: Endothelial dysfunction ↓ Oxidative Stress ↓ Inflammation ↓ Tissue remodelling↓ Schmieder et al. Lancet 2007;369:1208−1219Image reproduced with kind permission of Professor Böhm

  6. ACEI and ARBs block the renin–angiotensin system (RAS) in different ways ACE Inhibitor ACE-independent ANG II formation by Chymase, etc. ACE ARB Bradykinin/NO Angiotensin I Inactive fragments Angiotensin II AT2 RECEPTOR AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis SNS = sympathetic nervous system Hanon S, et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R, et al. Hypertension 2003;42:542–547; Hurairah H, et al. Int J Clin Pract 2004;58:173–183;Steckelings UM, et al. Peptides 2005;26:1401–1409

  7. RAS blockade with ACE inhibitors

  8. ACE-Inhibitors reduce CV events* in CV high-risk and HF patients * 3-fold composite CV endpoint: Death, MI, Stroke † All deaths instead of CV deaths Dagenais et al. Lancet 2006;368:581–88

  9. Ramipril* reduces CV mortality and morbidity beyond BP lowering (HOPE study) Composite CV endpoint† Death from CV causes MI Stroke 0 –4 –22% p<0.001 –26% p<0.001 –32% p<0.001 –20% p<0.001 –8 –12 –16 % risk reduction (treatment vs. placebo) –20 –24 –28 –32 –36 Ramipril, n=4,645 Placebo, n=4,652 –40 High-risk patients; mean baseline SBP/DBP 139/79 mmHg * Ramipril is indicated (EMEA, Harmonized SPC) for the reduction of CV morbidity and mortality in patients with manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or diabetes with at least one additional cardiovascular risk factor † Composite CV endpoint = death from CV causes + MI + stroke HOPE = Heart Outcomes Prevention EvaluationYusuf S, et al. N Engl J Med 2000;342:145–153

  10. The HOPE study showed the effect of ramipril in CV high-risk patients in the middle of the CV continuum Myocardial infarction and stroke Remodelling Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death HOPE study Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952

  11. Side effects of ACE inhibitor therapy limit tolerability and increases non-adherence Cough affects up to 35% of patients treated with ACE inhibitors1 Treatment should be discontinued irrespective of the temporal relationship between onset of cough and treatment initiation Angio-edema affects 0.1–0.7% of patients receiving ACE inhibitors2,3 Immediate discontinuation of treatment is essential 1. Dicpinigaitis PV. Chest 2006;129(Suppl 1):169S-173S 2.Miller DR, et al. Hypertension 2008;51:1624-1630 3. Weber MA, & Messerli FH. Hypertension 2008;51:1465-1367.

  12. Who is at greatest risk of ACEI adverse events? Cough Aged 60-69 years Female East Asian ethnicity Smoker (ex or current) 1 2 3 4 5 6 Angioedema African-American ethnicity Smoker (ex or current) History of ACEI cough n=2225 1 11 21 31 Adjusted hazard ratio (discontinuation of treatment) (95% CI) Morimoto et al. J Eval Clin Practice 2004;10:499-509

  13. Patients who discontinue medications are at increased mortality risk Any Medications 0 Medications Impact of Medication Therapy Discontinuation on Mortality 100 > 10% 95 90 85 80 75 Survival, % 70 65 Discontinuation one month after myocardial infarction vs. continued use of at least one medication 60 55 50 0 1 3 6 9 12 (n=1521) (n=1509) (n=1487) (n=1475) (n=1450) Months Ho et al. Arch Intern Med 166 (2006): 1842-1847

  14. RAS blockade with ARBs

  15. ARBs offer a better-tolerated alternative to ACE inhibitors Percent (%) P value* <0.001 <0.001 <0.001 0.060 * ARB p value vs each of the other classes (Chi-Square) Chaput AJ. Can J Cardiol 2000;16(suppl F):194A

  16. Several indications are derived from ARB trials Myocardial infarction and stroke Remodelling Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death LIFEVALUE ValHeFTVALIANTCHARM Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952

  17. ARB CV outcome studies in hypertensive patients – evidence unclear LIFE Losartan reduced incidence of stroke compared with atenolol in patients with severe hypertension and LVH1 However, atenolol is a weak comparator since it provides poor CV protection compared with all other antihypertensive classes2 VALUE Valsartan was not better than amlodipine in reducing CV risk in patients with hypertension and risk factors3 Valsartan was significantly worse than amlodipine on the incidence of MI 1. Dahlöf B et al. Lancet 2002; 359:995-1003 2. Carlberg et al. Lancet 2004;364:1684–9 3. Julius S, et al. Lancet. 2004;363:2022-31

  18. ARB CV outcome studies demonstrate effectiveness in heart failure Three key ARB trials have shown the effectiveness of ARBs in patients with heart failure Val-HeFT and VALIANT showed that valsartan is effective in patients with heart failure or patients with heart failure/LV dysfunction after a recent MI*, respectively CHARM showed candesartan is also effective in heart failure * VALIANT (VALsartan In Acute myocardial iNfarction Trial) was conducted in clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours – 10 days) myocardial infarction. 1. Pfeffer MA, et al. N Engl J Med 2003;349:1893-906; 2. Cohn JN, et al. N Engl J Med 2003;345;1667-75;3. Pfeffer MA, et al. Lancet 2003 362: 759–66;

  19. Before ONTARGET, ARB trials had not addressed CV high-risk patients in the middle of the CV continuum Myocardial infarction and stroke Remodelling LIFEVALUE ValHeFTVALIANTCHARM Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952

  20. Which ARB to reduce events in CV high-risk patients? Before ONTARGET, no ARB had been tested for protective effects in CV high-risk patients To demonstrate effectiveness equal to the gold-standard ramipril, an ARB with the optimal pharmacology was selected Telmisartan has a unique pharmacology among ARBs This translates to meaningful clinical benefit over other ARBs Burnier M. JIMR 2009;37(6) e-publish ahead of print

  21. Telmisartan’s unique pharmacology among ARBs † Active metabolite EXP 3174 Receptor dissociation half life (min) † Val-sartan Lo-sartan Cande-sartan Olme-sartan Telmi-sartan Longest half life, Highest receptor affinity, Highest tissue penetration and selective PPARg activation Longest plasma half life Highest receptor affinity Plasma half life (h) range Epro-sartan Lo-sartan Val-sartan Cande-sartan Olme-sartan Irbe-sartan Telmi-sartan Most lipophilic (high tissue penetration) Highest selective PPARgactivation 500 PPARg fold activation Volume of distribution (L) range Cande-sartan Olme-sartan Val-sartan Lo-sartan Irbe-sartan Epro-sartan Telmi-sartan Telmi-sartan Irbe-sartan Cande-sartan Val-sartan Olme-sartan Epro-sartan EXP 3174(Losartan) Burnier M. & Brunner H.R., Lancet 2000;355:637–645; Brunner H.R., J Hum Hypertens 2002;16(Suppl 2):S13–S16; Kakuta H., et al.Int J Clin Pharmacol Res 2005;25:41–46; Wienen W., et al. Br J Pharmacol 1993;110:245-252; Song J.C. & White C.M., Formulary 2001;36:487–499; Asmar,R., Int J Clin Pract. 2006;60:315-320; Israili,Z.H., J Hum.Hypertens. 2000;14 Suppl 1: S73-S86; Benson S.C. et al. Hypertension 2004;43:993–1002

  22. Telmisartan’s unique pharmacology translates to meaningful clinical benefit In hypertensive diabetic nephro-pathy patients: 39% more proteinuria reduction with telmisartan for the same BP reduction (Telmisartan 80 mg DBP -3.3 mmHg; Losartan 100 mg DBP- 2.9 mm Hg) gMean UPC (mg/g creatinine) P = 0.03 n=860 Bakris et al. Kidney Int 2008; DOI:10.1038/ki.2008.204

  23. ONTARGET trial –CV High-Risk patients

  24. ONTARGET filled the CV High-Risk patient gap in the CV continuum Myocardial infarction and stroke Remodelling LIFEVALUE ValHeFTVALIANTCHARM Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death ONTARGET Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952

  25. The ONTARGET Trial in CV High-Risk patients* – the largest ARB outcomes trial n=8,542 Telmisartan 80 mg n=25,620 n=8,576 Ramipril 10 mg n=8,502 Telmisartan 80 mg + Ramipril 10 mg 5.5 years Follow-up at 6 weeks and every 6 months *Age 55 years at high risk of a CVD event (i.e. with a history of: coronary artery disease, peripheral arterial occlusive disease (PAD), cerebrovascular event, or diabetes mellitus with end-organ damage) Teo K, et al. Am Heart J 2004;148:52–61; The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

  26. ONTARGET – like HOPE – is not a hypertension trial * TRANSCEND as of January 2004. Final TRANSCEND recruitment, n=5,926 † n=9538; ‡ n=9297.Sleight P. Acta Diabetol 2005;42:S50–56; Teo K, et al. Am Heart J 2004;148:52–61; Yusuf S, et al. N Engl J Med 2000;342:145–153.

  27. Telmisartan 80mg reduces devastating CV events similar to ramipril 10mg in CV High-Risk patients Telmisartan Ramipril Reduction in composite CV risk 0.20 0.15 0.10 Cumulative Hazard Ratio ‡p< 0.01 vs. non-inferiority margin (1.13) 0.05 0 Years of follow-up 0 1 2 3 4 5 No. at risk Telmisartan Ramipril 8,452 8,576 8,177 8,214 7,778 7,832 7,420 7,472 7,051 7,093 1,687 1,703 Reduction in composite CV risk (Primary endpoint: cardiovascular mortality, non-fatal myocardial infarction, hospitalisation for congestive heart failure, non-fatal stroke) The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

  28. Telmisartan 80mg reduces devastating CV events similar to ramipril 10mg in CV High-Risk patients Telmisartan Ramipril Composite Endpoint* ‡ Secondary composite: HOPE Primary endpoint† ‡p< 0.01 vs. non-inferiority margin (1.13) ‡ 1.1 1.0 1.2 0.9 0.8 Telmisartanbetter Ramiprilbetter * ONTARGET primary composite endpoint = CV death + MI + stroke+ hospitalisation for CHF † HOPE primary endpoint = CV death + MI + stroke The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

  29. Telmisartan is better tolerated than ramipril (ONTARGET® study) Ramipril (10 mg) Telmisartan (80 mg) Cumulative hazard rates (discontinuation from treatment)(%) Years offollow-up n at risk Telmisartan Ramipril 8,542 8,576 7,954 7,796 7,384 7,165 6,909 6,681 6,478 6,254 Data on File (Boehringer Ingelheim GmbH)

  30. ONTARGET® Trial summary Largest ever trial investigating the reduction of cardiovascular morbidity and mortality Telmisartan demonstrated long-term CV protection similar to the reference standard ACE-inhibitor, ramipril in a broad range of high-risk patients Results demonstrate the CV protective effects of telmisartan beyond blood pressure reduction Telmisartan was better tolerated than ramipril and provided greater long-term adherence, despite the fact that patients were selected for ramipril tolerance at start

  31. Telmisartan indicated for reduction of CV morbidity

  32. Micardis® for the reduction of CV morbidity MICARDIS® (telmisartan) is indicated* for the reduction of CV morbidity in patients with manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or diabetes with documented target organ damage Because telmisartan’s unique pharmacology leads to proven differences in organ protection a class effect cannot be assumed * EMEA: European Medicines AgencyBakris G, et al. Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy. Kidney Int 2008:74:364–369.

  33. Telmisartan is the only ARB indicated in CV high-risk patients – representing the majority of the patients typically seen in clinical practice Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk)

  34. Only MICARDIS® is indicated to reduce CV morbidity, such as MI and stroke in CV High-Risk patients Myocardial infarction and stroke Remodelling LIFEVALUE ValHeFTVALIANTCHARM Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death ONTARGET Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952

  35. Conclusions

  36. Conclusions Angiotensin II plays a central role in CV disease progression, and RAS blockade reduces cell and tissue damage The HOPE study showed that ramipril reduces the risk of CV events in a broad cross-section of high-risk patients beyond BP ACEI therapy is limited by intolerance and non-adherence; ARBs offer RAS blockade with fewer side effects and better treatment adherence ARBs have been investigated in different patient populations: hypertension with risk factors, CV High-Risk patients, and heart failure. Only Telmisartan is indicated to reduce cardiovascular morbidity in CV High-Risk patients (i.e. with diabetes and target organ damage, or atherothrombotic disease) – representing the majority of the patients typically seen in clinical practice

  37. Back-up slides

  38. The ONTARGET® Trial Programme in CV High-Risk patients – The largest ARB outcomes trial n=5,926 * n=8,542 Telmisartan 80 mg n=8,576 Ramipril 10 mg n=25,620 n=8,502 Telmisartan 80 mg + Ramipril 10 mg n=2,954 Telmisartan 80 mg n=2,972 Best standard of care 5.5 years Follow-up at 6 weeks and every 6 months * In patients intolerant of ACEIs Teo K, et al. Am Heart J 2004;148:52–61; The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559;The TRANSCEND Investigators. Lancet 2008; 372:1174-83.

  39. Composite endpoint of CV death, MI and stroke in TRANSCEND confirms protective effect of telmisartan in CV High-Risk patients Telmisartan + Standard of Care Standard of Care Hazard ratio 0.87 (95% CI 0.76 - 1.00); p = 0.048 13.0% Cumulative incidence(%) Years offollow-up n at risk Telmisartan+ Standard of Care Standard of Care 2,954 2,972 2,839 2,866 2,745 2,745 2,634 2,626 2,344 2,306 1,127 1,103 Reduction of composite CV risk (Secondary endpoint: CV death, MI, stroke [=HOPE primary endpoint])The TRANSCEND Investigators. Lancet 2008; 372:1174-83. Primary endpoint (Composite endpoint of CV death, MI, Stroke and hospitalization for Heart failure) Hazard ratio 0.92 (not significant)

  40. TRANSCEND patients on current best standard care were as protected ramipril patients in HOPE 17.8% 14.8% 14% 13% Event rate (%) The TRANSCEND Investigators. Lancet 2008;372:1174–1183 Yusuf S, et al. N Engl J Med 2008;342:145–153

  41. Use of added BP-lowering drugs was higher in control group than telmisartan group (TRANSCEND study) *p<0.0001 versus telmisartan 80 mg; Tel = telmisartan + standard care; Control = standard care Data on File (Boehringer Ingelheim GmbH)

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