Zofia Oko-Sarnowska Department of Clinical Pharmacology

1. Recommendations for the pharmacological treatment of atherosclerotic cardiovascular disease based on clinical trials Zofia Oko-Sarnowska Department of Clinical Pharmacology

2. Chronic(stable)plaque Little lipide core Thick fibrous cap A low inflammatory cells migration A low MMP content Acute(unstable)plaque Big lipide core Thin fibrous cap A high inflammatory cells migration A high MMP content Differences between chronic and acute atherosclerotic plaques

3. Pharmacological methods of stabilization of atherosclerotic plaque Proven effect Potencial effect

4. Stabilisation of atherosclerotic plaque • Influence on outside risk factor of transition from chronic to acute atherosclerosis -reduction of sudden change of blood pressure -reduction of vasospastic reaction -reduction of inflammatory process • Direct influence on atherosclerotic plaque - decrease volume of lipid core - reduction of inflammatory process in situ - reduction of MMP concentration

5. Classes of recommendations

6. Levels of evidence

7. Pharmacological methods of stabilization of atherosclerotic plaque Proven effect

8. Angiotensin converting enzyme inhibitors in cardiovacular disease • Heart failure (HF) • Asymptomatic left ventricular systolic dysfunction (LVSD) • Diatolic failure • Acute myocardial infarction (AMI) • Hypertension (HT) • Secondary prevention and high-risk of cardiovascular disease

9. Indication for ACE-I • Heart failure:CONSENSUS, SAVE, VheFT-IISOLVD Prevention, SOLVD Treatment • LVSD after MI (EF<40%)

10. Use of ACE-I in heart failure

11. Use of ACE-I in myocardial infarction

12. Use of ACE-I in hypertension

13. Use of ACE-I in secondary prevention and high-risk of cardiovacular disease

14. Hope study • Enrolled 9297 men and womenage > 55 years old • Indications:1. confirmed arterial disease (CHD, peripheral arterial disease, stroke2. Diabetes and one other risk factor (hypertension, cigarette smoking, micoalbuminuria or dyslipidaemia) • Randomisation to ACE-I (ramipril 2,5-10mg) or placebo • Follow-up: 5 years

15. Results: Hope study

16. Trials in low risk patients

17. Use of ACE-I to prevent sudden death • In patients with asymptomatic LV dysfunction, moderate and advanced HF treatement with ACE-I resulted in a reduction in mortality from sudden cardiac death (SCD) • This reduction varied from 20-54% and was statistically significant in some heart failure studies, although SCD was not the primary end-point in this trials. Priori et al. For the Task Force on Sudden Cardiac Death of the ESC.Eur Heart J 2001; 22: 1374-450 Update on the guidelines for SCD of the ESC. .Eur Heart J 2003; 24: 13-15

18. Use of ACE-I to prevent sudden death

19. Pharmacological methods of stabilization of atherosclerotic plaque Proven effect

20. Usefulness of beta-adrenoceptor antagonists in cardiovascular disease CAD HF H A DM CAD – coranry artery disease, HF-heart failure, H - hypertensionDM - diabetes, A - arrythmia

21. Use of beta-adrenoceptor antagonists in coronary heart disease • Acute myocardial infarction (AMI) • Post MI – secondary prevention • Acute coronary syndromes NSTEMI • Chronic, stable ischaemic heart disease • Heart failure (HF) • Arrythmias • Prevention of sudden cardiac death (SCD)

22. Use of beta-blockers in AMI

23. Use of beta-blockers in secondary prevention after MI

24. Use of beta-blockers in non-ST-segment elevation ACS (NSTEMI ACS)

25. Use of beta-blockers in chronic, stable ischaemic heart disease

26. Usefulness of beta-blockers in CAD based on clinical trials • Olson’s meta-analysis 1992 (5 trials with metoprolol) • Yusuf’s meta-analysis 1998(25 randomized studies) • Freemantle’s meta-analysis 1999 (82 trials post MI) 23% reduction of overall mortality despite ACE-I and ASA treatment

27. Use of beta-blockers in chronic heart failure

28. Use of beta-adrenoceptor antagonists in heart failure • Waagstein et al. – team from Gőteborg: the pioneers work on application of beta-blockers (metoprolol) in the treatment of HF (1970y) • CIBIS I1994 (bisoprolol). • USCP (USCarvedilol Programme) 1996 (carvedilol) • Australian/New Zealand Heart Failure Study1997 (carvedilol) • CIBIS II (Cardiac Insufficiency Bisoprolol StudyII)1999 • MERIT-HF 1999 (metoprolol CR) • COPERNICUS(Carvedilol Prospective Randomised Cumulative Survival Study)2001 (carvedilol) • CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) 2001 (carvedilol)

29. Most importent trials in the treatment of HF with beta-blockers

30. Use of beta-adrenoceptor antagonists in heart failure • Beta-blockers should be considered for the treatment of all patients (NYHA II-IV) with stable, mild, moderate, and severe heart failure from ischaemic or non-ischaemic cardiomyopathies and reduced LVEF on standard treatment, including diuretics, and ACE-I, unless there is a contraindication (Class I, level A) • Beta-blocking therapy reduces hospitalisations (all, cardiovascular, and HF), improves the functional class and leads to less worsening of HF. This beneficial effect has been consistently observed in subgroups of different age, gender, functional class, LVEF, and ischaemic or non-ischaemic aetiology (Class I, level A)

31. Use of beta-adrenoceptor antagonists in heart failure • In patients with LV systolic dysfunction, with or without symptomatic HF, following an AMI long-term beta-blockade is recommended in addition to ACE inhibition to reduce mortality (Class I, level B) • Differences in clinical effects may be present between different beta-blockers in patients with HF. Accordingly, only bisoprolol, carvedilol, metoprolol succinate and nebivolol can be recommended (Class I, level A)

32. Use of beta-adrenoceptor antagonists in diabetes • Beta-blockers are particularly effective in decreasing post-infarction mortality and new infarcts in patients with a history of DM. • Thus, oral BBs are, in the absence of contraindications, recommended for all diabetic patients with ACS(Class IIa, level B) • Furthermore, such patients are more prone to develop heart failure and recent trials have documented the beneficial effects of beta-blockade in HF patients.

33. Use of beta-blockers in diabetes • Selective beta-1-antagonist may be preferred in case of insulin treatment • Alpha-1-beta-adrenergic antagonists such as carvedilol may offer additional benefits for patients with peripheral artery disease or substantial insulin resistance.

34. Pharmacological methods of stabilization of atherosclerotic plaque Proven effect

35. Angiotensin II receptor blockers (ARBs) – angioprotective action? • LIFE (losartan vs atenolol): 2002 N=9100; age>55lat Hypertension with LVHResults: Risk reduction of CV death, MI and stroke Risk reduction of fatal nad non-fatal stroke Decrease onset of new diabetes • SCOPE – beneficial effect of ARBs in primary prevention of stroke • MOSES – beneficial effect of ARBs in secondary prevention of stroke • DETAIL (telmisartan vs enalapryl): similar nephroprotecive effects in diabetes • VALUE – decrease onset of new diabetes

36. Use of angiotensin II receptor blockers (ARBs) in heart failure • ARBs can be used as an alternative to ACE-I in symptomatic patients intolerant to ACE-I to improve morbidity and mortality (Class I, level B) (ELITE II, OPTIMAAL) • ARBs and ACE-I seem to have similar efficiacy in CHF on mortality and morbidity (Class IIa, level B). In AMI with signs of HF or LVD ARBs and ACE-I have similar or equivalent effects on mortality (Class I, level B) (CHARM-Added)

37. CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARMAlternative CHARM Added CHARMPreserved n=2028 LVEF £40%ACE inhibitor intolerant n=2548 LVEF £40%ACE inhibitor treated n=3025 LVEF >40%ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death Pfeffer et al, Lancet 2003

38. CHARM-AlternativePrimary outcome, CV death or CHF hospitalisation % 50 406 (40%) Placebo 40 334 (33%) 30 Candesartan 20 10 HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001 0 0 1 2 3 3.5 years Number at risk Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126 Granger et al, Lancet 2003

39. CHARM-AlternativeConclusions • Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan waswell tolerated • In patients with symptomatic CHF and ACE inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity Granger et al, Lancet 2003

40. CHARM-AddedPrimary outcome, CV death or CHF hospitalisation % 50 538 (42.3%) Placebo 40 483 (37.9%) 30 Candesartan 20 10 HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010 0 0 1 2 3 3.5 years Number at risk Candesartan 1276 1176 1063 948 457 Placebo 1272 1136 1013 906 422 McMurray et al, Lancet 2003

41. CHARM-AddedPrespecified subgroups, CV death or CHF hospitalisation p-value for treatment interaction Candesartanevent/n Placeboevent/n Beta- Yes 223/702 274/711blocker No 260/574 264/561 Recom. Yes 232/643 275/648dose of No 251/633 263/624ACE inhib All patients 483/1276 538/1272 0.14 0.26 0.6 0.8 1.0 1.2 1.4 Candesartan better Hazard ratio Placebo better McMurray et al, Lancet 2003

42. CHARM-AddedConclusions • Addition of candesartan to an ACE inhibitor (and beta-blocker) leads to a further and clinically important reduction in CV mortality and morbidity in patients with CHF • The benefit of candesartan corresponds to a NNT of 23 (for a mean of 3.0 years) to prevent one CV death or a first CHF hospitalisation • This benefit is obtained with relatively few adverse effects, although there is an increased risk of hypotension, hyperkalaemia and renal dysfunction McMurray et al, Lancet 2003

43. CHARM - Low EF trials: baseline characteristics Candesartan Placebo n=2289 n=2287 Mean age (years) 65 65 Women (%) 26 26 NYHA class (%) II 35 34 III 62 62 IV 3 4Mean LVEF (%) 29 29 Medical history (%) myocardial infarction 59 58 diabetes 29 29 hypertension 48 50 atrial fibrillation 26 26 Young et al, Circulation 2004

44. Two year HR 0.77 p<0.001 One year HR 0.70 p<0.001 CHARM - Low EF trials CV death or CHF hospitalisations CV death or CHF hosp (%) Placebo 944 (41.3%) 50 40 Candesartan 817 (35.7%) 30 20 10 Hazard ratio 0.82 (95% CI 0.74 – 0.90), p<0.001 0 0 1 2 3 3.5 yrs Number at risk Candesartan 2289 2105 1894 1382 580 Placebo 2287 2023 1811 1333 548 Young et al, Circulation 2004

45. CHARM-Low EFImplications • Candesartan significantly reduces cardiovascular death, hospital admission for heart failure, and all-cause mortality in patients with CHF and LVEF 40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist • This approach offers the clinician an opportunity to make additional improvements in the poor prognosis of CHF patients when left ventricular systolic dysfunction is present Young et al, Circulation 2004

46. CHARM-OverallCV death or CHF hospitalisation % 50 40 1310 (34.5%) Placebo 1150 (30.2%) 30 Candesartan 20 10 HR 0.84 (95% CI 0.77-0.91), p<0.0001Adjusted HR 0.82, p<0.0001 0 0 1 2 3 3.5 years Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 Pfeffer et al, Lancet 2003

47. CHARM-Overall Conclusions Treatment of a broad spectrum of patients with symptomatic CHF with candesartan resulted in a: • 9% reduction in all cause deaths (p=0.055, covariate adj. p=0.032) • 12% reduction in CV mortality (p=0.012) • 21% reduction in CHF hosp. (p<0.0001) • 16% reduction in CV deaths or CHF hosp. (p<0.0001) Pfeffer et al, Lancet 2003

48. Use of angiotensin II receptor blockers (ARBs) in heart failure • ARBs can be considered in combination with ACE-I in patients who remain symptomatic, to reduce mortality (Class IIa, level B) and hospital admissions for HF (Class I, level A) • Concerns raised by initial studies about a potential negative interaction between ARBs and beta-blockers have not been confirmed by recent studies in post-MI or CHF (Class I, level A)

49. Pharmacological methods of stabilization of atherosclerotic plaque Proven effect

50. Benefits of statin therapy