1 / 70

Current & Future Perspectives in the Treatment of Heart Failure

Current & Future Perspectives in the Treatment of Heart Failure. HF – More malignant than cancer?. Stewart et al. Eur J of Heart Failure 2001, 3(3):pp315-322. HF admission rates per annum – 7 countries 1978-1993. McMurray & Stewart, Heart 2000;83:pp596-602.

tanner
Download Presentation

Current & Future Perspectives in the Treatment of Heart Failure

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Current & Future Perspectives in the Treatment of Heart Failure

  2. HF – More malignant than cancer? Stewart et al. Eur J of Heart Failure 2001, 3(3):pp315-322.

  3. HF admission rates per annum – 7 countries 1978-1993 McMurray & Stewart, Heart 2000;83:pp596-602.

  4. Change in causal factors for HF Framingham 1950-1987 McMurray & Stewart, Heart 2000;83:pp596-602.

  5. Prevalence of HF by age in Framingham Rate per 1000 Age Lakatta & Levy, Circulation 2003;107:pp139-146

  6. HF Epidemiology - Australia • HF prevalence: 1% of patients aged 50-59yrs but >50% for those 85+ • Likely to be 300,000 Australians affected by CHF • 30,000 new cases annually • Between 1996 and 1997 • 41,000 hospitalisations for HF as principal diagnosis • CHF accounted for 0.8% of all hospitalisations (NHF guidelines, MJA 2001;174:pp.459-466)

  7. Chronic Heart Failure in Australian General Practice % of patients prescribed each class of drug 70 60 50 40 30 20 10 0 Diuretics ACEI Digoxin BB CCB-DHP CCB-nonDHP Aspirin Warfarin Spironolactone Hydralaz ine AIIRA Adapted from Krum et al. The Cardiac Awareness Survey & Evaluation (CASE study), MJA 2001; 174:pp.439-444.

  8. Causes of Chronic Heart Failure Systolic (impaired ventricular contraction) • Common • Ischaemic heart disease • Hypertension • Less common • Non-ischaemic idiopathic dilated cardiomyopathy Diastolic (impaired ventricular relaxation) • Common • Hypertension • Ischaemic heart disease • Diabetes • Less common • Valvular disease, especially aortic stenosis (NHF guidelines, MJA 2001;174:pp.459-466)

  9. Treatment of systolic HF – (LVEF<40%) Severe symptoms (NYHA Class IV) Identify/treat acute precipitant e.g. acute ischaemia/infarction arrhythmia non-compliance Non-pharmacological treatment Salt/fluid restriction Exercise/conditioning program Pharmacological Treatment Diuretic + ACE inhibitor No improvement Improvement *Patients with NYHA Class IV heart failure should be challenged with beta blockers provided they have been rendered euvolaemic and do not have any contra-indication to beta blockade. Add spironolactone +/- Digoxin Add Beta Blocker **Palliative care options may include use of multiple diuretics, hydralazine, nitrates and/or short term use of inotropic agents to control intractable heart failure symptoms. Add Beta Blocker (irrespective of NYHA class*) No improvement not tolerated Improvement Palliative care if unsuitable for heart transplantation** Consider heart transplantation if age <65yrs + no major co-morbidity Continue medical treatment (NHF guidelines, MJA 2001;174:pp.459-466)

  10. Management of diastolic HF Management of diastolic heart failure (heart failure with preserved systolic function) Is there fluid overload**? Is there an identifiable cause? Yes No Diuretic Treat cause Ischaemic heart disease Cardiomyopathy Hypertension Hypertrophic CM Investigate family hx Restrictive CM Anti-Hypertensive therapy*** Investigate suitability for revascularisation Endomyocardial biopsy for infiltrative diseases e.g. sarcoidosis amyloidosis Pharmacological treatment Beta blocker CCB Pharmacological treatment ACEI Beta blocker CCB If no specific cause found consider constrictive pericarditis **With rare exception, patients with diastolic heart failure present with symptoms and signs of fluid overload, either pulmonary or systemic congestion, or both Surgical pericardiectomy (NHF guidelines, MJA 2001;174:pp.459-466) ***Choice of therapy will vary according to clinical circumstances. E.g. thiazide diuretic – elderly, systolic hypertension ACEI – LVH, diabetes, IHD Beta blocker - angina

  11. Drug Use in Symptomatic Chronic Heart Failure First line agents • ACEI • Diuretics • Beta Blockers • for systolic heart failure despite appropriate doses of ACEI’s and diuretics/or for advanced symptoms of CHF • Spironolactone • for severe HF despite appropriate doses of ACEI • AIIRAs • (currently) for patients intolerant of ACEI Second-line agents • Digoxin • Hydralazine and isosorbide dinitrate • Where no other option exists (NHF guidelines, MJA 2001;174:pp.459-466) AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia

  12. Inhibition of the RAAS in HF • Because of the major importance of RAAS activation in the progression of CHF, blockade of this system has become the cornerstone of successful therapy for systolic ventricular dysfunction. • ACE inhibitors have been shown to: • prolong survival (compared with placebo) in patients with New York Heart Association Class II, III and IV CHF; • improve patient symptom status, exercise tolerance and reduce hospitalisation for worsening CHF (in some but not all studies); and • increase ejection fraction compared with placebo in many studies. Krum et al. MJA 2001; 174: 459-466

  13. Non-ACE pathways Angiotensinogen Renin t-PA Cathepsin G Angiotensin I ACE ACE inhibitor AT1-receptor Vaso- constriction Cell growth Sodium and fluid retention Sympathetic activation Angiotensin II is produced both by ACE and non-ACE dependent pathways Chymase CAGE Angiotensin II Peterson and Dunlap, CHF 2002, 8(5):pp.246-250. AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia

  14. AT1-Receptor Blockers (AIIRA)Clinical Outcome Studies HBP LIFE SCOPE VALUE 04? Vascular ONTARGET06 TRANSCEND 06 MI OPTIMAAL VALIANT 03 HF ELITE II Val-Heft CHARM 03 HEAAL 05 I-PRESERVE Stroke ACCESS PRoFESS MOSES Pre Diabetes NAVIGATOR 06 Diabetes Opht DIRECT 05 Diabetes Renal RENAAL IDNT These trials may discuss the use of non approved doses or indications, refer to Australian PI before prescribing AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia

  15. 27 3 6 9 12 15 18 21 24 0 Val-HeFT Subgroup without ACE-I therapy(n=366) 44.0%Risk ReductionP = 0.002 Event Free Survival Probability 0.6 Valsartan (N = 185) Placebo (N = 181) Time Since Randomization (Months) Cohn et al. NEJM 2001; 345(23):pp.1667-1675 AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia

  16. 8. Recent Heart Failure Data CHARM CandesartaninHeart failureAssessment ofReductioninMortalityand morbidity Presented 31st August 2003 at the European Society of Cardiology (ESC) meeting in Vienna, Austria, Published in the Lancet Sep 7, 2003. Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  17. CHARM Program 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARMAlternative CHARMAdded CHARMPreserved n=3025 LVEF >40%ACE inhibitor treated/not treated n=2028 LVEF £40%ACE inhibitor intolerant n=2548 LVEF £40%ACE inhibitor treated candesartan 4mg/8mg-32mg candesartan 4mg/8mg-32mg candesartan 4mg/8mg-32mg Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death McMurray et al. Eur J Heart Failure, 2003:pp.261-270 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  18. CHARM – Baseline Medication % McMurray et al. Eur J Heart Failure, 2003:pp.261-270 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  19. % 50 406 (40.0%) Placebo 40 334 (33.0%) 30 Candesartan 20 HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001 10 0 0 years 1 2 3 3.5 CHARM-Alternative: Primary outcomeCV death or CHF hospitalisation Number at risk candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126 Granger et al. Lancet, 2003;362:pp.772-776 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  20. p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69 p=0.50 CHARM-Alternative Permanent study drug discontinuations Percentof patients Placebo 25 21.5 Candesartan 19.3 20 15 10 6.1 5 3.7 2.7 1.9 0.9 0.4 0.2 0.3 0.1 0 0 AE/lab. abnorm. Hypo-tension Increased creatinine Increasedpotassium Cough Angio-edema Granger et al. Lancet, 2003;362:pp.772-776 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  21. CHARM-Alternative Permanent study drug discontinuations According to prior ACE-I intolerance Percentof patients Placebo 25 23.1 Candesartan 20 15 13.6 12.0 9.1 10 (1/39) 4.2 5 2.6 1.0 0.5 0.3 0 0 Hypo-tension Increased creatinine Cough Angioedema Increasedpotassium Granger et al. Lancet, 2003;362:pp.772-776 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  22. CHARM-AlternativeConclusions • Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan was well tolerated • In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity Granger et al. Lancet, 2003;362:pp.772-776 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  23. CHARM-Added:Primary outcomeCV 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 Number at risk Candesartan 1276 1176 1063 948 457 Placebo 1272 1136 1013 906 422 0 1 2 3 3.5 years McMurray et al. Lancet, 2003;362:pp.767-771 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  24. 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 • 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;362:pp.767-771 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  25. CHARM Program 3 component trials comparing candesartan to placebo 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: CV death or CHF hosp Yusuf et al. Lancet, 2003;362:pp.777-781 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  26. CHARM-Preserved: Primary outcomeCV death or CHF hospitalisation % 30 366 (24.3%) Placebo 25 333 (22.0%) 20 Candesartan 15 10 HR 0.89 (95% CI 0.77-1.03), p=0.118Adjusted HR 0.86, p=0.051 5 0 0 1 2 3 3.5 years Number at risk Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 Yusuf et al. Lancet, 2003;362:pp.777-781 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Yusuf et al. Lancet, 2003;362:pp.777-781

  27. CHARM-Preserved Development of new diabetes Number of cases HR p-value Candesartan Placebo (CI) 47 77 0.60 0.005 (0.41-0.86) Yusuf et al. Lancet, 2003;362:pp.777-781 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  28. CHARM-Overall All-cause death 35 30 945 (24.9%) Placebo 25 886 (23.3%) 20 % Candesartan 15 10 HR 0.91 (95% CI 0.83-1.00), p=0.055 Adjusted HR 0.90, p=0.032 5 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;362:pp.759-766 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  29. CHARM-Overall CV death and non-CV death CVdeath 30 HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006 % 25 Placebo 20 Candesartan 15 Non-CV death 10 p=0.45 Candesartan 5 Placebo 0 Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 0 1 2 3 3.5 years Pfeffer et al. Lancet, 2003;362:pp.759-766 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  30. CHARM-OverallCV death or CHF hosp. 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 Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 0 1 2 3 3.5 years Pfeffer et al. Lancet, 2003;362:pp.759-766 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  31. Increased creatinine AE/ lab. abnorm. Hypo-tension Increasedpotassium CHARM-OverallPermanent study drug discontinuations Percent of patients Placebo 25 21.0 Candesartan 20 16.7 15 10 6.2 5 3.5 3.0 2.2 1.7 0.6 0 p<0.0001 p<0.0001 p<0.0001 p<0.0001 Pfeffer et al. Lancet, 2003;362:pp.759-766 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  32. CHARM-OverallImplications The consistent effects of candesartan across the three CHARM trials suggest that: • The addition of the ARB, candesartan, can be considered in all patients with chronic heart failure irrespective of ejection fraction, age and sex • Benefits were achieved on top of other effective concomitant therapies including ACE inhibitors and beta-blockers Pfeffer et al. Lancet, 2003;362:pp.759-766 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

  33. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure MERIT-HF A Double-Blind, Placebo-Controlled Survival Study With Metoprolol CR/XL in Patients With Decreased Ejection Fraction (£0.40) and Symptoms of Heart Failure (NYHA II–IV) MORTALITY AND MORBIDITY RESULTS The MERIT-HF Study Group: Am J Cardiol 1997;80:54-58J Lancet 1999;353:2001-7 JAMA 2000;283:1295-302 MERIT-HF

  34. Primary Objectives To determine whether metoprolol CR/XL reduces: • Total mortality • The combined end point of all-cause mortality and all-cause hospitalisation (time to first event) Am J Cardiol 1997;80:54-58J MERIT-HF

  35. Total Mortality 20 Placebo 15 Metoprolol-XL % 10 P=0.0062 (adjusted) P=0.00009 (nominal) 5 Risk reduction = 34% 0 0 3 6 9 12 15 18 21 Months of follow-up Lancet 1999;353:2001-7 MERIT-HF

  36. Sudden Death 12 Placebo 9 Metoprolol-XL % 6 Risk reduction = 41% P=0.0002 3 0 3 6 9 12 15 18 21 Lancet 1999;353:2001-7 0 Months of follow-up MERIT-HF

  37. Death From Worsening Heart Failure 5 4 Placebo 3 % Metoprolol-XL 2 Risk reduction = 49% P=0.0023 1 0 0 3 6 9 12 15 18 21 Lancet 1999;353:2001-7 Months of follow-up MERIT-HF

  38. Withdrawal of Study Medicine 20 Placebo Metoprolol-XL 15 % 10 5 0 Adverse events -17% 234/196 Worsening HF -25% 85/64 All-cause -10% 310/279 No. of withdrawals JAMA 2000;283:1295-302

  39. Improvement in NYHA Functional Class and Quality of Life: Last Visit Change in NYHA Class P=0.0028 (n=3952) Change in QOL (OTE) P=0.0089* (n=741) * Among the 185 patients in the metoprolol CR/XL group who reported an improvement, 72% judged this improvement as important, very important, or extremely important to carry out daily activities. JAMA 2000;283:1295-302

  40. Conclusions Treatment with metoprolol CR/XL once daily added to standard heart-failure therapy: • Improves survival • Reduces the need for hospital admission due to worsening heart failure • Improves symptoms of heart failure • Increases well-being Lancet 1999;353:2001-7JAMA 2000;283:1295-302 MERIT-HF

  41. Interpreting Outcomes of Recent Major Cardiovascular Trials KB Swedberg (Göteborg, Sweden)

  42. 1.00 0.90 Risk Reduction 30% (- 18 - 40) P < 0.001 0.80 0.70 Probability of Survival Spironolactone 0.60 Placebo 0.50 0.40 0.30 0 3 6 9 1 2 15 18 21 24 27 30 33 36 39 Months RALES: All-cause Mortality • 1,663 Patients randomised to placebo/spironolactone • 95% background ACEI • 11% background  blocker Pitt et al NEJM 1999

  43. Val-HeFT: All-Cause Mortality or Morbidity • 5,010 patients in NYHA class II (61.7%), III (36.2%) or IV (3.1%) with mean EF 27% and age 63 years • Background: ACEI 92.3%,  blocker 35.5% 100 95 90 85 RR = 13.3% P = 0.009 Event-free Survival (%) 80 75 70 Valsartan Placebo 65 0 0 3 6 9 12 15 18 21 24 27 Months Cohn et al. NEJM 2002

  44. Conclusions • Treatment of heart failure has resulted in major survival benefits during the last 10-15 years • The challenge facing the medical community remains to ensure that ACE-inhibitors and  blockers are used in all appropriate patients • Inhibition of aldosterone seems to carry further benefits • Addition of an ARB could be considered in all patients • To optimise neurohormonal blockade, care delivery structures need to be revisited

  45. HOPE study results – primary endpoints Combined cardiovascular endpoint Cardiovascular mortality, myocardial infarction, stroke Cardiovascular mortality Myocardial infarction Stroke -20% p<0.001 -22% p<0.001 -26% p<0.001 -32% p<0.001 Ramipriln=4645, Placebon=4652 The HOPE Study Investigators, 2000

  46. Participating countries Argentina Finland Netherlands Spain Australia France Norway Sweden Austria Germany Philippines Switzerland Belgium Greece Poland Taiwan Brazil Hungary Portugal Turkey Canada Ireland Redcliffe Singapore UK China Italy Slovakia United Arab Emirates Czech Republic Korea South Africa USA Denmark Mexico

  47. Impact of Heart Failure

  48. Age (years) 50-59 80-89 All ages Men 8 66 7.4 Women 8 79 7.7 A prevalent condition Prevalence of HF (per 1000 population) Framingham Heart Study: Ho et al. 1993 J Am Coll Cardiol;22:6-13

  49. A growing burden Deaths from HF 1979-1997 (USA) Vital Statistics of the United States, National Center for Health Statistics

  50. An economic burden Annual cost of HF estimated to be $22.5 billion (USA) Healthcareproviders Home health/Othermedical durables Indirect Costs Drugs 1.5 1.1 2.2 2.2 15.5 Hospital/Nursing home Costs in billions of dollars American Heart Association, 2000 Heart and Stroke Statistical Update

More Related