(Circulation. 2002;105:2223.)
© 2002 American Heart Association, Inc.
Clinical Cardiology: New Frontiers |
From the Clinical Research Initiative in Heart Failure, University of Glasgow, Scotland (J.M.), and the Cardiovascular Division, Brigham and Womens Hospital, Boston, Mass (M.A.P.).
Correspondence to Dr John J.V. McMurray, Clinical Research Initiative in Heart Failure, University of Glasgow, Wolfson Building, Glasgow G12 8QQ, Scotland. E-mail J.McMurray{at}bio.gla.ac.uk
Key Words: diastole heart failure pharmacology trials molecular biology
| Introduction |
|---|
|
|
|---|
| Anticytokine and Immunomodulating Therapy |
|---|
|
|
|---|
|
| Matrix Metalloproteinase Inhibitors |
|---|
|
|
|---|
| Antithrombotic Therapy |
|---|
|
|
|---|
4500 patients with NYHA class II to IV CHF and an LVEF
0.35. The primary end point is a composite of death, nonfatal MI, and nonfatal stroke. Until the results of WATCH are available, low-dose aspirin remains the antiplatelet agent of choice in patients with CHF and atherosclerotic disease and should usually be coprescribed with an ACE inhibitor. | Metabolic Interventions |
|---|
|
|
|---|
| Inotropic Therapy |
|---|
|
|
|---|
| Anemia as a Treatment Target? |
|---|
|
|
|---|
| Adenosine Agonists |
|---|
|
|
|---|
| Targeting Pharmacological Therapy? |
|---|
|
|
|---|
600 black men and women with NYHA class III to IV CHF to placebo or hydralazine and isosorbide dinitrate and evaluate clinical status and ventricular function. | Tailoring Pharmacological Therapy? |
|---|
|
|
|---|
| Frameworks for Implementation of Pharmacological Therapy |
|---|
|
|
|---|
| Treatments Targeted at Coronary Artery Disease and Its Consequences in CHF |
|---|
|
|
|---|
Pharmacological Reversal of Myocardial Hiberation
A surprisingly high proportion of patients with CHF and coronary artery disease have substantial areas of hibernating myocardium.2426 The Carvedilol Hibernation Reversible ISchaemia Trial: MArker of Success (CHRISTMAS) study is attempting to determine whether the presence or absence of hibernating myocardium predicts improvement in LVEF in patients treated with carvedilol, ie, comparing the changes in LVEF in the randomized nonhibernating versus hibernating groups.26
Percutaneous and Surgical "Revascularization" in Patients With Coronary Artery Disease and CHF
The safety and efficacy of myocardial revascularization, especially surgical revascularization, is uncertain in CHF.25 A number of small and uncontrolled series have suggested that patients with large areas of viable myocardium may have a low interventional risk and a large potential benefit from revascularization.25 Consequently, 2 clinical trials are currently planned to address the impact of mechanical revascularization on outcome in such patients. One is the Heart Failure Revascularization TrialUnited Kingdom (HEART-UK) study, comparing percutaneous or surgical revascularization with optimal medical therapy, which will recruit
800 patients and have a minimum follow-up of
5 years and a primary end point of all-cause mortality.25 A planned US trial, Surgical Treatment for IsChemic Heart failure (STICH), intends to address 2 hypotheses, one being the revascularization hypothesis and the other an "LV reconstruction hypothesis."27 The latter concerns the possibility that surgical remodeling to achieve optimum LV shape and size will also reduce morbidity and mortality in these patients.
| Nonpharmacological Therapy for Low-LVEF CHF: Exercise Training, Devices, and Surgery |
|---|
|
|
|---|
Biventricular (Multisite) Pacing
Patients with CHF often have abnormal electrical activation of the myocardium, reflected as a prolonged PR interval and/or QRS duration of the surface ECG. This electromechanical dyssynchrony may lead to suboptimal atrioventricular coupling, uncoordinated ventricular contraction, and presystolic mitral regurgitation. Biventricular or multisite pacing may "resynchronize" cardiac contraction and reduce these abnormalities.29
Two relatively small, short-term trials, the MUltisite STImulation in Cardiomyopathy (MUSTIC) and Multicenter InSync Randomized Clinical Evaluation (MIRACLE) studies, have suggested that biventricular pacing can improve symptoms and exercise capacity in patients with prolonged QRS duration.30,31 Biventricular pacing may also lead to LV reverse remodeling and a reduction in mitral regurgitation. Long-term morbidity/mortality trials are either planned or under way, including the Comparison Of Medical therapy and Pacing ANd DefibrillatION in Chronic Heart Failure (COMPANION) and CArdiac REsynchronisation in Heart Failure (CARE-HF) trials.29
Implantable Cardioverter-Defibrillators
The Antiarrhythmics Versus Implantable Defibrillators (AVID) and Multicentre Automatic Defibrillator Implant Trial (MADIT) demonstrated that implantable cardioverter-defibrillators (ICDs) reduce mortality in patients with a low LVEF and spontaneous or inducible ventricular arrhythmias. Post hoc analysis of both trials suggested that the greatest benefit was obtained in patients with the lowest LVEF.32,33 Other primary and secondary prevention studies with ICDs are in general agreement with these findings, including the MADIT-II trial, which was recently stopped prematurely because of overwhelming evidence of a survival benefit in the ICD group. Consequently, there is interest in the role of ICDs in patients with CHF. One large study, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), is comparing ICD therapy with amiodarone treatment in
2500 patients with NYHA class II to III CHF and an LVEF
0.35. The primary end point is all-cause mortality.32,33 COMPANION (see above) is a 3-way comparison of medical therapy; medical therapy plus biventricular pacing; and medical therapy, biventricular pacing, and an ICD.29
Ventricular Assist Devices, Pumps, and Total Artificial Hearts
There is renewed interest in mechanical support for, or replacement of, the failing heart as a stand-alone therapy, rather than as a bridge to transplantation. A detailed review of this topic is beyond the scope of this review. The Randomized Evaluation of Mechanical Assistance for Treatment of Chronic Heart failure (REMATCH), however, showed that implantation of an LV assist device can improve survival in transplant-ineligible patients with end-stage CHF, but at the expense of frequent infective and hemorrhagic complications.34 Recently, the first implantations of a newly configured total artificial heart have taken place, using the device not as a bridge to transplantation but rather as a mechanical replacement for otherwise terminal CHF.
| Molecular Approaches to Treatment: Cell and Gene Therapy for CHF |
|---|
|
|
|---|
| Current Recommendations for the Treatment of Low-LVEF CHF |
|---|
|
|
|---|
|
| Treatments for Preserved-LVEF CHF |
|---|
|
|
|---|
1000 patients >70 years of age with CHF and no major LV systolic dysfunction (LVEF <0.40 or wall motion index <1.4).48 Patients will receive double-blind treatment with placebo or perindopril. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors (SENIORS) trial is randomizing patients
70 years of age with CHF, many of whom will have a normal LVEF, to treatment with either placebo or nebivolol. There will undoubtedly be more trials in this previously neglected minority of patients with CHF. | Challenges Ahead |
|---|
|
|
|---|
Conclusions
The past 20 years have seen enormous progress in our understanding of the pathophysiology of CHF and its treatment. Pathophysiological progress has suggested therapeutic approaches, and the successes and failures of clinical trials have refined pathophysiological concepts as well as the science of trial design and conduct. The next 2 decades will present at least as many challenges as the past 2 and perhaps less prospect of the same enormous breakthroughs with pharmacological agents. Nevertheless, our patients with CHF can still expect further improvement in their quantity and quality of life.
Note Added in Proof
Both OVERTURE and ENABLE have recently completed and reported. There was no significant difference in mortality between the omapatrilat and enalapril groups in OVERTURE. Bosentan was not superior to placebo in ENABLE. Both of these trials were presented at the "late-breaking trials hot-line" at the American College of Cardiology Meeting in March 2002 (Atlanta, Ga).
| Footnotes |
|---|
Both authors have received research support for clinical trials and honoraria for advisory boards, lectures, and other activities related to a number of the pharmacological agents mentioned in this review.
| References |
|---|
|
|
|---|
2.
Skudicky D, Bergemann A, Sliwa K, et al. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol. Circulation. 2001; 103: 10831088.
3.
Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation. 2001; 103: 220225.
4.
Cohn JN, Ferrari R, Sharpe N, on behalf of an International Forum on Cardiac Remodeling. Cardiac remodeling: concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000; 35: 569582.
5. Feldman AM, Li YY, McTiernan CF. Matrix metalloproteinases in pathophysiology and treatment of heart failure. Lancet. 2001; 357: 654655.[CrossRef][Medline] [Order article via Infotrieve]
6.
Latini R, Tognoni G, Maggioni AP, et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol. 2000; 35: 18011807.
7. Katz AM. Heart failure in 2001: a prophesy revisited. Am J Cardiol. 2001; 87: 13831386.[CrossRef][Medline] [Order article via Infotrieve]
8. Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol. 1999; 84: 4650.[Medline] [Order article via Infotrieve]
9. Shakar SF, Bristow MR. Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving beta-blocking agents. Curr Cardiol Rep. 2001; 3: 224231.[Medline] [Order article via Infotrieve]
10.
Slawsky MT, Colucci WS, Gottlieb SS. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000; 102: 22222227.
11.
Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomised controlled study. J Am Coll Cardiol. 2001; 37: 17751780.
12.
Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation. 2002; 105: 13481353.
13. Charron P, Komajda M. Are we ready for pharmacogenomics in heart failure? Eur J Pharmacol. 2001; 417: 19.[CrossRef][Medline] [Order article via Infotrieve]
14. Wood AJ. Racial differences in the response to drugs: pointers to genetic differences. N Engl J Med. 2001; 344: 13941396.
15.
Schwartz RS. Racial profiling in medical research. N Engl J Med. 2001; 344: 13921393.
16. Carson P, Ziesche S, Johnson G, et al. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999; 5: 178187.[CrossRef][Medline] [Order article via Infotrieve]
17.
Exper DV, Dries DL, Domanski MJ, et al. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. 2001; 344: 13511357.
18.
Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 16511658.
19.
Eichhorn E, Domanski M, Krause-Steinrauf H. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001; 344: 16591667.
20.
Yancy CW, Fowler MB, Colucci WS, et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med. 2001; 344: 13581365.
21. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000; 355: 11261130.[CrossRef][Medline] [Order article via Infotrieve]
22. McAlister FA, Lawson FM, Teo KK, et al. A systematic review of randomized trials of disease management programs in heart failure. Am J Med. 2001; 110: 378384.[CrossRef][Medline] [Order article via Infotrieve]
23.
Grady KL, Dracup K, Kennedy G, et al. Team management of patients with heart failure: a statement for healthcare professionals from the Cardiovascular Nursing Council of the American Heart Association. Circulation. 2000; 102: 24432456.
24.
Rahimtoola SH. Chronic myocardia hibernation. Circulation. 1994; 89: 19071908.
25. Cleland JGF, Alamgir F, Nikitin NP. What is the optimal medical management of ischaemic heart failure? Prog Cardiovasc Dis. 2001; 43: 433455.[CrossRef][Medline] [Order article via Infotrieve]
26. Cleland JG, Pennel D, Ray S, et al. The carvedilol hibernation reversible ischaemia trial: marker of success (CHRISTMAS). The CHRISTMAS Study Steering Committee and Investigators. Eur J Heart Fail. 1999; 2: 191196.
27.
Jones RH. Is it time for a randomized trial of surgical treatment of ischemic heart failure? J Am Coll Cardiol. 2001; 37: 12101213.
28. Coats AJ. Exercise training in heart failure. Curr Control Trials Cardiovasc Med. 2000; 1: 155160.
29. Varma C, Camm AJ. Pacing for heart failure. Lancet. 2001; 357: 12771283.[CrossRef][Medline] [Order article via Infotrieve]
30.
Cazeau S, Leclercg C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001; 344: 873880.
31. Louis A, Cleland JG, Crabbe S, et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail. 2001; 3: 381387.[CrossRef][Medline] [Order article via Infotrieve]
32. Klein H, Anricchio A, Reek S, et al. New primary prevention trials of sudden cardiac death in patients with left ventricular dysfunction: SCD-HEFT and MADIT-II. Am J Cardiol. 1999; 83: 91D97D.[CrossRef][Medline] [Order article via Infotrieve]
33. Glikson M, Friedman PA. The implantable cardioverter defibrillator. Lancet. 2001; 357: 11071117.[CrossRef][Medline] [Order article via Infotrieve]
34.
Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345: 14351443.
35.
Hajjar RJ, del Monte F, Matsui T, et al. Prospects for gene therapy for heart failure. Circ Res. 2000; 86: 616621.
36. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet. 2001; 357: 279280.[CrossRef][Medline] [Order article via Infotrieve]
37. Reinlib L, Field L. Cell transplantation as future therapy for cardiovascular disease? A workshop of the National Heart, Lung, and Blood Institute. Circulation. 2000; 101: E182E187.
38.
Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med. 2002; 346: 515.
39. Bartling B, Milting H, Schumann H, et al. Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure. Circulation. 1999; 100 (suppl II): II-216II-223.
40. Isner JM. Myocardial gene therapy. Nature. 2002; 415: 234239.Review.[CrossRef][Medline] [Order article via Infotrieve]
41.
Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 1999; 33: 19481955.
42. Petrie M, McMurray J. Changes in notions about heart failure. Lancet. 2001; 358: 432434.[CrossRef][Medline] [Order article via Infotrieve]
43.
Vasan RS, Benjamin EJ, Levy D. Congestive heart failure with normal left ventricular systolic function: clinical approaches to the diagnosis and treatment of diastolic heart failure. Arch Intern Med. 1996; 156: 146157.
44. Sweitzer NK, Stevenson LW. Diastolic heart failure: miles to go before we sleep. Am J Med. 2000; 109: 683685.[CrossRef][Medline] [Order article via Infotrieve]
45.
Vasan RS, Benjamin EJ. Diastolic heart failure: no time to relax. N Engl J Med. 2001; 344: 5659.
46.
Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation. 2000; 101: 21182121.
47. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. J Card Fail. 1999; 5: 276282.[CrossRef][Medline] [Order article via Infotrieve]
48. Cleland JG, Tendera M, Adamus J, et al. Perindopril for elderly people with chronic heart failure: the PEP-CHF study. Eur J Heart Fail. 1999; 1: 211217.[CrossRef][Medline] [Order article via Infotrieve]
49. Remme WJ. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN): rationale and design. Cardiovasc Drugs Ther. 2001; 15: 6977.[CrossRef][Medline] [Order article via Infotrieve]
50. Packer M. Proposal for a new clinical end-point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001; 7: 176182.[CrossRef][Medline] [Order article via Infotrieve]
51.
Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J. 2001; 22: 15271560.
52.
Hunt HA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America. Circulation. 2001; 104: 29963007.
53. McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice. Eur J Heart Fail. 2001; 3: 495502.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
K. Albouaini, M. Egred, A. Alahmar, and D. J. Wright Cardiopulmonary exercise testing and its application Postgrad. Med. J., November 1, 2007; 83(985): 675 - 682. [Abstract] [Full Text] [PDF] |
||||
![]() |
K Albouaini, M Egred, A Alahmar, and D J Wright Cardiopulmonary exercise testing and its application Heart, October 1, 2007; 93(10): 1285 - 1292. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. Liu, J. A. Simpson, K. R. Brunt, C. A. Ward, S. R. R. Hall, R. T. Kinobe, V. Barrette, M. Y. Tse, S. C. Pang, A. S. Pachori, et al. Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H48 - H59. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF] |
||||
![]() |
G. H Skrepnek, J. Abarca, D. C Malone, E. P Armstrong, F. M Shirazi, and R. L Woosley Incremental Effects of Concurrent Pharmacotherapeutic Regimens for Heart Failure on Hospitalizations and Costs Ann. Pharmacother., November 1, 2005; 39(11): 1785 - 1791. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Nishikimi, J. R. Hagaman, N. Takahashi, H.-S. Kim, H. Matsuoka, O. Smithies, and N. Maeda Increased susceptibility to heart failure in response to volume overload in mice lacking natriuretic peptide receptor-A gene Cardiovasc Res, April 1, 2005; 66(1): 94 - 103. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. T. Yan, R. T. Yan, and P. P. Liu Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials Ann Intern Med, January 18, 2005; 142(2): 132 - 145. [Abstract] [Full Text] [PDF] |
||||
![]() |
U. Corra, A. Mezzani, E. Bosimini, and P. Giannuzzi Cardiopulmonary Exercise Testing and Prognosis in Chronic Heart Failure*: A Prognosticating Algorithm for the Individual Patient Chest, September 1, 2004; 126(3): 942 - 950. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Heusch and K. R. Sipido Myocardial Hibernation: A Double-Edged Sword Circ. Res., April 30, 2004; 94(8): 1005 - 1007. [Full Text] [PDF] |
||||
![]() |
M. R. Mehra and B. H. Greenberg Cardiac resynchronization therapy: caveat medicus! J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1145 - 1148. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Bito, F. R. Heinzel, F. Weidemann, C. Dommke, J. van der Velden, E. Verbeken, P. Claus, B. Bijnens, I. De Scheerder, G. J.M. Stienen, et al. Cellular Mechanisms of Contractile Dysfunction in Hibernating Myocardium Circ. Res., April 2, 2004; 94(6): 794 - 801. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2002 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |