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JACC: HEART FAILURE VOL. 3, NO. 8, 2015 ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC. ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2015.04.010 EDITORIAL COMMENT The Ongoing Evolution of Optimal Clinical Endpoints for Heart Failure Trials* Henry Krum, MBBS, PHD, Ingrid Hopper, MBBS A dvances in heart failure (HF) drug and device III symptoms and a weighted average left ventricular therapies over the past 3 decades have made ejection fraction of 27%. The trials were divided into major inroads into the lethality of this dis- 3 groups according to the proportion of patients ease. Angiotensin-converting enzyme (ACE) inhi- treated with a beta-blocker. The proportion of CV bitors and angiotensin receptor blockers (ARBs), deaths decreased from 87% with low beta-blocker use beta-blockers, mineralocorticoid receptor antagonists to 80% with high beta-blocker use. Non-CV deaths (MRAs), as well as device-based approaches including rose from 11.4% to 19.1% with high beta-blocker cardiac resynchronization therapy and implantable therapy, representing a proportional increase of cardioverter defibrillator therapy, have resulted in two-thirds in non-CV deaths. The reduction in CV substantial mortality, morbidity and quality of life mortality was associated with a rise in non-CV deaths, (QoL) benefits to such patients, particularly those which was due mostly to malignancy. with HF and reduced ejection fraction (HFREF). This analysis confirms what we have known for Beta-blockers are arguably the most potent therapy some time, which is that mortality rates are falling in reducing mortality in HF. Mortality reductions in with modern HF treatment; these data allow us to go mild to moderate as well as advanced HFREF in the some way in quantifying the major therapeutic ad- pivotal trials additional to background ACE inhibitors vances that have been made in this field. This analysis and diuretics were consistently of the order of 30% examines background beta-blocker use within these (1–3). This was accompanied by improvements in trials, and as the authors acknowledge, concomitant cardiac remodeling parameters, HF symptoms, and with increased beta-blocker use over recent years QoL measures. has been increased use of ACE inhibitor/ARB, rapid SEE PAGE 603 In this issue of JACC: Heart Failure, Rush et al. (4) have reviewed the totality of HF randomized controlled trials in the past 3 decades, evaluating cardiovascular (CV) mortality according to beta-blocker usage in the trials. The authors have been meticulous in including all of the major, predominantly HFREF, randomized control trials over this period. The analysis included 66 trials, including 136,182 participants and 32,140 deaths, with participants mostly with New York Heart Association (NYHA) functional class II and uptake of MRAs following the RALES study (Randomized Aldactone Evaluation Study) (5) and the EMPHASIS-HF study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) (6) as well as the advent of devices, and it is therefore impossible to attribute improved CV mortality (and accompanying relative increase in non-CV mortality) entirely to beta-blocker therapy alone. However, a sensitivity analysis adjusting for ACE inhibitor/ARB use and adjusting for MRA use, and also using a metaanalytic approach, demonstrated that beta-blockers contributed most to the reduction in CV deaths. This analysis includes the individual study out- *Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash Uni- comes of the placebo group and the intervention group. Many of these interventions are of novel agents that turned out to result in neutral or even adverse clinical outcomes. Examples include the versity, Melbourne, Australia. Drs. Krum and Hopper have reported that BEST The Beta-Blocker Evaluation of Survival Trial they have no relationships relevant to the contents of this paper to disclose. study (7), in which bucindolol failed to improve 616 Krum and Hopper JACC: HEART FAILURE VOL. 3, NO. 8, 2015 AUGUST 2015:615–7 Endpoints for HF Trials survival in NYHA functional class III and IV HF, and associated with admissions are meaningful for health the GISSI-HF (Gruppo Italiano per lo Studio della care payers. Again there are major issues with this as a Sopravvivenza nell’Infarto miocardico study) (8), in clinical outcome. HF hospitalization may reflect which rosuvastatin failed to improve survival in regional practices and preferences, with significant NYHA functional class II to IV HF. By definition, none regional variation in bed days and need for admission. of these interventions constitute standard therapy Some centers use short-stay units or give outpatient and thus their inclusion in the analysis may poten- intravenous diuretics in an effort to avoid “formal” tially skew the results. An analysis examining just the admissions, which further blurs the definition of a HF placebo group would be informative. hospitalization. It can also be difficult to determine the The falls in CV mortality have had consequences relative contribution of HF to an admission when for the design of HF clinical trials. As the authors multiple organ dysfunction exists; for example, with note, all-cause mortality has become an increasingly primary pneumonia resulting in HF decompensation. insensitive endpoint in HF clinical trials. Although All of these outcomes do not necessarily reflect this is an easily definable and confirmable endpoint, what is important to the patient. This has been it has the obvious weakness that causes of death such termed the “patient journey.” QoL measures have as trauma and malignancy that are unrelated to HF (or traditionally been viewed as soft science, because its treatment) are included. More recent trials have they are somewhat subjective and often have not required a more refined approach to capturing out- been particularly well-correlated with harder mor- comes of most interest and over the past 15 years, HF tality outcomes (10). However, for the patient, these trials have used CV mortality rather than all-cause measures may be far more meaningful than the blunt mortality as at least a component of the primary instruments described previously. Alternatives to endpoint. All-cause mortality should not be aban- describe the patient journey have been suggested in doned as an outcomes measure, because no reduction the literature (11–13); however, these have not been in all-cause mortality in the presence of a reduction in widely accepted nor stringently validated, and regu- CV mortality may be a safety signal that the treatment lators are somewhat uncertain of their clinical utility. is shifting the cause of death. This was seen in HF mortality is laudably falling due in large part to The Digitalis Investigation Group trial (9), in which the addition of beta-blockers to our clinical arma- symptomatic HF decreased with reduced HF hospi- mentarium. However, these major gains cannot be talizations, but no reduction in mortality was seen seen in isolation from the contribution of other due to a presumed rise in arrhythmic deaths. therapies to improvements in HF mortality. Beta- CV mortality allows greater precision with regard to blockers continue to be underprescribed in HF, and evaluation of the benefits or otherwise of a HF thera- this continues to be a major challenge going forward. peutic agent, but practically, it is expensive because Additionally, this analysis demonstrates that im- independent adjudication committees are required to provements in HF mortality forecast increasing diffi- review the medical records and determine cause of culty demonstrating improved outcomes in future death. There is also residual uncertainty about the trials, and work is needed to develop appropriate cause of death in the absence of post-mortems and clinical endpoints in contemporaneous HF trials. This when the study participant is found deceased at home endpoint evaluation work is urgently needed to with an unwitnessed death. There is uncertainty about optimize evaluation of new treatments to reduce the whether these deaths should be included as CV mor- still unacceptably high mortality and morbidity tality or excluded from the analysis, but as the authors associated with the condition. found, this accounted for only 5.7% of all deaths. The inclusion of HF hospitalizations in outcomes REPRINT REQUESTS AND CORRESPONDENCE: Prof. has received increasing interest. One of the advan- Henry Krum, Centre of Cardiovascular Research and Ed- tages of this outcome is that it reflects costs of HF ucation in Therapeutics, School of Public Health and treatment, which are rapidly increasing. Multiple Preventive Medicine, Monash University, 99 Commercial admissions for HF reflects poor prognosis, and Road, Melbourne, Victoria 3004, Australia. E-mail: henry. this outcome can capture that aspect, and the costs [email protected]. REFERENCES 1. CIBIS Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 1999;353:9–13. 2. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002; 106:2194–9. Krum and Hopper JACC: HEART FAILURE VOL. 3, NO. 8, 2015 AUGUST 2015:615–7 Endpoints for HF Trials 3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7. 7. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–67. 11. 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;7:176–82. 4. Rush CJ, Campbell RT, Jhund PS, et al. Falling cardiovascular mortality in heart failure with reduced ejection fraction and implications for clinical trials. J Am Coll Cardiol HF 2015;3:603–14. 8. Tavazzi L, Maggioni A, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, doubleblind, placebo-controlled trial. Lancet 2008;372: 1231–9. 12. Cleland JG. How to assess new treatments for the management of heart failure: composite 5. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. 6. EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 9. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33. 10. Anker SD, Agewall S, Borggrefe M, et al. The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. Eur Heart J 2014;35:2001–9. scoring systems to assess the patients’ clinical journey. Eur J Heart Fail 2002;4:243–7. 13. Cohn J, Cleland JG, Lubsen J, et al. Unconventional end points in cardiovascular clinical trials: should we be moving away from morbidity and mortality? J Card Fail 2009;15: 199–205. KEY WORDS beta-blockers, clinical trials, endpoints, mortality 617