Author + information
- Published online June 26, 2017.
- John G.F. Cleland, PhD, MDa,b,∗ (, )
- Pierpaolo Pellicori, MDc,
- Andrew L. Clark, MDc and
- Mark C. Petrie, MDd
- aRobertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, Scotland, United Kingdom
- bNational Heart and Lung Institute, Imperial College, London, United Kingdom
- cDepartment of Cardiology, University of Hull, Kingston-upon-Hull, United Kingdom
- dInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
- ↵∗Address for correspondence:
Prof. John G.F. Cleland, Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow, G12 8QQ Scotland, United Kingdom.
“It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so”
—Mark Twain (1)
Most patients with heart disease develop heart failure before they die (2). Medical articles usually portray heart failure as a disease that follows an inexorable downhill course unless suddenly interrupted by a fatal arrhythmia. This doom-laden narrative is usually reinforced by a series of “mantra” cut-and-pasted with little thought from a handful of original articles: “5.7 million Americans have heart failure” (defined exactly how and does no other nationality matter?); “the annual cost of heart failure is >$30 billion” (to whom?); “five-year survival is dismal” (for all patients and compared to what?); “morbidity and mortality remain unacceptably high” (exactly what would be acceptable?). Is this depressing depiction of heart failure really true, or has it become true only through frequent repetition and uncritical acceptance of received wisdom? Perhaps there might be a benefit in encouraging each other to be more optimistic for our patients? Who would want to invest (public) money in a lost cause; who would invest in failure? Patients are potentially the greatest resource (civil, political, and medical) for improving health care, but it is difficult to ask for a patient’s help if the doctors or nurses appear as harbingers of doom. Doctors must distinguish the “spin” of the lobbyists, who believe that a message of fear and failure will obtain more resources for research and care, from the clinical facts, which are not the same for all patients. Without facts how can we inform patients properly and consequently ensure that joint decisions in care are optimal? We require data and its correct interpretation. It is time now to re-examine some of the shibboleths of heart failure.
In this issue of JACC: Heart Failure, Kalogeropoulos et al. (3) provide us with some granular data, describing the incidence of progression from chronic stable (Stage C) to advanced (Stage D) heart failure in a substantial cohort of patients with heart failure with reduced ejection fraction (HFrEF) managed in a high-quality academic health care system, Emory Health Care. There is no agreed definition of Stage D. In this report, it was based on medical judgment and/or the need for desperate measures (e.g., heart transplantation, left ventricular assist device, inotropic therapy, or palliative care). Many more patients might have been deemed to have progressed had another definition been used, such as recurrent hospitalization for heart failure. Age and comorbidity may influence the use of treatments for advanced heart failure and therefore the nature of the patients reaching an endpoint defined by the need for by extreme interventions.
Why is this analysis important? Most pharmacological treatments for patients with chronic stable heart failure are generic and low-cost, although many patients with HFrEF will require an implanted electrical device, which has substantial acquisition and maintenance costs. Most of the other costs of managing heart failure arise due to the inability to control congestion adequately, resulting in hospitalization. The importance of Stage D is that it reflects intractable or recurrent congestion that is debilitating for patients and costly for health services. Controlling congestion and preventing sudden death are key therapeutic goals in the management of heart failure; indeed, poorly controlled congestion may be an important trigger for ventricular and supraventricular arrhythmias and sudden death.
In the Emory cohort, the average patient age was 62 years, similar to that observed in many clinical trials but about 15 years younger than the epidemiological average. Many patients were in New York Heart Association (NYHA) functional class III or IV at baseline and might have already been in Stage D. Younger age or referral patterns might account for the low rate of some comorbidities. Most patients were treated with angiotensin-converting enzyme inhibitors and beta-blockers at the time of evaluation but only one-half of the patients had an implantable defibrillator. Presumably utilization of guideline-recommended therapies increased after initial patient evaluation under the aegis of an expert health care system. Within 3 years, about 25% of patients had died or progressed to Stage D, which is about 9% per year. This is remarkably similar to the rate of the primary outcome observed in the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial for patients with chronic stable heart failure assigned to sacubitril or valsartan. In the Emory cohort, the annual rate of progression to Stage D was 4.5% (but perhaps 6% if some gray-cases were included). Overall between 112 and 154 of 964 patients in this cohort progressed to Stage D over 3 years, but only 21 of these received a left ventricular assist device and only 7 a heart transplant. However, death prevented the possibility of reaching Stage D in a further 4.7% patients each year. Presumably most of these deaths were sudden, although some may have been non-cardiovascular. More African American patients progressed to Stage D, but this may be because they were less likely to die before progressing. Progression to Stage D is, in some senses, good news because it is potentially reversible, unlike death. Prediction models for nonfatal outcomes in populations with a high mortality must be interpreted with extreme caution because there are 2 ways to prevent non-fatal events, only one of which is good news. Death may pre-empt progression or progression may be prevented by an effective therapeutic package. This is a major limitation of the risk score presented by Kalogeropoulos et al. (3).
Treatment with either beta-blockers or angiotensin-converting enzyme inhibitors was strongly associated with lower mortality before reaching Stage D but not with progression to Stage D. This is best explained by a reduction in sudden death, as these agents are not known to reduce non-cardiovascular mortality, combined with a reduction in disease progression (4). Treatments that reduce sudden death but do not delay disease progression, as might be expected with an implantable defibrillator, may increase the number of patients in Stage D and therefore the costs of health care. However, in the Emory cohort, implantable defibrillators were neither associated with a lower mortality before reaching Stage D nor an increase in patients progressing to Stage D. Perhaps patients with implanted devices were at lower risk (younger age or milder symptoms) or had better pharmacological treatment. However, it is possible that sophisticated statistical analysis has disguised rather than illustrated the effect of treatment on outcomes. Simpler reporting of data is often better. Statistical models show only associations that often reflect variables that are surrogates for the true drivers of outcomes. Multivariable analyses should always be supported by expert clinical interpretation of an accompanying univariate analysis. Also, data-driven models should be compared with models based on clinical selection of key prognostic markers.
Publishing from the same dataset, Kalogeropoulos et al. (5) previously reported that 16.2% of patients with HFrEF had recovery of their left ventricular ejection fraction. The mortality at 3 years among these patients was 4.8% compared with 13.2% among those patients whose left ventricular ejection fraction had not recovered. This is an important message corroborated by other reports. For instance, for patients aged <67 years randomized to cardiac resynchronization therapy in the CARE-HF (Cardiac Resynchronization—Heart Failure) study (NYHA functional class III or IV heart failure with left ventricular ejection fraction <35%), more than one-half were still alive 10 years later; many were in NYHA functional class II (6). This much more optimistic scenario is surely more appealing to patients, their advocacy groups, health professionals, and research funders alike (Figure 1).
In summary, Kalogeropoulos et al. (3) have provided interesting analyses that provide new insights both into the progression of heart failure and its recovery. More trials are required to show that interventions such as inotropic therapy and left ventricular assist devices lead to worthwhile improvements in well-being and outcome compared with expert pharmacological therapy in patients who have progressed to Stage D. However, it is strategically important that the heart failure community works harder on public relations, putting more emphasis on success and less on failure. Let us dispel the narrative of gloom and doom.
“Nothing succeeds like success”
—Sir Arthur Helps (7)
↵∗ 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.
Dr. Cleland has received research grants from Amgen, Medtronic, Novartis, Philips, and Stealth Biotherapeutics; honoraria for serving on the advisory boards of Amgen, Bristol-Myers Squibb, Medtronic, and Vifor; and speaking fees from Servier. Dr. Clark has received research grants from Amgen, Novartis, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- ↵BrainyQuote: Mark Twain quotes. Available at: https://www.brainyquote.com/quotes/quotes/m/marktwain109624.html. Accessed April 17, 2017.
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