Author + information
- Milton Packer, MD∗ ()
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, Texas 75226.
Ask 10 cardiologists to describe the syndrome of acute heart failure, and you will receive 50 wrong answers. Is it a sudden catastrophic event or some ill-defined combination of changing signs and symptoms? Are the mechanisms of the disease understood, and are they amenable to treatment? What are the objectives of therapy for acute heart failure, and are these goals being adequately met with current drugs? Unfortunately, the answers we generally provide to these questions are derived on the basis of a variety of assumptions that are demonstrably false; it is no wonder that this syndrome has been an unlimited source of therapeutic disappointment. We need a radical change in our thinking.
We Have Always Been Confused About Acute Heart Failure
For most of the history of medicine, physicians thought that all patients with heart failure had acute heart failure. Patients were given the diagnosis of heart failure when they presented with clinical decompensation and fluid retention; if they improved and achieved medical remission, they were no longer considered to have heart failure. Heart failure was considered to be an episodic disorder that was present only when patients sought the assistance of physicians. The fact that these patients had severe cardiovascular abnormalities that were present between episodes was not recognized until the advent of invasive and noninvasive assessments of cardiac structure and function in the 1960s and 1970s.
Today we recognize that patients with acute heart failure typically have severe, long-standing structural disease that has worsened either mechanically (as in the case of an acutely insufficient aortic or mitral valve) or functionally (as in the case of sudden cardiac ischemia or supraventricular arrhythmia). In most cases, the diagnosis of the underlying structural heart disease in a patient with acute heart failure was established before the patient’s clinical presentation, and often the diagnosis of heart failure is not even new. Patients with chronic heart failure (especially when suboptimally treated) are expected periodically to exhibit worsening signs and symptoms requiring urgent medical attention. As a result, for many patients, “acute heart failure” overlaps substantially with “worsening heart failure,” typically requiring hospitalization for stabilization. However, the reasons that patients with chronic heart failure experience clinical worsening vary enormously and include a lack of adherence to medical therapy (e.g., diet or drugs), subtle changes in the pathophysiology of the underlying cardiac disorder, and superimposition of a new cardiovascular stressor (e.g., pulmonary infection or overtransfusion). These precipitating causes represent dramatically different mechanisms, even though they may occur in patients with the same underlying disease. There is no common mechanism that can serve as a reliable therapeutic target in large populations of patients with acute heart failure, at least as it is currently defined.
There Is Nothing Acute About Acute Heart Failure
Use of the term acute generally denotes structural or functional changes that occur minutes or hours before a patient’s clinical presentation (e.g., acute myocardial infarction). When viewed from this perspective, there is little about most patients with acute heart failure that is truly acute. Hospitalization for worsening heart failure is often preceded by an increase in cardiac filling pressures that occurs days or weeks before patients seek medical attention (1).
The primary symptom that drives a patient with acute heart failure to a physician is dyspnea, and physicians generally identify dyspnea relief as the major goal of treatment. However, dyspnea is extraordinarily subjective; it is difficult to assess and quantify and is not closely correlated with any objective pathophysiological measurement. There is little relationship between the severity of dyspnea and the elevation of cardiac filling pressures or circulating natriuretic peptides. The clinical course of dyspnea relief is not related to the rapidity of diuresis and is not consistently affected by peripheral vasodilators that act to produce cardiac decompression or intravascular decongestion (2,3). Given these circumstances, is dyspnea relief still a clinical relevant endpoint for the assessment of new treatments for patients with acute heart failure? In the setting of chronic heart failure, dyspnea relief is no longer the primary focus of treatment; instead, physicians focus on reducing the risk of worsening heart failure and minimizing the risk of death. However, clinical trials in patients with acute heart failure have always targeted short-term dyspnea relief as the main identifier of therapeutic benefit, even though these trials have consistently failed to find any meaningful effect on dyspnea, despite demonstration of numerous physiological benefits. We need to question the clinical relevance of dyspnea relief in this syndrome.
There Is No Immediate Unmet Medical Need in Acute Heart Failure
We have long assumed that there is an unmet medical need in the immediate treatment of acute heart failure. The basis of such an argument has largely been that we use drugs with little supporting evidence from clinical trials and administer them at empirically derived doses with uncertain benefits; furthermore, patients often have a prolonged hospital stay and a high likelihood of heart failure recurrence in the following weeks and months. The perception of a vast unmet need has led to the belief that an effective new drug for in-hospital use could be priced at several thousand dollars per day. The anticipation of major financial rewards triggered the development of dozens of new therapeutic agents, most with no special properties or actions.
However, most patients who are hospitalized for worsening heart failure improve substantially with existing treatments. Although clinical trials have not defined the role or optimal use of diuretics, peripheral vasodilators, and positive inotropic agents, most patients who receive 1 or more of these drugs exhibit very meaningful improvement in the first hours or days after hospital admission. If the initial clinical response is inadequate, the doses of current drugs are increased or the drugs are used empirically in combination. As a result, <10% of patients with acute heart failure fail to report an adequate symptomatic response after several days (4); failure to achieve rapid clinical improvement is rarely a reason to prolong a patient’s hospital stay. The length of hospital stay for acute heart failure has been reduced dramatically during the past 15 years, in the absence of any meaningful therapeutic advances.
More recently, investigators have recognized that some patients improve initially but experience worsening of their heart failure syndrome while they are still in the hospital (3–5). These in-hospital events have been associated with both the early release of cardiac troponins and an increased risk of subsequent rehospitalization and death (3,5). Some peripheral vasodilators reduce the risk of in-hospital worsening events, but such benefits have not been associated with any reliable reduction in the long-term risk of rehospitalization or death (3,4). One could argue that the prevention of in-hospital worsening events is itself meaningful, yet the incidence of in-hospital worsening events in clinical trials is low (approximately 5%). Thus, it has been difficult to make the case that patients should routinely receive prophylactic therapy to prevent these uncommon events when doing so has no other favorable effects on the clinical course of patients. Indeed, some investigators have suggested that effective treatments do not actually prevent these events, but only delay them, so that their occurrence now takes place after hospital discharge, consequently leading to an increased rate of early readmission (5).
Acute Heart Failure Is an Event Rather Than a Disease
More recently, the field of acute heart failure has focused on the intriguing hypothesis that the fluid shifts and ventricular distention occurring in acute heart failure cause cardiac microinjury and accelerated disease progression and that emergency pharmacological ventricular decompression would interrupt this process and favorably change the natural history of these patients (3). Although substantial ventricular decompression and intravascular decongestion have been achieved with novel therapeutic agents, these physiological benefits have not yielded meaningful decreases in the extent of cardiac microinjury, and they have had little impact on the subsequent clinical course of patients (3).
The heterogeneity of patients, the lack of any common mechanism, the absence of evidence of meaningful physiological suddenness, the inability of new agents to influence the primary presenting symptom of dyspnea, and the failure of new short-term interventions to produce any demonstrably meaningful clinical benefits suggest that acute heart failure should no longer be regarded as a disease, but instead should be considered an event. Admittedly, it is a serious event, but fortunately, most patients respond to existing therapeutic agents. Therefore, instead of developing new intravenous treatments to be given for only several hours or days during a patient’s hospital stay, innovators should focus on treating and alleviating the causal cardiac condition. Our major need is not to propose novel therapies to be given only during the acute heart failure event, but instead, to develop new drugs to prevent these events by acting to change the course of the underlying disorder. Our current focus is obsessed with caring for the patient during hospitalization; instead, we need to ensure that the patient is managed well between hospitalizations. Such a change in strategy has major implications for our understanding of heart failure, the development of new drugs, and the goals of health delivery systems.
Dr. Packer has consulted for Amgen, Bayer, Boehringer Ingelheim, Cardiorentis, Celyad, Relypsa, Sanofi, and ZS Pharma; and was the principal investigator in 2 large-scale clinical trials of acute heart failure, REVIVE and TRUE-AHF.
- Received May 3, 2017.
- Accepted May 17, 2017.
- 2018 American College of Cardiology Foundation
- Zile M.R.,
- Bennett T.D.,
- St. John Sutton M.,
- et al.
- Packer M.,
- O'Connor C.,
- McMurray J.J.,
- et al.,
- TRUE-AHF Investigators
- Packer M.,
- Colucci W.,
- Fisher L.,
- et al.,
- REVIVE Heart Failure Study Group