INTRODUCTION — Aging of the population and prolongation of the lives of cardiac patients by modern therapeutic innovations has led to an increasing incidence of heart failure (HF). Despite improvements in therapy, the mortality rate in patients with HF has remained unacceptably high [1]. (See "Epidemiology of heart failure".)
The prognosis of patients with HF with reduced ejection fraction (HFrEF) will be reviewed here. The many factors that can be used to predict survival in HFrEF and the prognosis in patients with asymptomatic left ventricular (LV) systolic or HF with preserved ejection fraction (HFpEF) are discussed separately. (See "Predictors of survival in heart failure with reduced ejection fraction" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
FACTORS AFFECTING MORTALITY RATES — Morbidity and mortality rates after the onset of symptomatic HF are high, although variable mortality rates have been reported which likely reflect differences in demographics, disease severity, and the use of appropriate medical therapy [2-8].
Effect of hospitalization — The need for hospitalization is an important marker for poor prognosis. The association of nonfatal hospitalization and subsequent mortality rates was studied using data on 7572 chronic HF patients with reduced or preserved LV ejection fraction (LVEF) in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials [9]. Mortality rate was increased after HF hospitalizations, even after adjustment for baseline predictors of death (hazard ratio [HR] 3.2; 95% CI 2.8-3.5). The increased risk of death was highest within one month of discharge and declined progressively over time.
The roles of drug and device therapy in reducing hospitalization in patients with HFrEF, the impact of drug therapy on hospitalization in patients with diastolic HF, and the use of disease management and other strategies to reduce hospitalization in patients with HF are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Systems-based strategies to reduce hospitalizations in patients with heart failure".)
Effect of demographic factors — The survival of patients with HF is influenced by age, gender, race, and the cause of the cardiomyopathy. However, many of these studies included patients with both systolic dysfunction and patients with preserved ejection fraction.
Effect of age — The mortality rate in treated patients with HF increases with age [3,10-13]. The following are representative studies:
●In a report from the Framingham Study, mortality increased with advancing age (HR 1.27 and 1.61 per decade in men and women, respectively) [3].
●In a population-based study from Canada, patients aged 65 to 74 and ≥75 had an independent increase in one-year mortality compared with patients aged 25 to 49 (odds ratio 2.18 and 4.24, respectively) [10].
●In a post-hoc analysis of data from nearly 7600 individuals in the CHARM program, patients were grouped into five age categories: 20 to 39 (n = 120), 40 to 49 (n = 538), 50 to 59 (n = 1527), 60 to 69 (n = 2395), and ≥70 years (n = 3019) [13]. Crude three-year all-cause mortality increased with age (12, 13, 13, 19, and 31 percent, respectively). This relationship remained significant after adjusting for known predictors of mortality and morbidity.
The prognosis of HF in older adults was assessed in a community-based review of over 5500 persons from the Cardiovascular Health Study [14]. Among the 5 percent with HF, the LVEF was normal in 63 percent, borderline low in 15 percent, and overtly reduced in 22 percent. Compared with the mortality rate of 25 deaths per 1000 person-years in those without HF or LV dysfunction, the mortality rates were 87, 115, and 154 per 1000 person-years in those with normal, borderline, and reduced LV function, respectively.
Despite the increase in risk in older adults, mortality improvements have occurred over time [15,16]. In the report from the Framingham Heart Study mentioned above of subjects between the ages of 65 and 74, five-year mortality between 1950 to 1969 and 1990 to 1999 fell from 66 to 54 percent in men and 47 to 40 percent in women who survived at least 30 days after the onset of HF [15].
Effect of gender — The prognosis has generally been better in women than men with HF [3,15,17]. In data from the Framingham Heart Study, the median survival time after diagnosis was 3.2 years in women and 1.7 years in men; after five years, 38 percent of women and 25 percent of men were alive [3]. If only persons who survived the first 90 days were considered, thereby excluding patients with acute myocardial infarction and those requiring early surgery, the five-year survival statistics improved to 53 percent in women and 35 percent in men. In the period from 1990 to 1999, five-year survival was 60 percent in women compared with 46 percent in men [15].
A reduced risk in women has also been noted in modern therapeutic trials [17-21]. A pooled analysis of five randomized trials testing a variety of therapies among patients with reduced LVEF (PRAISE, PRAISE II, MERIT HF, VEST, and PROMISE) included a total of 8791 men and 2851 women [17]. In multivariable analysis, female gender was associated with significantly longer survival (HR 0.77).
Similar findings were noted in a comparison of outcomes in 2400 women and 5199 men in the CHARM trial, which included patients with both reduced and preserved LVEF [21]. Women had lower risks of most fatal and nonfatal outcomes; these differences were not explained by LVEF or the cause of HF [21].
Effect of race — The effect of race on the prognosis of HF is uncertain since different studies have revealed contrasting findings:
●Higher mortality in Black patients in a post hoc analysis from the SOLVD trial of enalapril in patients with asymptomatic LV dysfunction or overt HF [22,23].
●Lower mortality in Black patients in an analysis of nearly 30,000 Medicare beneficiaries hospitalized for HF in 1998 and 1999 [24].
●No difference in mortality between White and Black patients in a post hoc analysis from the DIG trial of digoxin therapy [25].
Effect of cause of heart failure — The etiology of HF may be predictive of long-term outcome. (See "Definition and classification of the cardiomyopathies".)
This was addressed by one study of 1230 patients with an initially unexplained cardiomyopathy, which analyzed the outcome based upon the etiology of the cardiomyopathy; after a mean follow-up of 4.4 years, 34 percent of patients died and 4.6 percent underwent cardiac transplantation [26]. Compared with those with an idiopathic cardiomyopathy, which served as the reference group, the following findings were noted (figure 1):
●Survival was better in patients with peripartum cardiomyopathy (HR 0.31).
●Survival was worse in patients with infiltrative myocardial disease, particularly amyloidosis or hemochromatosis (HR 7.41 and 8.88, respectively), HIV infection (HR 5.86), doxorubicin therapy (HR 3.46), ischemic heart disease (HR 1.52), or connective tissue disease (HR 1.75).
●Survival was the same in patients with hypertension, myocarditis, sarcoidosis, substance abuse, or other causes.
In a review of patients from the SOLVD treatment trials, the presence of diabetes had a differential impact on mortality in patients with HF [27]. In adjusted analyses, diabetes significantly increased all-cause mortality in patients with ischemic cardiomyopathy but not those with nonischemic cardiomyopathy (relative risk 1.37 and 0.98, respectively).
Natural history of recent onset IDC — The natural history of recent onset idiopathic dilated cardiomyopathy (IDC) and HF is variable and difficult to predict. Although the one-year mortality may be as high as 25 percent, a substantial proportion of these patients improve spontaneously over time.
The frequency of reversible dysfunction was illustrated by the IMAC-2 study of 373 patients with recent onset IDC or myocarditis with an LVEF <40 percent (mean 24 percent) [28]. At six months, 70 percent demonstrated an increase in LVEF by at least 10 units and 30 percent had an increase of at least 20 units. Forty percent had an LVEF of ≥45 and 25 percent had an LVEF ≥50 percent at six months. Transplantation-free survival at one, two, and four years was 94, 92, and 88 percent, respectively.
The myocardial contractile response to exogenous catecholamines may be a method to predict those patients who will recover. This hypothesis was tested in a series of 22 patients with recently diagnosed (4±3 months) IDC and an LVEF <40 percent who underwent dobutamine echocardiography; the change in LVEF and LV geometry (sphericity index) in response to dobutamine predicted recovery of LV function [29]:
●Patients with an LVEF >40 percent at mean six-month follow-up had a mean increase in LVEF of 27 percentage points with dobutamine while patients with an LVEF that remained <40 percent at follow-up had a mean increase in LVEF of 10.5 percentage points with dobutamine.
●The LV sphericity index in end-diastole on dobutamine, defined as the ratio of LV length (from the apex to the middle of the mitral annular plane) to LV width (at the midpoint of left ventricular length in the four chamber view), correlated with the sphericity index at six months.
Role of ischemia — Although sudden death is most often the result of a ventricular tachyarrhythmia, the role of an acute coronary event in these patients may be underestimated. The prevalence of an acute coronary finding (coronary thrombus, ruptured plaque, or myocardial infarction) and its relationship to sudden death was examined in an autopsy study of 171 patients with HF [30]. In patients with significant coronary artery disease, an acute coronary finding was found in 54 percent who died suddenly and in 32 percent who died of myocardial failure, although an acute coronary event had not been clinically diagnosed before death. By contrast, an acute coronary finding was uncommon in those without coronary disease, present in only 5 percent of those dying from sudden death and 10 percent of those dying from myocardial failure.
Seasonal variation — Several studies have found a seasonal pattern of deaths from myocardial infarction and sudden death, with more fatal events occurring in the winter than the summer. (See "Psychosocial factors in acute coronary syndrome" and "Psychosocial factors in sudden cardiac arrest".) A similar seasonal variation has been seen in men and women with chronic HF [31,32]. In a large study from France, deaths from HF peaked during the winter months of December and January [31]. The distribution of monthly deaths differed by up to 35 percent when January was compared with August, which is when deaths were the lowest. Hospitalizations for HF followed the same seasonal pattern, with a winter-spring predominance (figure 2). Approximately one-fifth of the excess in winter admissions has been attributed to respiratory disease [32].
Circadian rhythm — Sudden death in patients with HF does not follow a circadian rhythm, in contrast to the circadian variation (most deaths between 6 AM and 12 PM) seen in the occurrence of out-of-hospital sudden death or acute myocardial infarction in the general population. An analysis of 1153 patients in the PRAISE trial found a uniform distribution of sudden death in patients with a nonischemic cardiomyopathy, while there was a PM peak in those with an ischemic cardiomyopathy [33]. This PM peak was not altered by the use of anti-ischemic or antithrombotic therapy. (See "Psychosocial factors in sudden cardiac arrest".)
EFFECT OF TREATMENT — Randomized controlled trials have demonstrated that certain drugs, devices, and other care strategies improve survival rates and reduce risk of hospitalization in patients with HF. Although these trials provide strong evidence of benefit, trial participants are often younger and have fewer comorbidities than clinical patient populations and the conduct of care in trials differs from that in routine clinical practice [34]. Therefore, observational studies of process-of-care measures (including adherence to evidence-based therapies) have been performed to assess the effects on outcome in real world settings.
Evidence from clinical trials — Evidence from randomized trials has demonstrated the efficacy of certain drugs and devices in the treatment of heart failure with reduced ejection fraction as discussed in detail in the various topic reviews. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.)
Although improved, mortality is still appreciable with appropriate medical therapy. For example, the following results were noted in the treatment arms of the major angiotensin converting enzyme (ACE) inhibitor trials (figure 3A-C):
●The mortality rate was 36 percent at one year for patients with New York Heart Association (NYHA) class III or IV disease compared with 52 percent in those not receiving an ACE inhibitor [35]. Similar results were noted in another study of 499 patients with class III or IV HF, 75 percent of whom were receiving an ACE inhibitor and 50 percent of whom were treated with digoxin [36]. The one-year mortality was 35 percent and the rate of death or hospital readmission (2.05 times and 27.6 days per year) was 81 percent.
●The mortality rate was 18 to 20 percent at two years for NYHA class II to III disease compared with 25 percent in those not receiving an ACE inhibitor [37,38].
Further improvements have been made with the addition of beta blockers and aldosterone antagonist (spironolactone or eplerenone) to ACE inhibition (figure 4A-B). A later trial found that sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), reduced mortality and morbidity compared with ACE inhibitor therapy when used in combination with other standard HF therapies.
The survival benefit associated with ACE inhibitors and hydralazine plus nitrates, although statistically significant, is relatively modest in absolute terms. Most studies have reported a 15 to 20 percent reduction in overall mortality. In the SOLVD trial of NYHA Class II and III HF, for example, enalapril lowered the four-year mortality rate from 42 to 36 percent; this represents an absolute improvement of 6 percent [37]. Averaging the benefit from these studies through the entire treated population translates into a mean increase in survival of less than six months [4]. Thus, the benefit is apparent only in large populations.
The survival benefit may be somewhat greater with beta blockers. As an example, a meta-analysis of 21 trials involving 5849 patients treated for a median of six months found that beta blockers reduced overall mortality by 39 percent [39]. It was estimated that during the first year this therapy would save 3.8 lives per 100 patients treated [40]. In the MERIT-HF trial of almost 4000 patients with NYHA class II to IV HF who were treated with ACE inhibitors and digoxin, the addition of metoprolol produced a significant reduction in one-year mortality (7.2 versus 11 percent with placebo) (figure 4A) [41].
The magnitude of benefit of combination therapy can be illustrated by the marked short-term improvement in survival of patients with NYHA class IV HF. In controlled trials, one-year mortality fell from 52 percent in the CONSENSUS trial published in 1987 in which ACE inhibitors and beta blockers were not used [35] to 11.4 percent in the COPERNICUS trial published in 2001 in which both drugs were used [42]. Although it is not possible to compare these trials directly due to differences in entry criteria, the mortality rate in some groups of patients with advanced HF is now in the range of 15 to 25 percent. The observed improvement is due to the use of HF drugs (such as ACE inhibitors and beta blockers) and other modalities aimed at underlying diseases (eg, aspirin, statins).
Comprehensive therapy — A retrospective analysis of the EMPHASIS-HF, PARADIGM-HF, and DAPA-HF trials compared the benefits of conventional therapy with an ACE inhibitor/angiotensin II receptor blocker and beta blocker with "comprehensive therapy" consisting of an ARNI, beta blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor. Compared to conventional therapy, comprehensive therapy decreased cardiovascular mortality or hospitalization for HF by 62 percent. These benefits were greatest in younger patients but were also significant in older patients, adding 8.3 years free of cardiovascular death or HF hospitalization for a 55-year-old and adding 2.7 years for an 80-year-old [43]. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)
In addition to these specific therapies for HF, better control of hypertension and of coronary risk factors also contribute to the improvement in outcome.
Unfortunately, there are major lags in the appropriate adoption of drugs and devices that improve survival in HF [4,44-46]. Even among treated patients, the doses used are often lower than those in the clinical trials [45].
Impact of management strategies — The impact of inpatient- and outpatient-based management strategies to reduce the risk of hospitalization and rehospitalization for patients with HF is discussed separately. (See "Systems-based strategies to reduce hospitalizations in patients with heart failure".)
TRENDS IN MORTALITY RATES
In-hospital mortality — Among patients hospitalized for HF, in-hospital mortality and length of hospital stay have decreased, despite an increase in the severity of HF [47-49]. As an example, a single-center study of 6676 patients hospitalized for HF found that, over a 10-year period (1986 to 1996), there was reduction in observed in-hospital mortality from 8.4 to 6.1 percent (despite slight increase in predicted mortality) and reduction in adjusted length of hospital stay from 7.7 to 5.6 days [47].
However, reductions in in-hospital mortality have been accompanied by lesser [48] or no decrease in 30-day mortality [49]. An analysis of 2,540,838 Medicare beneficiaries hospitalized with HF between 2001 and December 2005 revealed reduction in observed in-hospital mortality from 5.1 to 4.2 percent although 30-day mortality was unchanged at 11 percent. Nearly one in four patients was readmitted within 30 days of the index hospitalization.
The 30-day mortality data demonstrate that the use of in-hospital mortality alone in evaluating HF prognosis can be misleading, especially when the length of hospital stay is declining and readmission rates are high. They also raise the concern that reduction in the length of stay after hospitalization for HF has had adverse consequences, possibly increasing early post-discharge mortality because a greater number of patients are discharged in an unstable condition. However, it is also possible that in the later years of the studies more terminally ill patients were being discharged from the hospital to die in other settings.
Long-term mortality — Long-term mortality rates for patients with HF have improved over time [15,48-52]. A decline in HF mortality was noted in an analysis from the Mayo Clinic that included 4537 patients diagnosed, the majority hospitalized around the time of diagnosis [50]. For the periods 1979 to 1984 compared with 1996 to 2000, the one-year mortality fell from 30 to 21 percent in men and from 20 to 17 percent in women. The five-year mortality fell from 65 to 50 percent in men and from 51 to 46 percent in women. Survival improved most among younger men and least among older women.
Lower rates of improvement in HF mortality rates were observed in two studies of Medicare beneficiaries spanning shorter periods of time [49,52]:
●In a study of 3,957,520 Medicare beneficiaries hospitalized with HF between 1992 and 1999, the observed one-year mortality rate decreased only slightly (from 32.5 to 31.7 percent) during the study period due to a decline in mortality between 1993 and 1994 [52].
●In a study of 2,540,838 Medicare beneficiaries hospitalized with HF between 2001 and 2005, the observed one-year mortality rate (37 percent) did not fall over time, although the adjusted hazard of mortality at one-year was slightly lower in 2005 than in 2001 (hazard ratio 0.98; 95% CI 0.97-0.99) [49].
Lower mortality rates were observed in a population in which most patients were not hospitalized at the time of HF diagnosis. In a United Kingdom study of primary care records of 55,959 patients with a new diagnosis of HF (43 percent admitted around the time of initial diagnosis), the one-year mortality rate decreased from 26 percent in 2000 to 19 percent in 2016, the five-year mortality rate decreased from 59 percent in 2000 to 52 percent in 2012, and the 10-year mortality rate decreased from 80 percent in 2000 to 74 percent in 2007 [53]. The reduction in mortality was greater for patients not hospitalized at the time of diagnosis (five versus three years). Low socioeconomic status was associated with reduced median survival (9 versus 11 years for the highest socioeconomic group).
Mortality rates in the placebo arms of clinical drug trials, which represent a selected population, have been variable, depending in large part upon the severity of the HF. In the placebo arms of the angiotensin converting enzyme (ACE) inhibitor trials of patients with systolic dysfunction, in which few patients were taking the two other drugs known to improve survival, beta blockers and spironolactone, the mortality rate was 52 percent at one year for patients with New York Heart Association (NYHA) class III or IV disease [35] compared with 25 percent at two years for NYHA class II to III disease (table 1) [37,38]; among patients with asymptomatic LV dysfunction, the incidence of cardiovascular death or symptomatic HF was 39 percent at just over three years (figure 3A-C) [54].
The entry criteria and selection biases explain the better outlook in these trials than in the population-based studies. Trial participants generally have fewer complicating illnesses, such as significant ischemic symptoms amenable to therapy or valve disease, fewer older patients, and are more likely to receive optimal therapy. As a result, trials are expected to overestimate survival.
Cause of death — The two main causes of death in patients with HF are sudden death (defined as death within one hour of the onset of cardiovascular collapse in a previously stable patient) and progressive pump failure (defined as cardiac death with preceding symptomatic or hemodynamic deterioration) [35,37]. Estimates suggest that progressive pump failure, sudden death, and sudden death during episodes of clinical worsening each account for approximately one-third of deaths in patients with HF [55]. Published series have categorized approximately 30 to 50 percent of all cardiac deaths in patients with HF as sudden deaths, with or without preceding symptoms [8,37,41,51,54,56,57].
However, classification of death as sudden or due to progressive HF is imperfect with overlapping mechanisms, and as a result, clinical studies have classified deaths in differing ways [51]. It is often difficult to distinguish those dying suddenly and unexpectedly from those experiencing terminal arrhythmias in the setting of progressive hemodynamic deterioration [55,58,59]. Ventricular tachycardia degenerating into ventricular fibrillation is a common cause of sudden death in HF. However, a bradyarrhythmia or pulseless electrical activity (electromechanical dissociation) is responsible for 5 to 33 percent or more of cases of sudden death [55], and even higher frequencies may be seen in patients with advanced HF [60].
Evidence-based therapy for HF with reduced ejection fraction (HFrEF) reduces mortality due to progressive HF as well as sudden death. As discussed separately, standard therapy for HFrEF includes beta blocker therapy and mineralocorticoid receptor antagonists, each of which reduces overall mortality rates as well as risk of sudden cardiac death (SCD). ACE inhibitors also reduce overall mortality and may also reduce SCD rates. Angiotensin receptor-neprilysin inhibitor (ARNI) therapy also reduces mortality and SCD rates. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy' and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Guideline-directed medical therapy'.)
An analysis of data from 40,195 patients with HFrEF enrolled in 12 clinical trials with study periods spanning 1995 through 2014 examined the trend in risk of sudden death [51]. There was a 44 percent decline in the rate of sudden death across the trials. The cumulative incidence of sudden death at 90 days after randomization was 2.4 percent in the earliest trial and 1 percent in the most recent trial. Overall mortality also trended downward across the trials (from approximately 15 to 10 percent per year; p = 0.059), and the proportion of overall mortality attributed to sudden death was similar across the trials (at approximately one-third).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Heart failure (Beyond the Basics)")
SUMMARY
●Hospitalization for heart failure (HF) is a marker for poor prognosis. (See 'Effect of hospitalization' above.)
●Long-term mortality rates for patients with HF have improved over time. (See 'Long-term mortality' above.)
●The survival of patients with HF worsens with age, is generally better in women than men, and varies among different causes of cardiomyopathy. (See 'Effect of demographic factors' above.)
●Survival with HF is most limited in patients with amyloidosis, hemochromatosis, HIV infection, or doxorubicin toxicity. (See 'Effect of cause of heart failure' above.)
●Evidence from randomized trials has demonstrated the efficacy of certain drugs and devices in the treatment of HF with reduced ejection fraction as discussed in detail in the various topic reviews. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)
●The two main causes of death in patients with HF are sudden or arrhythmic death and progressive pump failure. (See 'Cause of death' above.)
