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Predictors of survival in heart failure with reduced ejection fraction

Predictors of survival in heart failure with reduced ejection fraction
Literature review current through: Jan 2024.
This topic last updated: Nov 01, 2022.

INTRODUCTION — Heart failure (HF) is a common clinical syndrome associated with a mortality rate that varies with the severity of disease. Among patients with HF who are considering therapies such as heart transplantation, left ventricular (LV) assist device placement, or palliative care, prognostic information can further inform a discussion of the risks and benefits of therapy. However, for most diagnostic and treatment decisions, the role of prognosis is limited.

The following discussion will review the major clinical and laboratory predictors of survival in patients with HF due to systolic dysfunction.

The overall prognosis of HF and the predictors in patients with diastolic dysfunction are presented separately. (See "Prognosis of heart failure" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

MAJOR PREDICTORS OF SURVIVAL — A major challenge in the management of HF is the accurate identification of those patients who have a poor prognosis and who would therefore be most likely to benefit from intensive medical therapy and/or cardiac transplantation. Many univariate predictors of reduced survival have been identified in HF (table 1). Identification of these factors should be part of the initial evaluation of any patient with HF. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

The most frequently used factors for predicting survival in patients with systolic HF, many of which are direct or indirect measures of the severity of cardiac dysfunction, include:

High New York Heart Association (NYHA) functional class (table 2).

Severity of the reductions in LV ejection fraction (LVEF) and reduced cardiac index (CI).

Concomitant diastolic dysfunction, as established by a mitral flow velocity pattern on Doppler echocardiogram.

Reduced right ventricular function.

Low peak VO2 with maximal exercise and exercise hemodynamics.

Markers of reduced tissue perfusion including low mean arterial pressure, decreased arterial pulse pressure, renal insufficiency (creatinine clearance <60 mL/min), and an attenuated response to diuretics.

Elevated plasma levels of natriuretic hormones B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). (See "Natriuretic peptide measurement in heart failure" and "Natriuretic peptide measurement in heart failure", section on 'Prognosis'.)

A lack of hemodynamic improvement with therapy, as indicated by failure to reduce LV filling pressure and persistence of signs of congestion (orthopnea, jugular venous distension, edema, weight gain, or increased need for diuretics), is also associated with a poorer prognosis [1].

In addition to these cardiac parameters, comorbid factors and the cause of the HF are important determinants of prognosis. As examples, the prognosis is worse in patients with diabetes mellitus [2,3] and ischemic cardiomyopathy in which the extent of the coronary artery disease is important [4,5]. Ventricular tachycardia is also an adverse prognostic factor [6,7].

NYHA functional class — The NYHA criteria are most often used to assess the functional class of patients with HF (table 2):

Class I – No limitation during ordinary activity

Class II – Slight limitation by shortness of breath and/or fatigue during moderate exertion or stress

Class III – Symptoms with minimal exertion that interfere with normal daily activity

Class IV – Inability to carry out any physical activity

Prospective studies evaluating the use of ACE inhibitors have demonstrated a strong relationship between the functional class and mortality (figure 1) [6,8-10].

These findings in control groups not receiving an ACE inhibitor can be summarized as follows:

Asymptomatic patients (class I) have a one- and four-year mortality rate of 5 and 19 percent (figure 2) [8].

Patients with NYHA class II or III HF have a one- and four-year mortality rate of 15 and 40 percent (figure 3) [9].

Patients with NYHA class IV do much worse with 6- and 12-month mortality rates of 44 and 64 percent in one large trial (figure 4) [10].

These observations indicate the importance of early treatment of HF in an attempt to slow progression to more severe disease. As an example, the improved outcome in patients treated with an ACE inhibitor is due primarily to better preservation of myocardial function.

Left ventricular ejection fraction — Dilated cardiomyopathy is characterized by a variable reduction in LVEF, the assessment of which is probably the most frequently performed cardiac function test in patients with HF. Clinically evident HF due to systolic dysfunction is generally not apparent until the LVEF falls below 35 to 40 percent, as determined by echocardiography or contrast or radionuclide angiography. (See "Tests to evaluate left ventricular systolic function".)

There is, however, no predictable relationship between symptoms or exercise tolerance and the LVEF. Some patients are asymptomatic with an LVEF below 20 percent, while others are moribund with an LVEF above 30 percent.

In general, survival is shorter in patients with lower LVEFs (figure 5 and figure 6) [11-14]. As an example, the relationship between LVEF and outcome was evaluated in 5010 patients enrolled in the Val-HeFT trial in whom echocardiograms were obtained at baseline [11]. Decreasing quartiles of LVEF were associated with increasing all-cause mortality at 23 months. Patients in the first quartile (mean LVEF 35 percent) had a significantly lower mortality rate than those in the fourth quartile (mean LVEF 17 percent) (14 versus 26 percent mortality, risk ratio 0.5). An LVEF below 20 percent is typically associated with poor survival [15,16]; some recommend cardiac transplantation in all such patients who are eligible [15].

However, relying on only a univariate predictor such as the LVEF to estimate survival is not very sensitive in the individual patient. As mentioned above, large trials have demonstrated that patients with NYHA class II or III HF have a worse prognosis than those who are asymptomatic. Despite the difference in outcome, the difference in mean LVEF between asymptomatic and symptomatic patients in these trials was small: 28 to 31 percent in asymptomatic patients [8,17] versus 25 percent in patients with moderate symptoms [9].

Concomitant diastolic dysfunction — Concomitant diastolic dysfunction is associated with decreased survival among patients with HF and a reduced LVEF. Studies evaluating diastolic compliance with Doppler echocardiography have shown that altered transmitral flow (short deceleration time ≤115 ms, and an early-to-late flow velocity or E/A ratio >1 (figure 7)) is a powerful independent predictor of mortality or the need for transplantation among patients with HF (figure 8) [18-22]. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)

The prognostic value of abnormal mitral flow velocity may be enhanced by assessing changes in this parameter during alterations in loading conditions (figure 7). This was illustrated in a report of 173 patients with chronic HF (53 percent ischemic cardiomyopathy) that measured the outcomes at 17 months in four subgroups that were distinguished by differences in changes in mitral valve flow velocity observed during nitroprusside infusion (resulting in a reversible or nonreversible restrictive pattern) and passive leg lifting (resulting in a stable or nonstable nonrestrictive pattern) [18]:

An irreversible restrictive pattern was associated with a 51 percent cardiac event rate (cardiac death or urgent transplantation).

An unstable nonrestrictive pattern was associated with a 33 percent cardiac event rate.

A reversible restrictive pattern was associated with a 19 percent cardiac event rate.

A stable nonrestrictive pattern was associated with a 6 percent cardiac event rate.

Support for these observations comes from a study of 144 patients with HF (76 percent ischemic cardiomyopathy) who initially had a restrictive pattern on Doppler echocardiography; this test was repeated after six months of optimal medical therapy that included digoxin, diuretics, an ACE inhibitor, and a beta blocker [21]. At a mean follow-up of 26 months, patients with reversal of the restrictive pattern at six months had a lower cardiac mortality (11 versus 37 percent) and a lesser likelihood of being admitted to the hospital for worsening of HF (11 versus 54 percent) than those with persistence of the restrictive pattern.

The effect of dobutamine stress on a restrictive pattern also appears to have prognostic value. This was illustrated in a review of 69 patients with ischemic dilated cardiomyopathy: 42 had a restrictive LV filling at rest, which reverted to a nonrestrictive pattern in 24 [23]. The patients with a persistent restrictive pattern had a significantly lower rate of survival at three years compared with those with a reversible restrictive pattern or those with a nonrestrictive pattern at rest (49 versus 79 and 89 percent, respectively). Persistence of the restrictive pattern was associated with a marked rise in left atrial pressure and a markedly attenuated inotropic response.

The presence of a restrictive pattern on Doppler echocardiogram also adds incremental predictive value to peak VO2, a measure of functional capacity, for establishing the prognosis in patients with HF [24]. (See "Exercise capacity and VO2 in heart failure".)

Other indicators of elevated LV filling pressure due to diastolic dysfunction and a restrictive pattern include a high pulmonary capillary wedge pressure (PCWP) and increased lung uptake of thallium (high thallium lung/heart ratio) on stress imaging. The latter finding may have incremental prognostic value over clinical and other imaging findings [25].

Right ventricular function — Right ventricular systolic dysfunction also may contribute to prognosis in patients with HF [26-30]. Echocardiographic measurements of reduced right ventricular function include a reduction in right ventricular ejection fraction (RVEF), right ventricular enlargement, and tricuspid regurgitation. (See "Echocardiographic recognition of cardiomyopathies".)

The prognostic importance of right ventricular function was illustrated in a series of 205 patients with class II or III HF; the RVEF was an independent predictor of one- and two-year survival and event-free cardiac survival [29]. At two years, the event-free survival rates from cardiovascular mortality and urgent transplantation for those with an RVEF ≥35 percent, ≥25 to <35 percent, and <25 percent were 93, 77, and 59 percent, respectively (figure 9). A similar adverse effect on outcome is seen with right ventricular enlargement, which is often associated with more severe tricuspid regurgitation (figure 10) [27], an abnormality that itself is associated with a worse prognosis (figure 11) [31].

Pulmonary artery pressure — Impaired right ventricular contractility in patients with left-sided HF may be due to primary myocardial disease or to poor LV function with an elevated pulmonary artery pressure. Right ventricular dysfunction appears to be of prognostic importance only when associated with elevated pulmonary artery pressure; assessment of right ventricular function in patients with normal pulmonary artery pressure does not improve risk stratification (figure 12) [30].

The importance of an elevated pulmonary artery pressure was further addressed in a prospective study of 1134 patients with a new cardiomyopathy who underwent right heart catheterization and endomyocardial biopsy and were followed for 4.4 years [32]. With a multivariate model, mean pulmonary artery pressure was the most important hemodynamic predictor of death, especially in the 93 patients (8.3 percent) with a diagnosis of myocarditis. For each 5 mmHg increase in baseline mean pulmonary artery pressure, the mortality in those with and without myocarditis increased with a relative hazard of 1.85 and 1.23, respectively.

Other echocardiographic findings — In addition to the LVEF and diastolic and right ventricular function, a number of other echocardiographic findings have been associated with prognosis. These include:

LV dilatation or an LV end-diastolic volume index >120 mL/m2 [11,33].

A restrictive mitral filling pattern and an LV systolic diameter index >2.75 cm/m2, particularly if associated with a QRS duration >144 ms [34].

Increased LV mass ≥298 g [12].

Increased left atrial size (dimension ≥4.17 or volume index >68.5 mL/m2 or 63 mL/m2) (figure 13) [12,35,36].

Augmentation of LVEF during dobutamine echocardiography is also of prognostic importance in patients with an idiopathic dilated cardiomyopathy [37,38]. (See "Dobutamine stress echocardiography in the evaluation of hibernating myocardium".)

QRS prolongation and LBBB — Among patients with HF, a QRS duration ≥120 ms is common and is associated with a significant increase in mortality. As an example, in a retrospective analysis from the EVEREST trial, 45 percent of 2962 enrolled patients hospitalized for HF had a QRS duration ≥120 ms [39]. QRS prolongation was associated with increased all-cause mortality (adjusted hazard ratio [HR] 1.28, 95% CI 1.10-1.49) at a median of 9.9 months follow-up.

The worse outcomes with QRS prolongation have been attributed in part to ventricular dyssynchrony resulting from the conduction defect. Many such patients are treated with cardiac resynchronization (biventricular pacing), since randomized trials have shown a clear survival benefit. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

Left bundle branch block (LBBB) on electrocardiogram (ECG), which is seen in 25 percent of patients with HF, is associated with increased all-cause [40,41] and sudden death mortality [40]. In analyses including LVEF, LBBB was an independent risk predictor of mortality in some studies [40] but not others [41], suggesting that LBBB may be a marker for but not a direct cause of increased mortality risk. (See "Left bundle branch block".)

Exercise variables — Because exercise requires an increase in cardiac work, evaluation of exercise capacity and cardiac function during exercise are effective ways of demonstrating a limitation in maximal cardiac performance, and thus, the severity of HF. Exercise may also reveal limitation in function that is not evident by history. Several exercise parameters including peak VO2, six-minute walk distance, and exercise hemodynamics have been correlated with patient survival. The predictive value of exercise parameters is discussed separately. (See "Exercise capacity and VO2 in heart failure".)

Neurohumoral activation and heart rate — The low output state in HF results in multiple physiologic responses due to increased release of neurohormones. These include hyponatremia and elevated plasma concentrations of norepinephrine, BNP, renin, endothelin-1, and big endothelin-1 (figure 14A-E) [42-48]. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Neurohumoral adaptations'.)

At present, only the plasma sodium and BNP concentrations are measured clinically:

Otherwise-unexplained hyponatremia is a poor prognostic finding. In a study of patients with severe HF, for example, patients with a plasma sodium concentration less than 137 meq/L had more than a 50 percent reduction in median survival (164 versus 373 days) (figure 14B) [42]. (See "Hyponatremia in patients with heart failure", section on 'Predictor of adverse prognosis'.)

Elevations in plasma BNP predict reduced survival in patients with chronic and acute decompensated HF (figure 14D) [44-46,49-53]. They also predict an increased risk for sudden death [54]. (See "Natriuretic peptide measurement in heart failure", section on 'Prognosis of HF'.)

An elevated heart rate, generally reflecting activation of the sympathetic nervous system, is also associated with a worse outcome [55-57] (see "Sinus tachycardia: Evaluation and management"). In an analysis of the placebo group in the BEAUTIFUL trial, cardiovascular outcomes were compared in 2693 patients with heart rates of ≥70 bpm and 2745 patients with heart rates <70 bpm [57]. All patients had coronary artery disease, LVEF <40 percent, and a resting heart rate of ≥60 bpm. For every 5 bpm increase, there were significant increases in cardiovascular death (8 percent), admission to hospital for HF (16 percent), and coronary revascularization (8 percent). This sign, though useful, is often absent in patients who are receiving adequate doses of a beta blocker.

Signs of reduced tissue perfusion — Clinical signs of reduced tissue perfusion are indicative of more severe disease and a worse prognosis. These include a low mean arterial blood pressure, renal insufficiency, an attenuated response to diuretics, and lack of hemodynamic improvement with therapy, as indicated by failure to reduce LV filling pressure, which are all also associated with a poorer prognosis [58-63].

Low blood pressure — Low systolic, diastolic, and mean arterial blood pressures have all been associated with increased mortality in patients with HF [58,64]. The mean arterial blood pressure can be estimated from the following formula:

Mean arterial pressure  =  (systolic blood pressure  +  [2  x  diastolic blood pressure]  /  3)

In the SOLVD trial, each 10 mmHg decrease in baseline mean arterial pressure was associated with a 14 percent increase in total and cardiovascular mortality [58], while a post-hoc analysis from the DIG study database found that mortality was highest in patients with systolic blood pressure <100 mmHg and diastolic blood pressure <60 mmHg [64].

A narrowing of the pulse pressure is also indicative of a decrease in cardiac output.

Reduced glomerular filtration rate — There are a number of important interactions between heart disease and kidney disease. The interaction is bidirectional as heart disease can affect renal function and renal disease can affect cardiac function. As an example, reduced renal function is associated with increased mortality in patients with HF, as will be discussed below. On the other hand, patients with chronic kidney disease have an increased risk of both atherosclerotic cardiovascular disease and HF, and cardiovascular disease is responsible for up to 50 percent of deaths in patients with renal failure. In addition, acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. The term cardiorenal syndrome has been applied to these interactions. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

A reduced glomerular filtration rate (GFR) is associated with increased mortality risk in patients with HF. The magnitude of the effect can be illustrated by the findings in a systematic review of 16 studies with over 80,000 patients [65]. The mortality rate at a follow-up of one year or more was 24 percent in those with a normal GFR compared with 38 and 51 percent in patients with mild and moderate to severe reductions in GFR, respectively (adjusted HR 1.6 and 2.3). An elevated blood urea nitrogen (blood urea) is also associated with increased mortality, an effect that may be in part independent of the GFR. Optimal management of these patients is not well defined. These issues are discussed in detail elsewhere. (See "Cardiorenal syndrome: Prognosis and treatment", section on 'Reduced GFR and prognosis'.)

Reduced myocardial blood flow — In patients with idiopathic cardiomyopathy, reduced myocardial blood flow, as assessed by positron emission tomography at rest and after intravenous dipyridamole, is an independent predictor of subsequent cardiac events (death or the development or progression of HF) [66]. This association is independent of other clinical and functional variables. Because of the decreased availability and higher cost of this test, it is unclear what its clinical role may be.

Atrial fibrillation — The prevalence of AF in patients with HF varies from 10 to 30 percent, depending upon the population studied. There are conflicting data as to whether AF is an independent predictor of increased mortality in patients with HF; data from the SOLVD trials and the Framingham Heart Study suggest such an increase, while data from the V-HeFT I and II trials do not. (See "The management of atrial fibrillation in patients with heart failure", section on 'Prognosis'.)

Anemia — Several studies have demonstrated that there is an association between anemia and increased mortality in patients with HF, although it is unclear whether anemia is responsible for worse outcomes or merely a marker for more severe HF. At least one small study has suggested that erythropoietin therapy may reduce mortality in anemic HF patients [67]. However, benefit has not been proven and there is the potential for harm. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure", section on 'ESAs (not recommended)'.)

Diabetes — The CHARM trials evaluated the role of an angiotensin II receptor blocker in the treatment HF due to both systolic and diastolic dysfunction. A retrospective analysis of 7599 patients from these trials assessed the prognostic significance of approximately 50 baseline variables [3]. In addition to age and LVEF, diabetes was among the most powerful independent predictors of mortality and HF hospitalizations.

PREDICTIVE MODELS — There are drawbacks to using any single factor to determine prognosis or to guide therapy. Although the factors listed above influence survival, the aggregate effect of such factors on overall prognosis is difficult to quantify. Accordingly, a number of predictive models have been developed from retrospective data to more accurately quantify prognosis [68-71].

In general, prognostic risk models can be used in selected clinical scenarios to more accurately communicate prognosis to the patient but should not be routinely used to guide therapy [72].

Potential benefits of using prognostic models for HF include the following [72]:

Enables patients and their caregivers to have a more realistic expectation of the prognosis.

Enables appropriate allocation of resources, including transplantation, mechanical circulatory assist devices, and implantable defibrillators.

Enables selection of therapies most likely to positively affect the quality and quantity of life.

Promotes open, honest communication between clinicians, patients, and their caregivers to define the goals of therapy.

Potential limitations of using prognostic models for HF include the following [72]:

The model was derived from a population of patients different from patients seen in clinical practice.

Patient compliance, preference, or attitudes are not incorporated.

New therapies become available, making the models obsolete.

Uncertainty in applying the model to an individual patient cannot be quantified and this uncertainty may be difficult for clinicians to effectively explain to patients and their caregivers.

Scores from the models may replace informed, compassionate, clinician-patient conversations.

Scores have a limited impact on outcomes.

The role of predictive models as a component of routine care is unclear; most studies of risk scores assessed their accuracy and not their clinical impact. One trial found that providing clinicians with a measure of HF prognosis did not alter processes of care or outcomes:

In a trial that included 3124 patients with HF who were randomly assigned to routine display of a one-year mortality estimate to their clinician via the electronic health record or to usual care, the combined risk of one-year mortality and 30-day hospital readmission was similar between the two groups (39 percent) [73]. In addition, clinician behavior, as measured by the use of either guideline-directed medical therapy or advanced HF therapies (eg, palliative care, cardiac transplantation) was similar between the groups.

EFFECT model — The EFFECT model was derived, tested, and intended to be used in patients hospitalized for HF [68]. The derivation cohort included 2624 patients in the EFFECT study, who presented with HF at 34 hospitals in Ontario, Canada between 1999 and 2001. The model was then validated in 1407 patients presenting between 1997 and 1999.

Multiple clinical characteristics, including both HF-related factors (respiratory rate, systolic pressure, blood urea nitrogen, and serum sodium concentration) and comorbidities (eg, chronic obstructive pulmonary disease [COPD], anemia, malignancy) were correlated with 30-day and one-year mortality. Points were assigned to each significant predictor; the sum of the points results in a risk score ranging from ≤60 (very low; 30-day mortality <1 percent and one year mortality <10 percent) to >150 (very high; 30-day mortality >50 percent and one year mortality >70 percent).

Heart Failure Survival Score — The Heart Failure Survival Score (HFSS) is another prospectively validated model, developed in and for patients with advanced HF (New York Heart Association [NYHA] class III or IV) (table 2) [69]. This score was derived from a multivariable analysis of 268 ambulatory patients referred for consideration of cardiac transplantation and validated in 199 similar patients. The predictors of survival in the HFSS include:

Presence or absence of coronary artery disease

Resting heart rate

LVEF

Mean arterial blood pressure

Presence or absence of an intraventricular conduction delay on ECG

Serum sodium

Peak VO2

In a version of the HFSS that incorporates invasive hemodynamic data, pulmonary capillary wedge pressure is included as an eighth variable. The HFSS stratifies patients into low-, medium-, and high-risk categories, based upon a sum of the variables above multiplied by defined coefficients. Among the patients in the validation sample, one-year survival rates without transplant for these three strata were 88, 60, and 35 percent, respectively.

The HFSS is often used as an aid to selecting patients for cardiac transplantation. However, the above survival rates may not be applicable to current practice since the model was derived before the use of modern therapies that improve survival in patients with HF, including beta blockers, angiotensin II receptor blockers, aldosterone antagonists, implantable cardioverter-defibrillators, and cardiac resynchronization therapy [74]. In addition, some of these therapies directly affect some of the parameters in the risk model (eg, beta blockers and resting heart rate, and cardiac resynchronization therapy and conduction delay). (See "Heart transplantation in adults: Indications and contraindications", section on 'Heart Failure Survival Score'.)

Seattle Heart Failure Model — The Seattle Heart Failure Model differs from the prior models in two ways [70]:

The model was derived and validated in a broad HF population, including both general outpatients and advanced HF patients.

The model incorporates a wide range of readily available clinical variables, including medications and devices.

The model was derived in 1125 advanced HF patients from the PRAISE trial (average LVEF 21 percent, average NYHA class 3.6). None of the patients in the derivation cohorts were treated with beta blockers, aldosterone antagonists, or implantable cardioverter-defibrillators (ICDs), but validation of the model in cohorts from subsequent trials evaluated the impact of these interventions. The model was prospectively validated in five additional cohorts totaling 9942 HF patients and 17,307 person-years of follow-up.

The diversity of the validation cohorts is illustrated by the following:

Average LVEF ranged from 22 to 35 percent

Average NYHA class ranged from 2.2 to 2.9 (table 2)

Wide ranges of use of beta blockers (24 to 72 percent) and potassium-sparing diuretics (5 to 35 percent)

Across these populations, the model provided an extremely accurate estimate of one-, two-, and three-year survival (R values ranging from 0.97 to 0.99).

The Seattle model also provides information about the likely mode of death. In an analysis of 10,538 ambulatory patients with predominantly HFrEF (NYHA class II to IV), the score was predictive of the risk of sudden death and of pump failure [75]. Compared with patients with a score of 0, the risk of sudden death progressively increased with higher scores, up to a sevenfold higher risk with a score of 4. Conversely, the proportion of deaths caused by sudden death versus pump failure decreased from a ratio of 7:1 with a score of 0 to a ratio of 1:2 with a score of 4.

An online calculator is available at https://depts.washington.edu/shfm/?width=1024&height=819. The calculator can also estimate the effect of adding new therapies on the risk of mortality.

OTHER PREDICTORS OF SURVIVAL — There are a number of other findings that have been associated with the outcome of patients with HF.

Physical findings

S3 gallop and jugular venous pressure — The presence of an S3 gallop and/or elevated jugular venous pressure appear to have prognostic significance. In a review of 2569 patients from the SOLVD treatment trial, 24 percent had an S3 gallop and 11.8 percent had an elevated jugular venous pressure [76]. After adjusting for other markers of disease severity, an S3 gallop and elevated jugular venous pressure were each associated with an increased risk of hospitalization for HF (relative risk 1.42 and 1.32, respectively) and of death from pump failure (relative risk 1.40 and 1.37). One limitation to these observations is the operator-dependence for the detection of these physical findings.

Functional MR — Patients with advanced HF often develop functional or secondary mitral regurgitation (MR) due to annular enlargement secondary to LV dilatation and/or papillary displacement due to LV remodeling. Although data are limited, patients with moderate to severe MR appear to have a worse prognosis.

C-reactive protein — Elevations in serum C-reactive protein (CRP) are associated with worse outcomes in patients with atherosclerotic cardiovascular disease. Data in HF have been limited, but suggest an association between CRP and outcomes [77-79]. (See "C-reactive protein in cardiovascular disease".)

The possible predictive value of serum CRP was addressed in a post hoc analysis from the Val-HeFT trial of valsartan therapy in HF [77]. The median serum CRP was higher in patients with HF compared with the general population and the cumulative likelihood of death or a first morbid event increased progressively with quartiles of serum CRP (eg, the adjusted hazard ratio [HR] for mortality was 1.53 in the highest compared with the lowest quartile for serum CRP). At one year, serum CRP was stable in the placebo group but fell in patients receiving valsartan who were not receiving an ACE inhibitor but not in those who were.

Similar findings were noted in a review of 546 consecutive patients (mean age 56) with stable systolic HF (mean LVEF 33 percent) [78]. Almost all patients were treated with ACE inhibitors and beta blockers. A serum CRP >3 mg/L was an independent predictor of cardiovascular mortality (HR 1.78). This effect, which was only seen in patients with ischemic cardiomyopathy, was independent of other major predictors, such as peak VO2 and serum B-type natriuretic peptide (BNP).

Heart rate variability — Reduced heart rate variability, which indicates increased sympathetic or reduced parasympathetic tone [80-82], is associated with a worse prognosis in patients with HF. In one study of 433 patients, the annual mortality for those with standard deviation of normal RR intervals (SDNN) of >100 ms, 50 to 100 ms, and <50 ms was 5.5, 12.7, and 51.4 percent, respectively; values below 100 ms indicate absence of heart rate variability (figure 15) [80]. (See "Evaluation of heart rate variability".)

Planar QRS-T angle — In a report of 455 patients with nonischemic cardiomyopathy, New York Heart Association (NYHA) class I to III HF, and nonsustained ventricular tachycardia (VT) or frequent ventricular ectopy, a planar QRS-T angle greater than 90 degrees was a predictor of the composite end point of total mortality, appropriate implantable cardioverter-defibrillator shock, or resuscitated cardiac arrest [83]. Changes in the QRS-T angle correlated with changes in LVEF and QRS duration over time.

Troponins — Circulating troponin levels are a sensitive marker of acute myocardial injury but elevations also occur in a variety of other disorders. (See "Troponin testing: Clinical use" and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)

Elevations in circulating troponin T (TnT) and troponin I (TnI) are predictors of adverse outcomes in hospitalized as well as stable ambulatory patients with HF [53,84-93]. Elevations in both troponin and BNP are associated with an increased risk compared with elevations in either measurement alone [53,89,92,93].

The predictive value of plasma troponin T is illustrated by the following studies:

In a study of 4053 patients with chronic HF with LVEF <40 percent enrolled in the Val-HeFT trial, plasma troponin T was detectable in 10.4 percent of the population with the traditional (cTnT) assay and in 92 percent of the population using a highly sensitive assay (hsTnT) [89]. In models adjusting for other risk factors, both baseline TnT and baseline hsTnT were significantly associated with all-cause mortality and first hospitalization for HF at median two-year follow-up. In addition, hsTnT was significantly associated with mortality in the 90 percent of the population with undetectable cTnT by the traditional assay.

Baseline cTnI level was an independent predictor of risk of first hospitalization for HF after exclusion of myocardial infarction (per 0.01 microg/L of cTnI; adjusted HR 1.31, 95% CI 1.16-1.47) during nine-year median follow-up of a population of 1089 70-year-old men [93].

Baseline hsTnT level and increases in hsTnT levels were significantly associated with new onset HF and cardiovascular death during 11.8-year median follow-up in a nationwide cohort of 4221 adults ≥65 years of age enrolled in the Cardiovascular Health Study [91]. The addition of baseline hsTNT to clinical risk factors yielded a significant but modest improvement in discrimination of risk.

Small studies have found an association between worsening LVEF and baseline troponin level [88] or persistently elevated troponin levels [85]. Persistently elevated troponin levels were also associated with higher cardiac event rates [85,90].

Myocardial strain and myocyte death are two related mechanisms that can contribute to the troponin elevations. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Heart failure'.)

Low serum cholesterol — In contrast to the beneficial effect of a low serum cholesterol induced by statin therapy in patients with coronary heart disease, a low serum cholesterol in patients with HF is associated with higher mortality. This issue and the possible role of statin therapy is discussed in detail elsewhere. (See "Statin therapy in patients with heart failure".)

Hyperuricemia — An elevated serum uric acid (UA) concentration was associated with an increase in mortality in an evaluation of 112 patients with HF [94]. These patients formed a derivation sample to identify a threshold value for UA of 9.5 mg/dL (565 micromol/L). In a validation sample of 182 patients with HF, those with a serum UA above the threshold value had a much poorer survival rate at four years than those with lower levels (19 versus 79 percent).

These observations do not address the issue of whether hyperuricemia is simply a marker for more severe heart disease, since both a low cardiac output and diuretic therapy reduce uric acid excretion. There is some evidence that lowering uric acid may be beneficial in patients with HF. In patients with hyperuricemia and HF, allopurinol therapy improved endothelial function and local blood flow [95].

A similar effect on endothelial function has been seen in patients with HF without hyperuricemia in association with reduced markers of oxidative stress, suggesting that xanthine oxidase inhibition itself may be important [96]. Furthermore, in an animal model of HF, long-term allopurinol therapy improved LV function and prevented LV remodeling, benefits that were associated with a transient reduction in reactive oxygen species [97]. The EXACT-HF Trial tested the effect of allopurinol therapy in 253 patients with symptomatic HF and an elevated serum uric acid (>9.5 mg/dL). In this trial, allopurinol treatment for 24 weeks deceased serum uric acid but had no effect on several markers of clinical outcome including survival, worsening HF, patient global assessment, quality of life, submaximal exercise capacity, and LVEF. These results suggest that although elevated uric acid is a marker of adverse outcomes, the lowering of uric acid with allopurinol is not clinically effective.

Hyperuricemia has also been evaluated as a risk factor for coronary heart disease. (See "Overview of possible risk factors for cardiovascular disease", section on 'Urate'.)

Weight loss and body mass index — Weight loss in patients with HF (sometimes called "cardiac cachexia" if severe) is linked to a poor prognosis. Both increased energy expenditure and decreased energy intake may contribute [98]. (See "Approach to the patient with unintentional weight loss".)

In an analysis of data on 1929 patients from the SOLVD treatment trial, 39 percent of whom had died by three years, weight loss of 6 percent at eight months was the best threshold value for predicting reduced survival [99]. This model was then validated using data on 619 patients from the V-HeFT II trial, 30 percent of whom had died at nine months. Weight loss of 6 percent or more at any time during follow-up was a predictor of mortality (adjusted HR 2.10, 95% CI 1.77-2.49).

In an analysis of data on 7599 patients with symptomatic HF with a broad range of LVEF from the CHARM clinical trials, 29 percent died by 38 months [100]. Patients with body mass index (BMI) <30 kg/m2 had greater mortality than those with BMI between 30 and 34.9 kg/m2; this association was not altered by LVEF. Lower BMI was associated with a greater risk of all-cause death in patients without edema but not in those with edema.

High plasma adiponectin levels are an independent predictor of mortality in chronic HF patients with systolic dysfunction [101,102]. Plasma adiponectin levels are negatively associated with BMI, so the elevated adiponectin levels in HF patients may be a marker for wasting.

Although obesity is a risk factor for cardiovascular disease, including HF and mortality, it does not appear to be a risk factor for mortality in HF, despite its association with hypertension, diabetes, and hypercholesterolemia [103,104]. (See "Overview of established risk factors for cardiovascular disease".)

Hypoalbuminemia and liver function abnormalities — Hypoalbuminemia is common among patients with HF though its causes have not been established [105,106]. In a study of 1726 systolic HF patients (LVEF 23±7 percent), hypoalbuminemia was present in 25 percent and it was a risk factor for one- and five-year mortality (HR 2.2 for both), even after adjustment for multiple prognostic factors including BMI, LVEF, and creatinine [105]. Hypoalbuminemia was not associated with BMI. Factors in addition to nutritional status, such as hepatic function, hemodilution, and inflammatory state, may contribute to hypoalbuminemia.

The predictive value of liver function tests and albumin level was evaluated in 2679 patients including 1594 with impaired LV systolic function (LVEF ≤40 percent) and 1085 with preserved LV function (LVEF >40 percent) enrolled in the CHARM program [106]. Hypoalbuminemia was present in 18 percent, elevated alkaline phosphatase in 14 percent, elevated total bilirubin in 13 percent, elevated alanine aminotransferase in 3 percent, and elevated aspartate aminotransferase in 4 percent. Elevated total bilirubin was nearly twice as common among patients with impaired LVEF as compared with those with preserved LVEF (16 versus 9 percent); the prevalences of the other abnormalities were not markedly different between the two LVEF groups. In univariate analysis adjusted for clinical variables, hypoalbuminemia as well as elevated total bilirubin were predictors of outcomes (cardiovascular death or HF hospitalization) with median 38 months follow-up. In a multivariable model including all clinical and laboratory predictors, total bilirubin (but not albumin) remained a significant predictor of outcomes (HR 1.1 per 1SD).

Hematologic abnormalities — As noted above, anemia is associated with increased mortality in patients with HF. (See 'Anemia' above.)

Polycythemia, as well as anemia, is associated with increased mortality in patients with HF. This was illustrated in a study of 3044 patients participating in the ELITE II trial [107]. The relationship between baseline hemoglobin concentration and survival was U-shaped, with the highest two-year survival rate (83 percent) among those with a hemoglobin of 14 to 15 g/dL. Patients in the subsets with lowest and highest hemoglobin (<12.5 g/dL and >15 g/dL, respectively) both had lower two-year survival rates (75 and 78 percent, respectively). The reason for the association between a high hemoglobin concentration and mortality noted in this study is not clear. While the correlation persisted after correction for the diagnosis of chronic obstructive pulmonary disorder (in 9 percent of the subjects), no data were provided on the incidence of cigarette smoking or its correlation with hemoglobin concentration.

Another independent predictor of morbidity and mortality is an elevated red cell distribution width (RDW) [108]. Among 36 laboratory values considered in the CHARM program of chronic HF patients (with depressed and preserved LVEF), higher RDW showed the greatest association with morbidity and mortality. This finding was replicated in the Duke Databank, in which higher RDW was strongly associated with all-cause mortality. (See "Microcytosis/Microcytic anemia", section on 'RDW (size variability)'.)

Other hematologic abnormalities have been associated with increased mortality, such as a decreased percentage of lymphocytes, which reflect stress-induced cortisol release [109]; a white blood cell count >7000/microL in ischemic cardiomyopathy [110]; and an erythrocyte sedimentation rate ≥15 mm/h, which reflects an acute phase response to inflammation or infection [111]. (See "Acute phase reactants".)

Low plasma T3 — The role of plasma T3 (triiodothyronine) concentrations as a prognostic indicator was evaluated in a report of 281 patients with systolic HF, 122 of whom (43 percent) had a plasma total T3 concentration below the lower limit of normal (≤80 ng/dL [1.2 nmol/L]) [112]. Low plasma T3 was an independent predictor of mortality independent of the LVEF. Whether low plasma T3 is a prognostic marker or contributes to progressive disease is not known.

Cytokines and other markers of inflammation — A number of cytokines and other markers of inflammation may be important in the pathogenesis of HF and serum levels may provide prognostic information. This issue is discussed separately. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Other factors'.)

Anabolic hormones — An imbalance in anabolic and catabolic forces, favoring catabolism, is present in patients with advanced HF. Deficiencies in anabolic hormones (eg, testosterone, dehydroepiandrosterone, and insulin-like growth factor) are associated with increased morbidity and mortality in the general population of adult men, and may have similar implications in men with HF.

This possibility was supported in a study of 208 men with HF, in whom anabolic hormone deficiencies were common [113]. At a follow-up of three years, these deficiencies were associated with increased mortality, and mortality rates were further increased among men with multiple hormone deficiencies. It is not known if these deficiencies contributed to the severity of HF, were themselves the result of advanced HF, or if they were simply markers of the severity of general chronic illness. In addition, because anabolic deficiencies are known to be associated with worse outcomes in the general population, it is not known if this finding is uniquely ominous in men with HF.

Albuminuria — Albuminuria may be an adverse prognostic indicator in patients with HF as well as in those with other cardiovascular disease. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

Albuminuria (identified by spot urinary albumin to creatinine ratio) was common in the class II to IV HF patients enrolled in the CHARM trials; 30 percent had microalbuminuria and 11 percent had macroalbuminuria. Albuminuria was associated with increased risk of mortality as well as the composite outcome (death from cardiovascular causes or admission to hospital with worsening HF), even after adjustment for other prognostic variables, including renal function and diabetes [114].

Depression — Depression appears to be both relatively common and associated with a worse prognosis in patients with HF [115]. In one study, major depression was associated with increased mortality at three and six months (odds ratio 2.5 and 2.23, respectively, compared with no depression) and with an increased rate of readmission (odds ratio 1.9 and 3.07, respectively) [116]. In another report, higher Beck Depression Inventory scores were independently associated with greater increases in mortality starting at approximately three months and continuing throughout the mean follow-up period of 971 days [117]. In this cohort, depression, but not antidepressant or selective serotonin reuptake inhibitor (SSRI) use, was independently associated with increased mortality [118].

Other psychosocial factors, such as marital quality, also are of prognostic importance [119]. (See "Psychosocial factors in sudden cardiac arrest".)

Randomized trials evaluating the effect of psychological interventions on the outcome of depressed patients with HF have not been performed [120].

mIBG imaging — Iobenguane I-123 (diagnostic) (also known as iodone-123 metaiodobenzylguanidine [mIBG]) is an analog of norepinephrine (NE) that is taken up into cardiac sympathetic nerve endings in the same manner as NE. This uptake is decreased in HF. Radionuclide scintigraphy using I-123-mIBG correlates with established indices of HF severity, including LVEF, CI, PCWP and peak VO2 [121]. Findings on mIBG imaging are associated with risk of death or transplantation [121], risk of sudden death [122] and with the likelihood of benefit from beta blocker therapy [123]. The mIBG imaging parameter with greatest prognostic value has differed among studies [121,123,124].

The prospective multicenter ADMIRE-HF study evaluated the predictive value of mIBG imaging in 961 subjects with NYHA functional class II or III HF (table 2) and LVEF ≤35 percent [125]. The heart/mediastinal uptake ratio (H/M) on mIBG imaging was compared with time to first occurrence of NYHA functional class progression, potentially life-threatening arrhythmic event (sustained ventricular tachycardia, cardiac arrest, or appropriate ICD discharge), or cardiac death. Twenty-five percent of subjects experienced events during median follow-up of 17 months. The two-year event rate was 15 percent for an H/M ≥1.6 as compared with 37 percent for an H/M ≤1.6. The H/M was a predictor for each of the individual event categories of HF progression, arrhythmic events and cardiac death (HR 0.48, 0.37, and 0.14, respectively). In a multivariable model, H/M, LVEF, BNP, and NYHA functional class were independent predictors for time to cardiac events.

Subsequent to the ADMIRE-HF study, the prognostic value of mIBG imaging in HF patients with longer-term follow-up (mean 78 months) was reported from a pooled analysis of six prospective HF cohort studies [126]. All-cause mortality was inversely related to H/M ratio, with annual all-cause mortality exceeding 7 percent for those with H/M ratio ≤1.2 (compared with less than 2 percent for patients with H/M ratio ≥2).

Sleep disordered breathing — Cheyne-Stokes respiration and sleep apnea are discussed separately. (See "Sleep-disordered breathing in heart failure", section on 'Prognostic implications'.)

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

Role of prognosis in patients with heart failure – Among patients with heart failure (HF) who are considering therapies such as heart transplantation, left ventricular (LV) assist device placement, or palliative care, prognostic information can further inform a discussion of the risks and benefits of therapy. However, for most diagnostic and treatment decisions, the role of prognosis is limited. (See "Management of refractory heart failure with reduced ejection fraction", section on 'Components of therapy' and "Heart transplantation in adults: Indications and contraindications", section on 'Prognosis scores' and "Palliative care for patients with advanced heart failure: Indications and systems of care", section on 'Disease course and prognosis'.)

Prognostic factors – Patients with HF often have one or more factors associated with decreased survival despite maximal medical therapy. Routine evaluation to estimate severity should include determination of New York Heart Association (NYHA) class; echocardiography to measure LV ejection fraction (LVEF), assessment of diastolic and right ventricular function, and identification of other abnormalities such as regional wall motion abnormalities; and measurement of the plasma natriuretic peptides, sodium, and creatinine concentrations. (See 'Major predictors of survival' above and "Heart failure: Clinical manifestations and diagnosis in adults".)

Prognostic models – In general, prognostic risk models can be used in selected clinical scenarios to more accurately communicate prognosis to the patient but should not be routinely used to guide therapy. (See 'Predictive models' above.)

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Topic 3477 Version 35.0

References

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