Heart failure (HF) is a clinical syndrome caused by structural or functional abnormalities of the heart, resulting in a reduction in cardiac output or elevation of ventricular filling pressures at rest or during exercise. The major manifestations of HF are breathlessness, decreased exercise tolerance, and fatigue, which may be accompanied by signs of fluid retention, including peripheral edema, elevated jugular venous pressure, and crackles in the lungs.
Given their increasing role in managing HF, PCPs are in a position to work with patients to improve clinical outcomes. Recent data have highlighted how considerable further improvement in outcomes in apparently stable patients with HF is possible if PCPs optimize their care. This article outlines management recommendations, with a focus on patients with stable but progressive HF.
1.1 Classification and Management of the Stages of HF
Historically, HF was dichotomized based on measurement of the left ventricular (LV) ejection fraction (EF) [
2,
10]. Patients with LVEF ≥ 50% were considered to have HF with normal or preserved EF (HFpEF) and those with LVEF ≤ 40%, HF with reduced EF (HFrEF) [
2,
10]. This left patients with an LVEF in the range of 40–49% in a “grey area,” which has been varyingly defined [
10]. Most recently, the 2016 European Society of Cardiology HF guidelines defined such patients as having HF with mid-range EF (HFmrEF) [
10]. However—as discussed later in this article—for the sake of management, patients with HFpEF and HFmrEF are considered collectively. Epidemiological studies suggest that approximately 50% of the total HF population have HFrEF and the remainder have HFpEF and HFmrEF [
2,
11]. Therapeutic strategies for the management of HF differ based on EF classification because the response to therapy varies between the two groups [
2]. Moreover, recommendations for the use of pharmacological GDEM have been more extensively developed for HFrEF than for HFpEF, because clinical trials have demonstrated benefits with such therapies in patients with HFrEF but not in patients with HFpEF [
12]. As such, this review focuses primarily on HFrEF management. GDEM for patients with HFpEF focuses primarily on managing symptoms and addressing risk factors and comorbidities for disease progression [
2].
In 2009, the American College of Cardiology (ACC)/American Heart Association (AHA) further classified HF into stages that emphasized the progressive nature of the disease, from risk factors to development of structural heart disease. The stages complement the NYHA functional classifications that focus on limitation of exercise capacity and the symptomatic status of the patient. At each stage of the new classification, management is aimed at preventing the development of the next stage.
Stage A patients have risk factors for the development of HF but do not have structural or functional heart disease and are asymptomatic. Management of risk factors prevents the development of HF in patients at this stage. For example, long-term treatment of hypertension has been shown to reduce the risk of developing HF by approximately 50% [
2,
13‐
17]. Similarly, treatment of hyperlipidemia with statin therapy reduces the risk of developing cardiovascular disease (CVD), including HF [
18]. In addition, insulin resistance has been shown to increase the risk of developing HF [
19‐
23], and glycated hemoglobin (HbA
1c) concentration ≥ 10.5% was associated with increased risk for developing HF compared with HbA
1c concentration < 6.5% [hazard ratio (HR) 3.98; 95% confidence interval (CI) 2.23–7.14] [
22]. Although hyperglycemia contributes to the development of HF, its treatment as a risk factor for CVD has been controversial because some hypoglycemic medications have been shown to increase the risk of cardiovascular events [
24]; however, recent data indicate that sodium–glucose cotransporter-2 (SGLT2) inhibitors reduced the rate of cardiovascular outcomes, including HF, and may be considered to treat hyperglycemia in patients at high risk of CVD [
25]. In particular, an analysis of data from the EMPA-REG OUTCOMES (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; ClinicalTrials.gov number, NCT01131676) trial has shown that empagliflozin, an SGLT2 inhibitor, is associated with a reduced risk for HF-related hospitalization or death compared with placebo (HR 0.61; 95% CI 0.47–0.79;
P < 0.001) [
26]. Thus, the effective management of these risk factors received a recommendation [class of recommendation (COR) I, level of evidence (LOE) A] to prevent the development of HF [
2]. Both pharmacological treatments, such as SGLT2 inhibitors for patients with diabetes mellitus, and lifestyle modifications, including sodium restriction in patients with hypertension, are appropriate strategies to reduce the risk of developing HF at this stage [
2].
Stage B patients are those who have already developed structural heart disease, such as myocardial infarction, LV dysfunction or LV hypertrophy, but are asymptomatic [
2]. These stage B patients with asymptomatic LV dysfunction (ASLVD) are at an increased risk of experiencing a CV event (HR 3.32; 95% CI 1.98–5.58;
P < 0.0001) and mortality (HR 3.47; 95% CI 2.03–5.94;
P < 0.0001) [
27]. To reduce the risk of morbidity and mortality and prevent progression to symptomatic HF in patients with ASLVD, the ACC Foundation (ACCF)/AHA Guideline for the Management of Heart Failure provides a class I (LOE A) recommendation for the use of the angiotensin-converting enzyme inhibitor (ACEI) enalapril [
2]. This recommendation is based on the results of the SOLVD (Studies of Left Ventricular Dysfunction) prevention trial, which reported that treatment with enalapril compared with placebo reduced the risk of death or hospitalization for congestive HF by 20% (95% CI 9–30;
P < 0.001) [
28]. Furthermore, an analysis of the 15-year post-trial follow-up data found that the beneficial effects of initial randomization to enalapril therapy, compared with placebo, continued to be seen throughout this period, with an overall absolute mortality risk reduction (ARR) of 6.5% (
P = 0.01) [
29]. These results underscore the importance of the early initiation of therapy and suggest that delaying treatment in patients with LV systolic dysfunction increases their risk of morbidity and mortality. Finally, myocardial revascularization to correct ischemia has been shown to be associated with better clinical prognosis [
30,
31]. Screening with non-invasive imaging to detect myocardial ischemia is recommended for patients with new-onset HFrEF and coronary artery disease without angina, unless the patient is not eligible for revascularization of any kind (COR IIA, LOE C) [
2].
Stage C patients have structural heart disease with prior or current symptoms of HF [
2]. Before the recent approval of the two new HF therapies, ivabradine and sacubitril/valsartan, the 2013 ACCF/AHA guidelines recommended that patients with stage C HFrEF receive GDEM, in addition to management of comorbidities, to reduce their risk of disease progression (COR I, LOE A) [
2]. The mainstay of GDEM for patients with stage C disease at that time included the use of recommended doses of ACEI—and if not tolerated, angiotensin receptor blocker (ARB) therapy (COR I, LOE A)—along with adequate doses of beta-blocker therapy with bisoprolol, carvedilol, or sustained-release metoprolol succinate (COR I, LOE A) to reduce the risk of morbidity and mortality [
2]. To further reduce morbidity and mortality, aldosterone receptor antagonists are recommended (COR I, LOE A) on top of ACEI/ARB and beta-blocker therapy in patients with NYHA class II–IV HFrEF, provided adequate renal function and potassium concentration < 5 mEq/dl [
2]. In symptomatic African American patients with NYHA class III–IV HFrEF already receiving optimal doses of ACEI/ARB and beta-blocker therapy, the combination of hydralazine and isosorbide dinitrate is recommended (COR I, LOE A) to further reduce morbidity and mortality [
2]. Although loop diuretics have not been shown to reduce mortality, they may be initiated in patients with NYHA class II–IV to reduce volume overload (COR I, LOE C) [
2].
Digoxin is a third-line treatment for HF, usually restricted as an add-on therapy to GDEM (COR IIA, LOE B) in patients with NYHA class III or IV HFrEF who remain symptomatic, to reduce the risk of hospitalization [
2]. In addition, digoxin is often used in patients with atrial fibrillation to achieve rate control as an adjunct to beta-blockers [
2]. However, physicians should be aware that digoxin toxicity may occur (1) with high doses (0.375–0.50 mg daily) [
32,
33]; (2) in patients with coexisting hypokalemia, hypomagnesemia, or hypothyroidism [
34,
35]; and (3) with the concomitant use of drugs that increase digoxin serum concentrations [
36‐
38]. To prevent toxicity, concomitant drug interactions and comorbidities should be considered upon digoxin initiation, and patients should be continually monitored [
2,
39].
Two types of devices are available for patients with stage C HFrEF [
2]. Implantable cardioverter-defibrillator (ICD) therapy is recommended (COR I, LOE A) for the primary prevention of sudden cardiac death in patients with NYHA class II–III HFrEF receiving GDEM who have either ischemic cardiomyopathy at least 40 days postmyocardial infarction or nonischemic dilated cardiomyopathy and a life expectancy over 1 year [
2]. Cardiac resynchronization therapy (CRT) is recommended for NYHA class II, III, or ambulatory NYHA class IV HFrEF (COR I, LOE A for NYHA class III/IV; LOE B for NYHA class II) patients receiving GDEM who are in sinus rhythm with a left bundle-branch block and a QRS duration of ≥ 150 ms [
2].
Stage D patients have advanced end-stage refractory HF and remain persistently symptomatic despite maximum pharmacological and device therapies [
2]. These patients need to be referred to advanced HF centers for specialized treatment strategies, such as insertion of mechanical circulatory assist devices and consideration of cardiac transplantation or end-of-life care [
2].
Many of the medications commonly prescribed in patients with HF, including antiarrhythmic drugs, nonsteroidal anti-inflammatory drugs, and thiazolidinediones, have been shown to potentially worsen HF [
2]. These should be avoided and discontinued whenever possible (COR III, LOE B) [
2]. Calcium channel-blocking drugs (other than amlodipine and felodipine) should not be used to treat patients with HFrEF (COR III, LOE A) because they may worsen outcomes for these patients [
40‐
44]. Additionally, the long-term use of infused positive inotropic drugs should be avoided in patients with HFrEF, except when used as palliation (COR III, LOE C), because they may worsen HF or precipitate death [
2].
Although GDEM improves patient outcomes, physician adherence to clinical practice guideline recommendations is suboptimal [
45]. For example, renin-angiotensin-aldosterone system (RAAS) blockers are recommended to reduce the risk of mortality and hospitalization in patients with HF [
2], but these drugs are underutilized [
45]. Optimal implementation of GDEM has the potential to prevent thousands of deaths each year based on estimates from Fonarow and colleagues (Table
1) [
45,
46].
Table 1
Estimated potential impact of optimal implementation of GDEM [
45,
46]
| 501,767 (20.4) | 6516 (9.6) |
| 361,809 (14.4) | 12,922 (19) |
Aldosterone antagonist [ 45] | 385,326 (63.9) | 21,407 (31.5) |
| 139,749 (92.7) | 6655 (9.8) |
| 199,604 (61.2) | 8317 (12.2) |
| 852,512 (49.4) | 12,179 (17.9) |
| 2,287,296 (eligibleb) | 28,484 |
1.3 Subclinical Progression in Stable HF
Patients with stable HF typically experience subtle disease progression that is often not clinically detectable. Even when patients are receiving GDEM, considerable cardiac damage and progression of HF can occur over time as a result of continued deleterious effects of activated RAAS and sympathetic nervous system pathways as well as inadequate effects of endogenous compensatory peptides (e.g., natriuretic peptides, bradykinin) [
48]. For example, many patients with clinically stable HF have elevated cardiac troponin T concentrations, suggesting continuous underlying cardiac myocyte injury [
49]. Elevated troponin concentrations in patients with stable HF are associated with increased risk of cardiovascular mortality and morbidity [
49,
50]. Disease progression can also occur as a result of prolonged endothelial dysfunction and alterations in the nitric oxide pathway, which promote increased vascular stiffness, myocardial damage, and vascular remodeling [
51].
Table
2 summarizes some clinical characteristics of patients with advanced HF that indicate
clinically obvious disease progression [
2]. For example, weight loss without other causes may indicate cardiac cachexia, which is associated with poor prognosis [
52]. Although these features of disease progression are often clear in patients with advanced HF, predicting which
clinically stable patients may decompensate is challenging. This difficulty is highlighted by studies such as PARADIGM-HF (Prospective Comparison of ARNI (angiotensin receptor–neprilysin inhibitor) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; NCT01035255), in which 26.5% of patients with apparently stable HF who received standard-of-care therapy, including enalapril, experienced a primary event of cardiovascular death or first hospitalization for worsening HF (WHF) during the trial (median duration of follow-up, 27 months) [
53]. Indeed, no simple means exist for physicians to predict when a seemingly stable patient will decompensate. Thus, it is important for physicians to remain aware of the significant risks associated with all stages of HF and to recognize therapies that may improve the underlying pathophysiology of HF for patients with stable yet progressive disease.
Table 2
Characteristics of patients with advanced HF [
2]
Repeated (≥ 2) hospitalizations or emergency department visits for HF in the past year |
Progressive deterioration in renal function |
Weight loss without other cause |
Intolerance to ACEIs due to hypotension and/or worsening renal function |
Intolerance to beta-blockers due to worsening HF or hypotension |
Frequent systolic blood pressure of < 90 mmHg |
Persistent dyspnea with dressing or bathing, requiring rest |
Inability to walk one block on level ground due to dyspnea or fatigue |
Recent need to escalate diuretics to maintain volume status, often reaching daily furosemide-equivalent dose of > 160 mg/day and/or use of supplemental metolazone therapy |
Progressive decline in serum sodium, usually to < 133 mEq/l |
Frequent implantable cardioverter-defibrillator shocks |