Ferric carboxymaltose (Injectafer – American Regent) is now FDA-approved for IV treatment of iron deficiency in adults with New York Heart Association (NYHA) class II/III heart failure to improve exercise capacity. Iron deficiency is present in approximately 30% of patients with heart failure; it has been associated with reduced quality of life and increased hospitalization and mortality. Injectafer is the first IV iron preparation to be approved for this indication. It was previously approved for treatment of iron deficiency anemia in children and adults.

The FDA has approved sotagliflozin (Inpefa – Lexicon), an oral sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor, to reduce the risk of hospitalization for heart failure (HF), urgent HF visits, and cardiovascular death in adults with either HF (with any left ventricular ejection fraction [LVEF]) or type 2 diabetes, chronic kidney disease (CKD), and other cardiovascular risk factors. Sotagliflozin is the first dual SGLT1/2 inhibitor to be approved in the US. Unlike SGLT2 inhibitors, it is not FDA-approved to improve glycemic control in adults with type 2 diabetes. Sotagliflozin is approved in the European Union as Zynquista for adjunctive treatment of type 1 diabetes.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga – AstraZeneca) was approved by the FDA in 2020 to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in adults with heart failure with reduced ejection fraction (HFrEF). The indication has now been expanded to include a reduction in the risk of urgent HF visits and use in adults with any left ventricular ejection fraction (LVEF).

The FDA has approved Furoscix (scPharmaceuticals), a subcutaneous formulation of the loop diuretic furosemide administered via a single-use, on-body infusor, for treatment of congestion due to fluid overload in adults with New York Heart Association (NYHA) Class II-III chronic heart failure (HF). Furosemide (Lasix, and generics) has been available for years in oral and IV formulations.

The FDA has approved mavacamten (Camzyos – MyoKardia/BMS), a modulator of cardiac myosin, to improve functional capacity and symptoms in adults with New York Heart Association (NYHA) class II or III obstructive hypertrophic cardiomyopathy (HCM) who have a baseline left ventricular ejection fraction (LVEF) ≥55%. Mavacamten is the first drug in its class to become available in the US.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance – Boehringer Ingelheim) was approved by the FDA in 2021 to reduce the risk of hospitalization for heart failure (HF) and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF; LVEF ≤40%), regardless of whether or not they have type 2 diabetes. The indication has now been expanded to include patients with HF with any ejection fraction. Empagliflozin is the first SGLT2 inhibitor to be approved in the US for this indication.

The FDA has approved an expansion of the peripheral artery disease (PAD) indication for the oral direct factor Xa inhibitor rivaroxaban (Xarelto – Janssen) to include patients who have recently undergone a lower extremity revascularization procedure for symptomatic PAD (see Table 1). Rivaroxaban is the first direct oral anticoagulant (DOAC) to be approved for use in patients with PAD.

Among patients with chronic heart failure, those with a left ventricular ejection fraction (LVEF) ≤40% are considered to have heart failure with reduced ejection fraction (HFrEF). Patients with a LVEF ≥50% are considered to have heart failure with preserved ejection fraction (HFpEF). Those with a LVEF of 41-49% are an intermediate group more similar to patients with HFpEF.

The oral fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan (Entresto – Novartis) was approved in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF; LVEF <40%). The FDA has now expanded its indication to include patients with chronic heart failure with any LVEF; the label specifies that benefits are most clearly evident in patients with LVEF below normal. Entresto is the first drug to be approved in the US for this indication.

The FDA has approved vericiguat (Verquvo – Merck), an oral soluble guanylate cyclase (sGC) stimulator, to reduce the risk of hospitalization for heart failure and cardiovascular (CV) death following a worsening heart failure event (hospitalization for heart failure or treatment with IV diuretics as an outpatient) in patients with symptomatic chronic heart failure and left ventricular ejection fraction (LVEF) <45%. Vericiguat is the second sGC stimulator to be marketed in the US. Riociguat (Adempas), which is FDA-approved for treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, was the first.

View the Comparison Table: Some Drugs for HFrEF

In a randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance – Boehringer Ingelheim/Lilly) reduced the composite risk of cardiovascular death or hospitalization for worsening heart failure (HF) in patients with heart failure with reduced ejection fraction (HFrEF), whether or not they had type 2 diabetes. To date, empagliflozin has not been approved by the FDA for such use. The SGLT2 inhibitor dapagliflozin (Farxiga) was approved by the FDA for this indication earlier this year.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga), which was initially approved by the FDA for treatment of type 2 diabetes and then to reduce the risk of hospitalization for HF in adults who have type 2 diabetes and established cardiovascular disease (CVD) or multiple cardiovascular risk factors, has now been approved for a third indication: to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with heart failure with reduced ejection fraction (with or without type 2 diabetes). It is the first SGLT2 inhibitor to be approved in the US for this indication.

In our Drugs for Chronic Heart Failure article,1 our description of the PARADIGM-HF trial comparing the combination of the ARB valsartan and the neprilysin inhibitor sacubitril (Entresto) with the ACE inhibitor enalapril for treatment of heart failure with reduced ejection fraction (HFrEF) characterized the dosage of enalapril as "suboptimal". Some readers have objected to that characterization.

The FDA-approved dosage of enalapril for treatment of HFrEF is 2.5-20 mg twice daily. In PARADIGM-HF, the dosage was capped at 10 mg twice daily, a widely used dosage that has been shown to reduce mortality in patients with HFrEF.2 In the trial, the rate of death from cardiovascular causes or hospitalization for heart failure was significantly lower with the combination of valsartan and sacubitril than with enalapril 10 mg twice daily (21.8% vs 26.5%). Whether allowing titration to 20 mg twice daily would have changed that result is a reasonable question, but there is no direct evidence that the higher dosage is more effective for this indication.3 We have removed the word "suboptimal" from the article as it appears online.

1. Med Lett Drugs Ther 2019; 61:49.
2. JJ McMurray et al. N Engl J Med 2014; 371:993.
3. N Bartell and WH Frishman. Cardiol Rev 2017; 25:315.

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Patients with a left ventricular ejection fraction (LVEF) ≤40% are considered to have heart failure with reduced ejection fraction (HFrEF). Patients with a LVEF ≤50% and symptoms of heart failure are considered to have heart failure with preserved ejection fraction (HFpEF). There is little evidence that drug treatment improves clinical outcomes in patients with HFpEF.

View the Expanded Table: Some Drugs for HFrEF

For many years, the goal of drug therapy for most patients with type 2 diabetes has been to achieve and maintain an A1C of <7%. Achieving that goal can prevent microvascular complications (diabetic retinopathy, nephropathy, neuropathy), but whether it prevents macrovascular complications (myocardial infarction [MI], stroke) has been less clear. The FDA now requires that cardiovascular safety studies be performed for all new drugs for type 2 diabetes.1 Recent findings that some of the newer second-line drugs for type 2 diabetes have cardiovascular benefits have led to new interest in the cardiovascular efficacy and safety of all antidiabetic drugs.

The FDA has approved Byvalson (Allergan), a fixed-dose combination of the beta blocker nebivolol (Bystolic) and the angiotensin receptor blocker (ARB) valsartan (Diovan, and generics), for treatment of hypertension. It is the only combination product that contains nebivolol, and the first to combine a beta blocker with an ARB.

The FDA has approved Entresto (Novartis), an oral fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan, to reduce the risk of cardiovascular death and heart failure hospitalization in patients with heart failure with reduced ejection fraction. Sacubitril is the first neprilysin inhibitor to become available in the US.

The FDA has approved ivabradine (Corlanor – Amgen) to reduce the risk of hospitalization for worsening heart failure in adults with stable, symptomatic chronic heart failure with left ventricular ejection fraction (LVEF) ≤35% who are in sinus rhythm with a resting heart rate ≥70 beats per minute and who are on maximum tolerated doses of beta blockers or have a contraindication to beta blocker use. Ivabradine has been available internationally for years as Procoralan and Corlentor for treatment of stable angina and heart failure.

Heart failure is usually associated with left ventricular dysfunction. According to recent guidelines, patients with a left ventricular ejection fraction (LVEF) ≤40% are considered to have heart failure with reduced ejection fraction (HFrEF) or systolic heart failure. Patients with a LVEF ≥50% and symptoms of heart failure are considered to have heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure; there is little evidence that drug treatment improves clinical outcomes in these patients. The treatment of acute heart failure is not included here.

Chronic systolic heart failure is usually associated with a left ventricular ejection fraction (LVEF) of ≤40%. Many patients with symptoms of heart failure have higher ejection fractions, but there is no evidence that drug treatment of heart failure with preserved systolic function (LVEF >40%) improves clinical outcomes. Some of the drugs commonly used now for treatment of chronic heart failure are listed in the table on page 71.

A recent editorial in The New England Journal of Medicine commented on the negative results of a clinical trial (published in the same issue) of nesiritide, a drug that had been approved by the FDA in 2001 (conditionally approved by Health Canada in 2007) for relief of dyspnea in patients with acutely decompensated heart failure. The authors of the recent clinical trial concluded: "On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure."1 The editorialist lamented the inadequacy of the data that had led to the approval of the drug in the first place, the 10 years of "fuzziness and ambiguity" that had followed regarding its use, and the "more than $1 billion" wasted on buying it.2

In 2001, when nesiritide was first approved in the US, The Medical Letter also expressed dissatisfaction with the quality of the data criticized by the 2011 editorialist, and concluded its assessment of nesiritide as follows: "Until more published data become available, nesiritide should probably be reserved for treatment of patients with heart failure who have not responded to nitroglycerin and cannot be treated with nitroprusside."3

1. CM O’Connor et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011; 365: 32.

2. EJ Topol. The lost decade of nesiritide. N Engl J Med 2011; 365:81.

3. Nesiritide for decompensated congestive heart failure. Med Lett Drugs Ther 2001; 43:100.

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The treatment of atrial fibrillation includes ventricular rate control, anticoagulation, conversion to normal sinus rhythm and maintenance of sinus rhythm. The choice of therapies that can achieve these goals is discussed in the text that follows. Some drugs are recommended here for indications that have not been approved by the FDA.

The range of drugs for treatment of chronic heart failure continues to expand. Some of those commonly used now are listed in the table on page 55. Mechanical therapies for the treatment of heart failure such as cardiac resynchronization, implanted cardiac defibrillators (ICDs), ventricular assist devices and ultrafiltration for the relief of congestion will not be reviewed here.

Effective treatment of hypertension can prevent organ damage and death. The choice of drugs for initial treatment continues to be controversial.

Nebivolol (Bystolic - Forest) is a new beta-blocker that has been approved by the FDA for treatment of hypertension. It has been marketed in Europe since 1999 for treatment of hypertension and heart failure.

Coenzyme Q10, a fat-soluble antioxidant also known as ubidecarenone, ubiquinone and CoQ10, is marketed as a dietary supplement in the US, both as a single ingredient and in various combination products.

The choice of drugs for treatment of chronic heart failure continues to evolve. Those most commonly used now are listed in the table on page 3. The use of implanted cardiac defibrillators (ICDs) to reduce the incidence of sudden death in patients with heart failure and the treatment of decompensated heart failure were discussed in previous issues.

BiDil (NitroMed), a fixed-dose combination of isosorbide dinitrate and hydralazine, was approved by the FDA for adjunctive use in the treatment of heart failure in black patients.Both drugs are oral vasodilators that have been used together off-label for many years to treat heart failure in patients not responding to other drugs.

The choice of drugs for treatment of chronic heart failure continues to evolve. It has become increasingly recognized that drugs used in heart failure produce beneficial effects through neurohormonal as well as hemodynamic mechanisms. The treatment of decompensated heart failure is not discussed here; drugs used for this indication were reviewed in Cardiovascular Drugs in the ICU, Treatment Guidelines from The Medical Letter 2002; 1:19.

Nesiritide, a recombinant human B-type natriuretic peptide (BNP), has been approved by the FDA of intravenous (IV) treatment of patients with decompensated congestive heart failure who have dyspnea at rest or with minimal exertion (New York Heart Association class IV).

The choice of drugs for treatment of heart failure depends on both hemodynamic and neurohormonal factors.

Cardiologist now emphasize the importance of neurohormonal as well as hemodynamic factors in the pathophysiology of chronic heart failure (JN Cohn, N Engl J Med, 335:490, August 15, 1996). Drugs that act on different mechanisms are commonly used together.

Chronic heart failure results from an iterplay between hemodynamic and neurohormonal factors (M Packer, Lancet, 340:88, 92, 1992). For patients with heart failure due to left ventricular dysfunction, drugs that decrease cardicac preload and afterload and those that increase contractility are commonly used together.

Flosequinan (Manoplax - Boots), a fluoroquinolone derivative, is now available in the USA for treatment of congestive heart failure. Labeling approved by the US Food and Drug Administration recommends the drug only for patients who cannot tolerate or have not responded adequately to an angiotensin-converting enzyme (ACE) inhibitor.

- Merck; Zestril - Stuart), a new angiotensin-converting enzyme (ACE) inhibitor, was recently approved by the US Food and Drug Administration (FDA) for once-daily treatment of . Two other ACE inhibitors, captopril (Capoten - Squibb) and e