Drugs for Heart Failure

moderate to severe symptoms or signs of heart failure.

< 30% and chronic HF, or acute HF complicating acute myocardial infarction.

Potassium supplements should be stopped. Serum potassium and creatinine should be checked every 1 to 2 weeks for the first 4 to 6 weeks and after dose changes. Dose is lowered if potassium is between 5.0 and 5.5 mEq/L ( 5.5 mmol/L) and stopped if potassium is > 5.5 mEq/L (5.5 mmol/L), if creatinine increases above 2.5 mg/dL (220 micromol/L), or if ECG changes of hyperkalemia are present. Aldosterone antagonists should not be used in patients receiving both an ACE inhibitor and an ARB because of the high risk of hyperkalemia and renal dysfunction.

In patients with HFrEF, an aldosterone antagonist plus either an ACE inhibitor or an ARB is preferred over the combination of an ACE inhibitor and ARB.

In patients with HFpEF,1). Thus, aldosterone antagonists should be used in patients with HFpEF, particularly if they are volume overloaded and/or have a history of HF hospitalization. Loop diuretics can be minimized if necessary to accommodate the use of aldosterone antagonists.

All patients with HFrEF should be given oral ACE inhibitors unless contraindicated (eg, by plasma creatinine > 2.8 mg/dL [> 250 micromol/L], bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, or previous angioedema due to ACE inhibitors).

• Arterial and venous vasodilation

• Sustained decreases in LV filling pressure during rest and exercise

• Decreased systemic vascular resistance

• Favorable effects on ventricular remodeling

ACE inhibitors prolong survival and reduce HF hospitalizations. For patients with atherosclerosis and a vascular disorder, these drugs reduce the risk of myocardial infarction and stroke. For patients with diabetes, they delay onset of nephropathy. Thus, ACE inhibitors may be used in patients with diastolic dysfunction and any of these disorders.

hyperkalemia) may result, especially in patients receiving potassium supplements. Cough occurs in 5 to 15% of patients, probably because bradykinin accumulates, but other causes of cough should also be considered. Occasionally, rash or dysgeusia occurs. Angioedema is rare but can be life threatening and is a contraindication to ACE inhibitors. Alternatively, ARBs can be used, although rarely cross-reactivity is reported. Both are contraindicated in pregnancy.

Serum electrolytes and renal function should be measured before an ACE inhibitor is started, at 1 month, and after each significant increase in dose or change in clinical condition. If dehydration or poor renal function due to acute illness develops, the ACE inhibitor dose may need to be reduced or the drug may be temporarily stopped.

In HFpEF,2). Given the very high prevalence of hypertension in HFpEF, it is reasonable to use an ACE inhibitor to control hypertension in these patients as these drugs may have secondary beneficial effects on exercise capacity in these patients.

These drugs are not demonstrably superior to ACE inhibitors but are less likely to cause cough and angioedema; they may be used when these adverse effects prohibit ACE inhibitor use.

In chronic HFrEF,

Adding an ARB to a regimen of an ACE inhibitor, beta-blocker, and aldosterone antagonist is unlikely to be helpful and should be avoided given the risk of hyperkalemia. If a patient who is taking an ACE inhibitor or ARB is still symptomatic, an aldosterone antagonist should be started and/or an angiotensin receptor/neprilysin inhibitor (ARNI) should be used.

In HFpEF,3) demonstrated reduced number of hospitalizations for recurrent HF; however, hospitalization was a secondary endpoint. In another trial (4

ARBs are contraindicated in pregnancy.

ARNIs are a new combination drug for the treatment of heart failure. They include an ARB and a newer class of drug, neprilysin inhibitors (eg, sacubitril). Neprilysin is an enzyme involved in the breakdown of vasoactive substances such as brain (B-type) natriuretic peptide (BNP) and other peptides. By inhibiting the breakdown of BNP and other beneficial vasoactive peptides, these drugs lower blood pressure, decrease afterload, and enhance natriuresis. Because neprilysin inhibitors increase BNP levels, NTproBNP levels (which are not increased by the drug) should be used instead to help diagnose and manage HF.

In HFrEF, a large randomized, controlled trial (5NYHA Classification of Heart Failure

Complications associated with use of ARNI include hypotension, hyperkalemia, renal insufficiency, and angioedema

In HFpEF,6, 7). However, there may have been lower hospitalization rates—further study is needed.

In patients with HFrEF, beta-blockers, unless otherwise contraindicated (by asthma, 2nd- or 3rd-degree atrioventricular block

In patients with HFpEF, beta-blockers have not shown clear benefits in clinical trials. However, data from large registries have suggested that beta-blocker use is associated with improved outcomes in HFpEF despite the relatively high prevalence of chronotropic incompetence (ie, the inability to raise heart rate in response to increased exertional demand) in HFpEF. All major guidelines for heart failure recommend beta-blockade as first-line therapy for conditions where ventricular rate control is indicated (ie, control of ventricular rate with atrial fibrillation).

≥

During a severe, acute decompensation, beta-blockers should not be started until patients are stabilized and have little evidence of fluid retention. For HFrEF patients with acute HF exacerbation already taking a beta-blocker, the dose should not be decreased or stopped unless absolutely necessary. Often the beta-blocker dose can be continued in patients with an acute HF exacerbation if the diuretic dose is temporarily increased.

In HFrEF, after initial treatment, heart rate and myocardial oxygen consumption decrease, and stroke volume and filling pressure are unchanged. With the slower heart rate, diastolic function improves. Ventricular filling returns to a more normal pattern (increasing in early diastole), which appears less restrictive. Improved myocardial function is measurable in some patients after 6 to 12 months but may take longer; ejection fraction (EF) and cardiac output (CO) increase, and LV filling pressure decreases. Exercise capacity improves.

Digoxin is excreted by the kidneys; elimination half-life is 36 to 40 hours in patients with normal renal function.

Digoxin has no proven survival benefit but, when used with diuretics and an ACE inhibitor, may help control symptoms and reduce the likelihood of hospitalization in patients with HFrEF. However, because of the availability of a large number of evidence-based treatments for HFrEF, digoxin use has dropped significantly and is reserved for patients with significant symptoms despite optimal treatment with other mortality lowering medications. Digoxin should not be used in HFpEF unless it is being used to control heart rate in concomitant atrial fibrillation or to augment RV function in patients with RV failure. Digoxin is most effective in patients with large LV end-diastolic volumes and a 3rd heart sound (S3). Acute withdrawal of digoxin may increase the hospitalization rate and worsen symptoms.

In patients with normal renal function, digoxin, 0.125 to 0.25 mg orally once a day depending on age, sex, and body size, achieves full digitalization in about 1 week (5 half-lives). More rapid digitalization can be achieved with digoxin 0.5 mg IV over 15 minutes followed by 0.25 mg IV at 8 and 16 hours or with 0.5 mg orally followed by 0.25 mg orally at 8, 16, and 24 hours. Prescription patterns vary widely by physician and by country, but in general, doses are lower than those used in the past, and a trough (8- to 12-hours post-dose) digoxin level of 0.8 to 1.2 ng/mL (1 to 1.5 nmol/L) is preferable. In addition, unlike in the treatment of atrial fibrillation, there is typically little reason to rapidly digitalize (ie, digoxin load) patients with HF. Thus, simply starting digoxin at 0.125 mg orally once a day (in patients with normal renal function) or digoxin 0.125 mg orally every Monday, Wednesday, and Friday (in patients with abnormal renal function) is sufficient in patients with heart failure.

Digoxin toxicityventricular fibrillation, ventricular tachycardia, complete atrioventricular block). Bidirectional ventricular tachycardia, nonparoxysmal junctional tachycardia in the presence of atrial fibrillation, and hyperkalemia are serious signs of digitalis toxicity. Nausea, vomiting, anorexia, diarrhea, confusion, amblyopia, and, rarely, xerophthalmia may occur. If hypokalemia or hypomagnesemia

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Diuretics are given to all patients with HF (regardless of underlying ejection fraction) who have current or previous volume overload; dose is adjusted to the lowest dose that stabilizes weight and relieves symptoms.

Loop diuretics should be used initially for control of volume overload, but their dose should be reduced when possible in favor of aldosterone antagonists.

furosemide 20 to 40 mg orally once a day or twice a day, bumetanide 0.5 to 1.0 mg orally once a day, and torsemide 10 to 20 mg orally once a day. If needed, loop diuretics can be titrated up to doses of furosemide 120 mg orally twice a day, bumetanide 2 mg orally twice a day, and torsemide 40 mg orally twice a day based on response and renal function. Bumetanide and torsemide have better bioavailability than furosemide. If patients are switched between different loop diuretics, they should be placed on equivalent doses. Furosemide 40 mg is equivalent to bumetanide 1 mg, and both are equivalent to torsemide 20 mg.

An aldosterone antagonist,²

Thiazide diuretics

Reliable patients are taught to take additional diuretic doses as needed when weight or peripheral edema increases. They should seek medical attention promptly if weight gain persists.

Vasopressin (antidiuretic hormone) receptor antagonists are not frequently used though they may be helpful in cases of severe refractory hyponatremia in patients with HF.

There is an inward sodium/potassium current that travels through a certain gated channel (funny or "f" channel) in sinus node (cardiac pacemaker) cells located in the posterior right atrium. This current is sometimes referred to as the inward funny current (I_f). Inhibition of this current prolongs the time it takes to achieve critical spontaneous depolarization of pacemaker cells, and thus lowers the heart rate.

_fNYHA Classification of Heart Failure) and heart rate > 70 beats/minute who are at target beta-blocker dose or cannot tolerate a further increase in beta-blocker dose (8).

910).

²), or rapidly worsening renal function.

may help patients truly intolerant of ACE inhibitors or ARBs (usually because of significant renal dysfunction), although limited studies show long-term benefit of this combination. However, in patients of African ancestry this combination, when added to standard therapy, has been shown to reduce mortality and hospitalization, and improve quality of life. As vasodilators, these drugs improve hemodynamics, reduce valvular regurgitation, and increase exercise capacity without causing significant renal impairment.

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When added to ACE/ARB therapy, hydralazinehydralazine-nitrate therapy to an ACE/ARB in patients of African ancestry with HF is patient specific and frequently determined by drug tolerance and symptom burden. In general, RAAS inhibitor therapy (ACE, ARB, or ARNI) should be used in this population, if tolerated.

angina11), where it was shown to be associated with increased adverse effects (eg, headache) and reduced physical activity. Thus, routine use of long-acting nitrates should be avoided in HFpEF.

hypertensionpulmonary edemaatrial fibrillationhypertrophic cardiomyopathy.

Various positive inotropic drugsnorepinephrine, epinephrine

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1. 1. Pitt B, Pfeffer MA, Assmann SF, et al: Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392, 2014. doi: 10.1056/NEJMoa1313731

2. 2. Cleland JG, Tendera M, Adamus J, et al: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27:2338–2345, 2006. doi: 10.1093/eurheartj/ehl250

3. 3. Yusuf S, Pfeffer MA, Swedberg K, et al: Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362:777, 2003. doi: 10.1016/S0140-6736(03)14285-7

4. 4. Massie BM, Carson PE, McMurray JJ, et al: Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359:2456–2467, 2008. doi: 10.1056/NEJMoa0805450

5. 5. McMurray JJ, Packer M, Desai AS, et al: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004, 2014. doi: 10.1056/NEJMoa1409077

6. 6. Solomon SD, McMurray JJ, Anand IS, et al: Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 381:1609–1620, 2019. doi: 10.1056/NEJMoa1908655

7. 7. McMurray JJV, Jackson AM, LAM CSP, et al: Effects of sacubitril-valsartan Versus valsartan in women compared with men with heart failure and preserved ejection fraction: Insights From PARAGON-HF. Circulation 41(5):338–351, 2020. doi: 10.1161/CIRCULATIONAHA.119.044491

8. 8. Swedberg K, Komajda M, Bohm M, et al: Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376(9744):875–885, 2010. doi: 10.1016/S0140-6736(10)61198-1

9. 9. McMurray JJV, Solomon SD, Inzucchi SE, et al: Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381(21):1995–2008, 2019. doi: 10.1056/NEJMoa1911303

10. 10. Anker SD, Butler J, Filippatos G, et al: Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 385(16):1451-1461, 2021. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189.

11. 11. Redfield M, Anstrom KJ, Levine JA, et al: Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 373:2314–2324, 2015. doi: 10.1056/NEJMoa1510774

12. 12. Armstrong PW, Pieske B, Anstrom KJ, et al: Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 382(20):1883–1893, 2020. doi: 10.1056/NEJMoa1915928