What medications may be used to decrease edema in congestive heart failure patients?

Medication Summary

The goals of pharmacotherapy for heart failure are to reduce morbidity and to prevent complications. Along with oxygen, medications assisting with symptom relief include: (1) diuretics, which reduce edema by reduction of blood volume and venous pressures; (2) vasodilators, for preload and afterload reduction; (3) digoxin, which can cause a small increase in cardiac output; (4) inotropic agents, which help to restore organ perfusion and reduce congestion; (5) anticoagulants, to decrease the risk of thromboembolism; (6) beta-blockers, for neurohormonal modification, left ventricular ejection fraction (LVEF) improvement, arrhythmia prevention, and ventricular rate control; (7) angiotensin-converting enzyme inhibitors (ACEIs), for neurohormonal modification, vasodilatation, and LVEF improvement; (8) angiotensin II receptor blockers (ARBs), also for neurohormonal modification, vasodilatation, and LVEF improvement; and (9) analgesics, for pain management.

The FDA approved vericiguat (Verquvo), a sGC stimulator, in 2021. Vericiguat stimulates sGC, the intracellular receptor for endogenous NO, which catalyzes cyclic guanosine monophosphate (cGMP) production. 

Ivabradine, an I(f) inhibitor is available in the United States. It blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I(f) "funny" current, which regulates heart rate without any effect on ventricular repolarization or myocardial contractility.

Sacubitril/valsartan (Entresto), an angiotensin receptor-neprilysin inhibitor (ARNI), was approved by the FDA in July 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with congestive heart failure (New York Heart Association [NYHA] class II-IV) and reduced ejection fraction. [135]  In 2021, this indication was expanded to include heart failure in adults with preserved ejection fraction based on the PARAGON-HF (Prospective Comparison of ARNI with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) study. [136]  

The selective sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in patients with heart failure and/or to reduce the risk of heart failure in patients with type 2 diabetes mellitus. The phase 3 trials Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) and EMPEROR-Preserved provided evidence for FDA approval of empagliflozin to reduce the risk of CV death or hospitalization for heart failure in patients with heart failure with either reduced or preserved ejection fraction (HFrEF or HFpEF). [139, 141]   

Dapagliflozin is indicated to reduce the risk of CV death and hospitalization for HF in patients with HFrEF. Approval was based on results from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) phase 3 clinical trial. [140]  Clinical trials (PRESERVED-HF, DELIVER) for dapagliflozin in HFpEF are ongoing. [142, 143]    

Drugs that can exacerbate heart failure should be avoided, such as nonsteroidal anti-inflammatory drugs (NSAIDs), calcium channel blockers (CCBs), and most antiarrhythmic drugs (except class III). NSAIDs can cause sodium retention and peripheral vasoconstriction, and they can attenuate the efficacy and enhance the toxicity of diuretics and ACEIs. Calcium channel blockers (CCBs) can worsen heart failure and may increase the risk of cardiovascular events; only the vasoselective CCBs have been shown not to adversely affect survival. Antiarrhythmic agents can have cardiodepressant effects and may promote arrhythmia; only amiodarone and dofetilide have been shown not to adversely affect survival.

Beta-Blockers, Alpha Activity

Class Summary

Beta-blockers inhibit the sympathomimetic nervous system and block alpha1-adrenergic vasoconstrictor activity. These agents have moderate afterload reduction properties and cause slight preload reduction. In addition to decreasing mortality rates, beta-blockers also reduce hospitalizations and the risk of sudden death; improve LV function and exercise tolerance; and reduce heart failure functional class. Although other beta-blockers with similar pharmacologic properties might hypothetically be beneficial in heart failure, the target doses have not been identified in clinical trials.

Carvedilol (Coreg, Coreg CR)

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Carvedilol is a nonselective beta- and alpha1-adrenergic blocker. It does not appear to have intrinsic sympathomimetic activity. Carvedilol at the target dose of 25 mg twice daily has been shown to reduce mortality in clinical trials of heart failure patients with reduced ejection fraction.

Beta-Blockers, Beta-1 Selective

Class Summary

Certain beta-1 blockers are selective in blocking beta-1 adrenoreceptors. These agents are used in heart failure to reduce heart rate and blood pressure.

Metoprolol (Lopressor, Toprol XL)

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Metoprolol is a selective beta1-adrenergic blocker at lower doses. It inhibits beta2-receptors at higher doses. It does not have intrinsic sympathomimetic activity. The long-acting formulation (metoprolol succinate) at a target dose of 200 mg daily has been shown to reduce mortality in a clinical trial of patients with heart failure and low ejection fraction.

Bisoprolol (Zebeta)

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Bisoprolol is a highly selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. Bisoprolol at the target dose of 10 mg daily has been shown to reduce mortality in a clinical trial of patients with heart failure and reduced ejection fraction, but is not approved for heart failure use in the US.

ACE Inhibitors

Class Summary

Angiotensin-converting enzyme inhibitors (ACEIs) prevent conversion of angiotensin I to angiotensin II, which results in lower aldosterone secretion. Use of ACEIs increases survival, improves symptoms, and decreases repeat hospitalizations.

Captopril

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Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. Captopril at a target dose of 25 mg three times daily has been shown to improve survival in patients with low ejection fraction after myocardial infarction.

Enalapril (Vasotec)

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Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps control blood pressure and proteinuria. Enalapril decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. It has a favorable clinical effect when administered over a long period. It helps prevent potassium loss in distal tubules. The body conserves potassium; thus, less oral potassium supplementation is needed. Enalapril at a target dose of 10 mg twice daily has been shown to improve survival in patients with heart failure and reduced ejection fraction.

Lisinopril (Prinivil, Zestril)

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Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. Lisinopril at a target dose of 10 mg daily has been shown to reduce mortality after myocardial infarction.

Ramipril (Altace)

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Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. Ramipril at a target dose of 5 mg twice daily has been shown to reduce mortality in patients with heart failure after myocardial infarction.

Quinapril (Accupril)

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Quinapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

ARBs

Class Summary

Angiotensin receptor blockers (ARBs) are reasonable first-line therapy for patients with mild to moderate heart failure symptoms and left ventricular (LV) dysfunction when patients are already taking these agents for other indications. ARBs block the renin-angiotensin-aldosterone system (RAAS) by competitive inhibition of the AT1 receptor, thereby decreasing afterload and preventing LV remodeling. The use of ARBs increases survival and decreases hospitalization rates, but these agents are not superior to angiotensin-converting enzyme inhibitors (ACEIs). ARBs can also be used as add-on therapy for patients who have refractory heart failure symptoms despite optimal heart failure therapy.

Losartan (Cozaar)

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Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at tissue receptor sites. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, and it does not affect the response to bradykinin (less likely to be associated with cough and angioedema). These agents are used in patients unable to tolerate ACE inhibitors. Losartan has not been demonstrated to improve survival in heart failure.

Valsartan (Diovan)

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Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. It is used in patients unable to tolerate ACE inhibitors. Valsartan at a target dose of 160 mg twice daily has been shown to improve survival in patients with heart failure and reduced ejection fraction.

Candesartan (Atacand)

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Candesartan blocks the vasoconstriction and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. Use candesartan in patients unable to tolerate ACE inhibitors. Candesartan at a target dose of 32 mg daily has been shown to improve survival in patients with heart failure and reduced ejection fraction.

Irbesartan (Avapro)

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Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at tissue receptor sites. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, and it does not affect the response to bradykinin (less likely to be associated with cough and angioedema). Irbesartan has not been shown to improve survival in heart failure.

Azilsartan (Edarbi)

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Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at tissue receptor sites. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, and it does not affect the response to bradykinin (less likely to be associated with cough and angioedema).

Inotropic Agents

Class Summary

Inotropic agents such as milrinone, digoxin, dopamine, and dobutamine are used to increase the force of cardiac contractions. Intravenous positive inotropic agents should only be used in inpatient settings — and then only in patients who manifest signs and symptoms of low cardiac output syndrome (volume overload with evidence of organ hypoperfusion).

Milrinone

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Milrinone is a type 3 phosphodiesterase inhibitor that increases inotropy, chronotropy, and lusitropy, acting via cyclic guanosine monophosphate (cGMP) to increase the intramyocardial adenosine triphosphate (ATP). It is a potent vasodilator agent, being a venous and arterial vasodilator, and it is used in patients with pulmonary hypertension. Milrinone can be used in the presence of a beta-blocker. Milrinone is thought to create less tachycardia, because it does not directly stimulate beta-receptors.

Digoxin (Lanoxin)

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Digoxin is a cardiac glycoside with direct inotropic effects, in addition to indirect effects, on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure. It is used to improve symptoms associated with HF by enhancing cardiac contractility. Although digoxin does not confer a survival benefit, it has reduced the number of hospitalizations that occur as a result of worsening heart failure.

Dopamine

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Dopamine is a naturally occurring catecholamine that acts as a precursor to norepinephrine. It stimulates both adrenergic and dopaminergic receptors. The hemodynamic effect is dose dependent. Low-dose use is associated with dilation within renal and splanchnic vasculature, resulting in enhanced diuresis. Moderate doses enhance cardiac contractility and the heart rate. Higher doses cause increased afterload through peripheral vasoconstriction. Administer by continuous intravenous infusion. It is usually used in severe heart failure and is reserved for patients with moderate hypotension (eg, systolic blood pressure 70-90 mm Hg). Typically, moderate or higher doses are used.

Dobutamine

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Dobutamine, a beta-receptor agonist, increases inotropy and chronotropy and decreases afterload, thereby improving end-organ perfusion. It produces vasodilation and increases the inotropic state. At higher dosages, it may cause increased heart rate, exacerbating myocardial ischemia. Careful hemodynamic and patient monitoring is required.

Vasodilators

Class Summary

In addition to diuretic therapy, vasodilators are recommended as first-line therapy for patients with acute heart failure in the absence of hypotension, for relief of symptoms. Vasodilators decrease preload and/or afterload as well as reduce systemic vascular resistance (SVR).

Nitroprusside sodium (Nitropress)

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Nitroprusside sodium is a potent balanced arterial and venous vasodilator, resulting in a very efficient decrease of intracardiac filling pressures. It requires careful hemodynamic monitoring using indwelling catheters and monitoring for cyanide toxicity, especially in the presence of renal dysfunction. It is particularly helpful for patients who present with severe pulmonary congestion in the presence of hypertension and severe mitral regurgitation. The drug should be titrated down to cessation rather than abruptly stopped, owing to the rebound potential.

Hydralazine

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Hydralazine decreases systemic resistance through direct vasodilation of arterioles. A hydralazine and nitrate combination reduces preload and afterload. Combinations of hydralazine and nitrates are recommended to improve outcomes for African Americans with moderate-to-severe symptoms of heart failure on optimal medical therapy with ACEIs/ARBs, beta-blockers, and diuretics.

Nitrates

Class Summary

Nitrates improve hemodynamic effects in heart failure by decreasing left ventricular filling pressure and systemic vascular resistance. These agents also result in a slight improvement on cardiac output.

Nitroglycerin (Nitrostat, Nitro-Dur, Nitrolingual, Nitro-Time, NitroMist, Minitran)

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Nitroglycerin is first-line therapy for patients who are not hypotensive. It provides excellent and reliable preload reduction. Higher doses provide mild afterload reduction. It has rapid onset and offset (both within minutes), allowing rapid clinical effects and rapid discontinuation of effects in adverse clinical situations. It produces vasodilation and increases inotropic activity of the heart. At higher dosages, it may exacerbate myocardial ischemia by increasing the heart rate.

Isosorbide dinitrate (Dilatrate-SR, Isordil Titradose)

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Isosorbide dinitrate relaxes vascular smooth muscle by stimulating intracellular cyclic GMP. It decreases left ventricular pressure (preload) and arterial resistance (afterload). By decreasing left ventricular pressure and dilating arteries, it reduces cardiac oxygen demand. Chronic use of isosorbide dinitrate as a sole vasodilating agent is not recommended.

Isosorbide dinitrate and Hydralazine (BiDil)

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This is a fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), a predominantly arterial vasodilator. It is indicated for heart failure in black patients, based in part on results from the African American Heart Failure Trial. Two previous trials in the general population of patients with severe heart failure found no benefit but suggested a benefit in black patients. Black patients showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure.

Isosorbide mononitrate (Monoket)

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Isosorbide mononitrate causes relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Dilation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload).

B-type Natriuretic Peptides

Class Summary

Human B-type natriuretic peptides (hBNPs) such as nesiritide are used in patients with acutely decompensated heart failure. These agents reduce pulmonary capillary wedge pressure and improve dyspnea.

Nesiritide (Natrecor)

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Nesiritide is a recombinant DNA form of hBNP that dilates veins and arteries. hBNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells. Binding to the receptor causes an increase in cGMP, which serves as a second messenger to dilate veins and arteries. It reduces PCWP and improves dyspnea in patients with acutely decompensated HF.

I(f) Inhibitors

Class Summary

The I(f) inhibitor ivabradine is used to lower heart rate and has been shown to reduce the risk for hospitalization.

Ivabradine (Corlanor)

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Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I(f) ‘funny' current, which regulates heart rate without any effect on ventricular repolarization or myocardial contractility. It is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with resting heart rate ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

Angiotensin Receptor-Neprilysin Inhibitors (ARNi)

Class Summary

Angiotensin receptor-neprilysin inhibitor (ARNI) combinations have been shown to significantly reduce cardiovascular death and hospitalization in patients with chronic heart failure.

Sacubitril/valsartan (Entresto)

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An angiotensin receptor-neprilysin inhibitor (ARNI). The cardiovascular and renal effects of sacubitril’s active metabolite (LBQ657) in heart failure are attributed to the increased levels of peptides that are degraded by neprilysin (eg, natriuretic peptide). Administration results in increased natriuresis, increased urine cGMP, and decreased plasma MR-proANP (mid-regional proatrial natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide). It is indicated to reduce the risk of cardiovascular death and hospitalization in chronic heart failure. Benefits for this indication are most clearly evident in patients with LVEF below normal. The combination drug is also indicated for symptomatic HF with systemic left ventricular systolic dysfunction in children aged 1 year and older.

Diuretics, Loop

Class Summary

Diuretics remain the mainstay of therapy and the current standard of care for acute heart failure. First-line diuretic therapy is a loop diuretic (furosemide, bumetanide, torsemide) in the lowest effective dose, either once or twice a day — although it can be used up to 3-4 times a day — depending on the individual response and renal function. Response to diuretic therapy often depends on bioavailability of the drug (better on an empty stomach) and nutritional level (loop diuretics are bound to proteins for renal delivery).

Furosemide (Lasix)

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Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The dose must be individualized to the patient. Depending on the response, administer furosemide at small dose increments (20-200 mg) until desired diuresis occurs.

Torsemide (Demadex)

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Torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the sodium, potassium, and chloride carrier system. It increases urinary excretion of sodium, chloride, and water, but does not significantly alter the glomerular filtration rate, renal plasma flow, or acid-base balance. Torsemide is roughly twice as potent as furosemide on a milligram basis. Depending on the response, administer furosemide at small dose increments (10-100 mg) until desired diuresis occurs.

Bumetanide

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Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced. Bumetanide is roughly four times as potent as furosemide on a milligram basis. Depending on the response, administer bumetanide at small dose increments (0.5-5 mg) until desired diuresis occurs.

Diuretics, Thiazide

Class Summary

If patients with heart failure do not have a response to treatment with loop diuretics, a thiazide diuretic such as hydrochlorothiazide or metolazone can be added 30 minutes before adminstration of the loop diuretic to enhance the response. Thiazide diuretics inhibit reabsorption of sodium and chloride in the cortical thick ascending limb of the loop of Henle and the distal tubules. They also increase potassium and bicarbonate excretion as well as decrease calcium excretion and uric acid retention. Combination diuretic therapy should be monitored closely for development of hypovolemia, hypokalemia, hypomagnesemia, and hyponatremia.

Hydrochlorothiazide (Microzide)

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Hydrochlorothiazide inhibits reabsorption of sodium in the distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.

Indapamide

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Indapamide has a diuretic effect that is localized at the proximal segment of the distal tubule of the nephron. Similar to other diuretics it may enhance sodium, chloride and water excretion.

Chlorthalidone (Thalitone)

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Chlorthalidone inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.

Chlorothiazide (Diuril)

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Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate

Diuretics, Other

Class Summary

Metolazone is a diuretic of the quinazoline class and has thiazidelike properties. This agent interferes with the renal tubular mechanism of electrolyte reabsorption.

Metolazone (Zaroxolyn)

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Metolazone increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in the distal tubules. Metolazone may be more effective in patients with impaired renal function.

Diuretics, Potassium-Sparing

Class Summary

The potassium-sparing diuretics interfere with sodium reabsorption at the distal tubules, resulting in decreased potassium secretion. These agents have a weak diuretic and antihypertensive effect when used alone. The potassium-sparing diuretics spironolactone or triamterene are usually used in addition to the loop diuretics. Note that careful monitoring of renal function and potassium is necessary for all diuretics.

Spironolactone (Aldactone)

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Spironolactone is used for the management of edema resulting from excessive aldosterone excretion. It competes with aldosterone for receptor sites in the distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. Spironolactone at a target dose of 25 mg has been shown to improve survival in patients with heart failure and reduced ejection fraction.

Amiloride (Midamor)

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Amiloride is unrelated chemically to other known antikaliuretic or diuretic agents. It is a potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.

Triamterene (Dyrenium)

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Triamterene is a potassium-sparing diuretic with relatively weak natriuretic properties. It exerts its diuretic effect on the distal renal tubules by inhibiting the reabsorption of sodium in exchange for potassium and hydrogen. It increases sodium excretion and reduces excessive loss of potassium and hydrogen associated with hydrochlorothiazide.

Aldosterone Antagonists, Selective

Class Summary

Aldosterone antagonists are weak diuretics that reduce mortality and the risk of sudden death by blocking the effects of aldosterone, thereby decreasing myocardial and vascular inflammation and collagen production. This, in turn, prevents apoptosis, decreases stimulation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS), and acts as a membrane stabilizer, thus preventing arrhythmia. Aldosterone antagonists are recommended for patients who have moderately severe and severe heart failure and reduced left ventricular (LV) systolic function (Randomized Aldactone Evaluation Study [RALES]) who can be carefully monitored for preserved renal function and normal potassium concentration.

Eplerenone (Inspra)

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Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, and brain) tissues; thus, it decreases blood pressure and sodium reabsorption. It is indicated to improve survival for heart failure or left LV dysfunction following acute MI. Compared with placebo, a significant risk reduction (15%) has been observed. The EMPHASIS-HF trial has shown that patients with systolic heart failure with mild symptoms treated with eplerenone have a significant reduction in cardiovascular death or heart failure hospitalization when compared with placebo.

SGLT2 Inhibitors

Class Summary

Empagliflozin and dapagliflozin are inhibitors of the sodium-glucose cotransporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. This action increases urinary glucose excretion. 

SGLT2 inhibitors also reduce sodium reabsorption and increase the delivery of sodium to the distal tubule. This may influence several physiologic functions, such as lowering both preload and afterload of the heart and downregulating sympathetic activity. 

Empagliflozin (Jardiance)

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Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure (HF) in adults with HF (either HF with reduced ejection fraction [HFrEF] or HF with preserved EF [HFpEF]).

It is also indicated to reduce the risk of CV death in adults with type 2 diabetes mellitus and CV disease.

Dapagliflozin (Farxiga)

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Dapagliflozin is indicated to reduce hospitalization risk for heart failure in adults with T2DM and established cardiovascular disease (CVD) or multiple CV risk factors. It is also indicated to reduce the risk of CV death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). 

Additionally, dapagliflozin is indicated to reduce the risk of sustained eGFR decline, ESRD, CV death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. 

Soluble Guanylate Cyclase Stimulators

Class Summary

Heart failure is associated with impaired nitric oxide (NO) synthesis and decreased soluble guanylate cyclase (sGC) activity, which may contribute to myocardial and vascular dysfunction. 

By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation and vasodilation. 

Vericiguat (Verquvo)

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Vericiguat stimulates sGC, the intracellular receptor for endogenous NO, which catalyzes cGMP production. It is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults following a hospitalization for HF or a need for outpatient IV diuretics, who have symptomatic chronic HF and an ejection fraction < 45%.

Alpha/Beta Adrenergic Agonists

Class Summary

In the presence of significant hypotension, adrenergic agonists are used to improve cardiac output and organ perfusion.

Epinephrine (Adrenaclick, Adrenalin, EpiPen, EpiPen Jr.)

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Epinephrine is an alpha-agonist and its effects include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta2-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Norepinephrine (Levophed)

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Norepinephrine is a naturally occurring catecholamine with potent alpha-receptor and mild beta-receptor activity. It stimulates beta1- and alpha-adrenergic receptors, resulting in increased cardiac muscle contractility, heart rate, and vasoconstriction. It increases blood pressure and afterload. Increased afterload may result in decreased cardiac output, increased myocardial oxygen demand, and cardiac ischemia. It is generally reserved for use in patients with severe hypotension (eg, systolic blood pressure < 70 mm Hg) or hypotension that is unresponsive to other medications.

Calcium Channel Blockers

Class Summary

Generally, calcium channel blockers (CCBs) should be avoided. CCBs do not play a direct role in the management of heart failure; however, these agents may be used to treat other conditions, such as hypertension or angina in heart failure patients.

CCBs may be used in heart failure with normal left ventricular ejection fraction. These drugs may also improve exercise tolerance via their vasodilatory properties.

Amlodipine (Norvasc)

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Amlodipine has antianginal and antihypertensive effects. It blocks the post-excitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the activation of ATPase on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of the coronary and peripheral arteries. It also increases myocardial oxygen delivery in patients with vasospastic angina.

Nifedipine (Adalat CC, Afeditab CR, Nifediac CC, Nifedical XL, Procardia, Procardia XL)

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Nifedipine relaxes coronary smooth muscle and produces coronary vasodilation, which in turn, improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.

Felodipine (Cabren, Cardioplen XL, Felendil XL)

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Felodipine is a dihydropyridine calcium channel blocker. It inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. The resultant decrease in intracellular calcium inhibits the contractile processes of the smooth muscle cells, resulting in dilation of coronary and systemic arteries.

Anticoagulants, Cardiovascular

Class Summary

Patients with heart failure and depressed left ventricular (LV) ejection fraction are thought to have an increased risk of thrombus formation due to low cardiac output. Hospitalized patients with heart failure are at a high risk for venous thromboembolism and should receive prophylaxis. Anticoagulation with an international normalized ratio (INR) goal of 2-3 is indicated in the presence of: (1) an LV thrombus, (2) a thromboembolic event with or without evidence of an LV thrombus, and (3) paroxysmal or chronic atrial arrhythmias.

Warfarin (Coumadin, Jantoven)

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Warfarin interferes with hepatic vitamin K–dependent carboxylation. It is used for the prophylaxis and treatment of thromboembolic disorders.

Dabigatran (Pradaxa)

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Competitive, direct thrombin inhibitor. Thrombin enables fibrinogen conversion to fibrin during the coagulation cascade, thereby preventing thrombus development. Inhibits both free and clot-bound thrombin and thrombin-induced platelet aggregation.

Opioid Analgesics

Class Summary

Opioid analgesics such as morphine sulfate may help to relieve patients’ anxiety, distress, and dyspnea.

Morphine sulfate (Astramorph, Avinza, DepoDur, Duramorph, Infumorph 200, Infumorph 500, Kadian, MS Contin, Oramorph SR, Roxanol)

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Morphine is the drug of choice for narcotic analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered intravenously may be dosed in a number of ways and commonly is titrated until the desired effect is obtained. Morphine sulfate also decreases preload in heart failure and relieves dyspnea.

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Author

Ioana Dumitru, MD Associate Professor of Medicine, Division of Cardiology, Founder and Medical Director, Heart Failure and Cardiac Transplant Program, University of Nebraska Medical Center; Associate Professor of Medicine, Division of Cardiology, Veterans Affairs Medical Center

Ioana Dumitru, MD is a member of the following medical societies: American College of Cardiology, Heart Failure Society of America, International Society for Heart and Lung Transplantation

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Yasmine S Ali, MD, MSCI, FACC, FACP Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine; President, LastSky Writing, LLC

Yasmine S Ali, MD, MSCI, FACC, FACP is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Medical Writers Association, National Lipid Association, Tennessee Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LastSky Writing;Philips Healthcare;M Health;Athena Health;PeerView Institute;Verywell Health; HealthCentral;MedEdicus;Pharmaceutical Training Institute;Elsevier;MedStudy;North American Thrombosis Forum;WellnessVerge;Prose Media; AKH, Inc.<br/>Serve(d) as a speaker or a member of a speakers bureau for: North American Thrombosis Forum.

Chief Editor

Gyanendra K Sharma, MD, FACC, FASE Professor of Medicine and Radiology, Director, Adult Echocardiography Laboratory, Section of Cardiology, Medical College of Georgia at Augusta University

Gyanendra K Sharma, MD, FACC, FASE is a member of the following medical societies: American Association of Cardiologists of Indian Origin, American Association of Physicians of Indian Origin, American College of Cardiology, American Society of Echocardiography, Society for Cardiovascular Magnetic Resonance, Society of Cardiovascular Computed Tomography

Disclosure: Nothing to disclose.

Additional Contributors

Mathue M Baker, MD Cardiologist, BryanLGH Heart Institute and Saint Elizabeth Regional Medical Center

Mathue M Baker, MD is a member of the following medical societies: American College of Cardiology

Disclosure: Nothing to disclose.

Henry H Ooi, MD, MRCPI Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Assistant Professor of Medicine, Vanderbilt University School of Medicine

Disclosure: Nothing to disclose.

Mariclaire Cloutier Freelance editor, Medscape Drugs & Diseases

Disclosure: Nothing to disclose.

Acknowledgements

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York AcademyofSciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

William K Chiang, MD Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Chief of Service, Department of Emergency Medicine, Bellevue Hospital Center

William K Chiang, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Joseph Cornelius Cleveland Jr, MD Associate Professor, Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center

Joseph Cornelius Cleveland Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, American Geriatrics Society, American Physiological Society, American Society of Transplant Surgeons, Association for Academic Surgery, Heart Failure Society of America, International Society for Heart and Lung Transplantation, Phi Beta Kappa, Society of Critical Care Medicine, Society of Thoracic Surgeons, and Western Thoracic Surgical Association

Disclosure: Thoratec Heartmate II Pivotal Tria; Grant/research funds Principal Investigator - Colorado; Abbott Vascular E-Valve E-clip Honoraria Consulting; Baxter Healthcare Corp Consulting fee Board membership; Heartware Advance BTT Trial Grant/research funds Principal Investigator- Colorado; Heartware Endurance DT trial Grant/research funds Principal Investigator-Colorado

Shamai Grossman, MD, MS Assistant Professor, Department of Emergency Medicine, Harvard Medical School; Director, The Clinical Decision Unit and Cardiac Emergency Center, Beth Israel Deaconess Medical Center

Shamai Grossman, MD, MS is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

John D Newell Jr, MD Professor of Radiology, Head, Division of Radiology, National Jewish Health; Professor, Department of Radiology, University of Colorado School of Medicine

John D Newell Jr, MD is a member of the following medical societies: American College of Chest Physicians, American College of Radiology, American Roentgen Ray Society, American Thoracic Society, Association of University Radiologists, Radiological Society of North America, and Society of Thoracic Radiology

Disclosure: Siemens Medical Grant/research funds Consulting; Vida Corporation Ownership interest Board membership; TeraRecon Grant/research funds Consulting; Medscape Reference Honoraria Consulting; Humana Press Honoraria Other

Craig H Selzman, MD, FACS Associate Professor of Surgery, Surgical Director, Cardiac Mechanical Support and Heart Transplant, Division of Cardiothoracic Surgery, University of Utah School of Medicine

Craig H Selzman, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Thoracic Surgery, American College of Surgeons, American Physiological Society, Association for Academic Surgery, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons, Southern Thoracic Surgical Association, and Western Thoracic Surgical Association

Disclosure: Nothing to disclose.

Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School

Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine

Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position; ProceduresConsult.com Royalty Other

Brett C Sheridan, MD, FACS Associate Professor of Surgery, University of North Carolina at Chapel Hill School of Medicine

Disclosure: Nothing to disclose.

George A Stouffer III, MD Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center

George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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