Heart failure is a clinical syndrome in which the heart is not able to meet the metabolic demands of the body due to a structural and or functional cardiac abnormality, leading to low cardiac output, elevated ventricular filling pressure, or both (see Heart Failure).
The primary medications for long-term management and improved survival in patients with heart failure, particularly heart failure with reduced ejection fraction, are:
Angiotensin receptor/neprilysin inhibitors (ARNIs) (or angiotensin converting enzyme [ACE] inhibitors or Angiotensin II receptor blockers [ARBs])
Additional medication classes used in patients with heart failure include:
All patients should be given clear and explicit information about their medications, including the following:
The importance of timely prescription renewal
The importance of adherence to therapy
How to recognize adverse effects
When to contact their physician
(See also Acute Heart Failure - Treatment, Chronic Heart Failure - Treatment, and Right Heart Failure for more information about medication selection.)
Classes of Medications for Heart Failure
Beta-blockers
Beta-blockers act by competitively inhibiting beta-adrenergic receptors. Bisoprolol and metoprolol are considered cardioselective beta-blockers, primarily acting on beta-1 adrenergic receptors. Carvedilol, a nonselective beta-blocker, is also a vasodilator with alpha-blocking and antioxidant effects. Beta-blockers produce a negative inotropic and chronotropic effect that reduces myocardial oxygen demand, modestly reduces left ventricular afterload, and moderates the release of catecholamines in response to stress.Beta-blockers act by competitively inhibiting beta-adrenergic receptors. Bisoprolol and metoprolol are considered cardioselective beta-blockers, primarily acting on beta-1 adrenergic receptors. Carvedilol, a nonselective beta-blocker, is also a vasodilator with alpha-blocking and antioxidant effects. Beta-blockers produce a negative inotropic and chronotropic effect that reduces myocardial oxygen demand, modestly reduces left ventricular afterload, and moderates the release of catecholamines in response to stress.
In patients with heart failure with reduced ejection fraction (HFrEF), beta-blockers, unless otherwise contraindicated (by asthma, second-degree or third-degree atrioventricular block, or previous significant intolerance), are a mainstay of treatment (1, 2). In acute decompensated HFrEF, beta-blockers are best started once the patient has stabilized and has no evidence of pulmonary congestion. For patients with HFrEF and acute heart failure exacerbation who are already taking a beta-blocker, the dose should not be decreased or stopped unless necessary. Specific beta-blockers such as carvedilol and metoprolol succinate (ie, long-acting metoprolol) improve left ventricular ejection fraction, survival, and other major cardiovascular outcomes in patients with chronic HFrEF, including those with severe symptoms. 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 increase, and LV filling pressure decreases. Exercise capacity improves.). In acute decompensated HFrEF, beta-blockers are best started once the patient has stabilized and has no evidence of pulmonary congestion. For patients with HFrEF and acute heart failure exacerbation who are already taking a beta-blocker, the dose should not be decreased or stopped unless necessary. Specific beta-blockers such as carvedilol and metoprolol succinate (ie, long-acting metoprolol) improve left ventricular ejection fraction, survival, and other major cardiovascular outcomes in patients with chronic HFrEF, including those with severe symptoms. 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 increase, and LV filling pressure decreases. Exercise capacity improves.
In patients with heart failure with preserved ejection fraction (HFpEF), beta-blockers are not generally recommended, although they can be used for rate control in atrial fibrillation with rapid ventricular response, or for control of hypertension in patients with coronary artery disease or prior myocardial infarction (1, 2).
The starting dose should be low (one-fourth of the target daily dose), then the dose is gradually increased over 8 weeks as tolerated. The acute negative inotropic effects of beta-blockade may initially cause cardiac depression and fluid retention. In such cases, a temporary increase in diuretic dose and slower upward titration of the beta-blocker dose is warranted. Tolerance may improve over time, and efforts should be made to reach target doses. Usual oral target doses are carvedilol 25 mg twice a day (50 mg twice a day for patients The starting dose should be low (one-fourth of the target daily dose), then the dose is gradually increased over 8 weeks as tolerated. The acute negative inotropic effects of beta-blockade may initially cause cardiac depression and fluid retention. In such cases, a temporary increase in diuretic dose and slower upward titration of the beta-blocker dose is warranted. Tolerance may improve over time, and efforts should be made to reach target doses. Usual oral target doses are carvedilol 25 mg twice a day (50 mg twice a day for patients≥ 85 kg), bisoprolol 10 mg once a day, or metoprolol succinate (extended-release) 200 mg once a day.85 kg), bisoprolol 10 mg once a day, or metoprolol succinate (extended-release) 200 mg once a day.
Renin-angiotensin system inhibiting medications
Angiotensin receptor/neprilysin inhibitors (ARNIs)
ARNIs are a combination medication for the treatment of heart failure. They include an ARB and a neprilysin inhibitor (eg, sacubitril). The ARB portion blocks the renin-angiotensin-aldosterone axis at the level of the angiotensin II receptor. 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 medications lower blood pressure, decrease afterload, and enhance natriuresis. Because neprilysin inhibitors increase BNP levels, NTproBNP levels (which are not increased by the medication) should be used instead to help diagnose and manage heart failure.
In patients with HFrEF, the ARNI sacubitril/valsartan reduces all-cause mortality and should be considered in all patients with HFrEF (1, 2). It is preferred over an ACE inhibitor or ARB if tolerated, and evidence supports early transition of patients from an ACE inhibitor or ARB to ARNI, even in the hospital setting. In patients with HFpEF, sacubitril/valsartan may be considered, particularly in specific subgroups (women and patients with left ventricular ejection fraction below 57%)., sacubitril/valsartan may be considered, particularly in specific subgroups (women and patients with left ventricular ejection fraction below 57%).
The starting dose of sacubitril/valsartan is 49/51 mg orally twice a day for patients previously taking an ACE inhibitor or ARB, and 24/26 mg for patients previously taking a low dose of an ACE inhibitor or ARB (eg, ≤ 10 mg enalapril daily) or in those patients who have not taken an ACE inhibitor or an ARB or who have low or borderline blood pressure. ACE inhibitors should be discontinued 36 hours before initiation of The starting dose of sacubitril/valsartan is 49/51 mg orally twice a day for patients previously taking an ACE inhibitor or ARB, and 24/26 mg for patients previously taking a low dose of an ACE inhibitor or ARB (eg, ≤ 10 mg enalapril daily) or in those patients who have not taken an ACE inhibitor or an ARB or who have low or borderline blood pressure. ACE inhibitors should be discontinued 36 hours before initiation ofsacubitril/valsartan. Patients previously taking an ARB can simply switch to sacubitril/valsartan without a washout period.
Complications associated with use of ARNI include hypotension, hyperkalemia, renal insufficiency, and angioedema. Sacubitril is coupled with valsartan (an ARB) because of the increased risk of angioedema with the use of sacubitril alone or in combination with an ACE inhibitor. For this reason, combined ACE inhibitor plus ARNI therapy is absolutely contraindicated. . Sacubitril is coupled with valsartan (an ARB) because of the increased risk of angioedema with the use of sacubitril alone or in combination with an ACE inhibitor. For this reason, combined ACE inhibitor plus ARNI therapy is absolutely contraindicated.
Angiotensin converting enzyme (ACE) inhibitors
All patients with HFrEF should be given oral ACE inhibitors unless contraindicated.
ACE inhibitors reduce production of angiotensin II and breakdown of bradykinin, mediators that affect the sympathetic nervous system, endothelial function, vascular tone, and myocardial performance. Hemodynamic effects include:
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 hospitalizations due to heart failure (1, 2). In patients with HRrEF, their current role is as a second-line agent for those who cannot tolerate ARNi or those for whom ARNi is not available, cost-prohibitive, or otherwise unfeasible. For patients with HRpEF, ACE inhibitors are not typically initiated unless they are already being used for other indications such as atherosclerosis, hypertension, and diabetic nephropathy.
The starting dose typically should be low (usually one-fourth to one-half of the target dose depending on blood pressure and renal function); the dose is gradually adjusted upward over 8 weeks as tolerated, then continued indefinitely. Usual target doses of representative medications include enalapril 10 to 20 mg twice a day, lisinopril 20 to 30 mg once a day, and ramipril 5 mg twice a day; there are many others.The starting dose typically should be low (usually one-fourth to one-half of the target dose depending on blood pressure and renal function); the dose is gradually adjusted upward over 8 weeks as tolerated, then continued indefinitely. Usual target doses of representative medications include enalapril 10 to 20 mg twice a day, lisinopril 20 to 30 mg once a day, and ramipril 5 mg twice a day; there are many others.
Serum electrolytes and renal function should be measured before an ACE inhibitor is initiated, 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 temporarily discontinued. Contraindications include 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.
The hypotensive effect (more marked in patients with hyponatremia or volume depletion), if troublesome, can often be minimized by separating administration of other blood pressure–lowering medications, reducing the dose of concomitant diuretics, using a longer acting ACE inhibitor (eg, perindopril), or giving the dose at bedtime. ACE inhibitors often cause mild to moderate reversible serum creatinine elevation due to vasodilation of the efferent glomerular arteriole. An initial 20 to 30% increase in creatinine is not a reason to stop the medication but does require closer monitoring, slower increases in dose, reduction in diuretic dose, or avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs). Because aldosterone’s effect is reduced, potassium retention (or volume depletion), if troublesome, can often be minimized by separating administration of other blood pressure–lowering medications, reducing the dose of concomitant diuretics, using a longer acting ACE inhibitor (eg, perindopril), or giving the dose at bedtime. ACE inhibitors often cause mild to moderate reversible serum creatinine elevation due to vasodilation of the efferent glomerular arteriole. An initial 20 to 30% increase in creatinine is not a reason to stop the medication but does require closer monitoring, slower increases in dose, reduction in diuretic dose, or avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs). Because aldosterone’s effect is reduced, potassium retention (hyperkalemia) may result, especially in patients receiving potassium supplements. Cough occurs in many patients, probably because bradykinin accumulates, but other causes of cough should also be considered. If cough limits use, an ARB is a reasonable alternative. 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.
Angiotensin II receptor blockers (ARBs)
ARBs target the angiotensin II receptor rather than the angiotensin converting enzymes. They are less likely to cause cough and angioedema than ACE inhibitors, and may be used when these adverse effects prohibit ACE inhibitor use (Heidenreich).
In patients with HFrEF, ACE inhibitors and ARBs are likely equally effective. In patients with HFpEF, ARBs (as with ACE inhibitors) are not typically initiated unless they are already being used for other indications such as hypertension, diabetic kidney disease, or microalbuminuria.
Usual oral target doses are valsartan 160 mg twice a day, candesartan 32 mg once a day, and losartan 50 to 100 mg once a day. Introduction, upward dose adjustment, and monitoring of ARBs and ACE inhibitors are similar. Like ACE inhibitors, ARBs can cause reversible renal dysfunction, and the dose may need to be reduced or stopped temporarily during an acute dehydrating illness.Usual oral target doses are valsartan 160 mg twice a day, candesartan 32 mg once a day, and losartan 50 to 100 mg once a day. Introduction, upward dose adjustment, and monitoring of ARBs and ACE inhibitors are similar. Like ACE inhibitors, ARBs can cause reversible renal dysfunction, and the dose may need to be reduced or stopped temporarily during an acute dehydrating illness.
Adding an ARB to a regimen of an ACE inhibitor, beta-blocker, and mineralocorticoid receptor 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 still has symptoms, an mineralocorticoid receptor antagonist should be started, and/or an angiotensin receptor/neprilysin inhibitor (ARNI) should be used.
ARBs are contraindicated in pregnancy.
Mineralocorticoid receptor antagonists (aldosterone antagonists)
Mineralocorticoid receptor antagonists block aldosterone receptors in the distal convoluted tubule and collecting ducts of the kidney. They are considered potassium-sparing diuretics due to their relatively weak diuretic effect and the fact that, unlike most other diuretics, they do not waste serum potassium. For patients with heart failure, these agents offer blockade of the renin-angiotensin-aldosterone system that is complementary to the mechanism of ACE inhibitors and ARBs.
A mineralocorticoid receptor antagonist (MRA, also termed aldosterone antagonists) is recommended for patients with HRrEF, particularly those with symptoms (New York Heart Association Class II to IV) (1, 2). In patients with HRpEF, MRAs appear to have the most benefit as primary heart failure therapy in patients at the lower end of the ejection fraction spectrum and are also routinely used in patients with preexisting hypertension or coronary artery disease.
Typical medications include spironolactone 25 to 50 mg orally once a day and eplerenone (which does not cause gynecomastia in males as Typical medications include spironolactone 25 to 50 mg orally once a day and eplerenone (which does not cause gynecomastia in males asspironolactone can). Mineralocorticoid receptor antagonists can reduce mortality, including from sudden death, in patients with left ventricular ejection fraction (LVEF) < 30% and chronic heart failure, or acute heart failure 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.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i)
SGLT2i were originally used in treatment of diabetes to block glucose reabsorption, thus causing glycosuria and lowering plasma glucose; they may also have effects on the myocardium and vasculature. These medications had previously been shown to prevent the onset of heart failure in patients with type 2 diabetes. The SGLT2i dapagliflozin and empagliflozin were subsequently shown to reduce cardiovascular mortality and hospitalization in patients with SGLT2i were originally used in treatment of diabetes to block glucose reabsorption, thus causing glycosuria and lowering plasma glucose; they may also have effects on the myocardium and vasculature. These medications had previously been shown to prevent the onset of heart failure in patients with type 2 diabetes. The SGLT2i dapagliflozin and empagliflozin were subsequently shown to reduce cardiovascular mortality and hospitalization in patients withHRrEF who are symptomatic (New York Heart Association Class II to IV). Thus, SGLT2i therapy is recommended for all HRrEF patients with symptoms. SGLT2i therapy also appears beneficial in patients with HRpEF.
Dapagliflozin and empagliflozin may be given 10 mg orally once a day. With treatment, there is a mild (10 to 15%) reduction in estimated glomerular filtration rate (eGFR) which does not progress, glucosuria, and a small reduction in body weight. Risks include genital fungal infection, and in patients with diabetes, a very small risk of hypoglycemia and diabetic ketoacidosis. These medications are generally not indicated in patients with type I diabetes, low blood pressure, or low eGFR (< 30 mL/min/1.73 mDapagliflozin and empagliflozin may be given 10 mg orally once a day. With treatment, there is a mild (10 to 15%) reduction in estimated glomerular filtration rate (eGFR) which does not progress, glucosuria, and a small reduction in body weight. Risks include genital fungal infection, and in patients with diabetes, a very small risk of hypoglycemia and diabetic ketoacidosis. These medications are generally not indicated in patients with type I diabetes, low blood pressure, or low eGFR (< 30 mL/min/1.73 m2).
Digoxin
Digoxin inhibits the sodium-potassium pump (Na+, K+-ATPase), causing weak positive inotropy, reduces sympathetic activity, blocks the atrioventricular node (slowing the ventricular rate in atrial fibrillation or prolonging the PR interval in sinus rhythm), reduces vasoconstriction, and improves renal blood flow.Digoxin inhibits the sodium-potassium pump (Na+, K+-ATPase), causing weak positive inotropy, reduces sympathetic activity, blocks the atrioventricular node (slowing the ventricular rate in atrial fibrillation or prolonging the PR interval in sinus rhythm), reduces vasoconstriction, and improves renal blood flow.
Digoxin has no proven survival benefit but, when used in addition to standard guideline-directed medical therapy, may help control symptoms and reduce the likelihood of hospitalization in patients with HFrEF (1, 2). Digoxin may also be used for rate control in patients with atrial fibrillation and both HFrEF and HFpEF.
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 but, unlike in the treatment of atrial fibrillation, there is typically little reason to rapidly digitalize (ie, digoxin load) patients with heart failure. 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 toxicity is a concern given its narrow therapeutic window, especially in patients with renal dysfunction and perhaps in women. These patients may need a lower oral dose, as may older patients, patients with a low lean body mass, and patients also taking amiodarone. The most important toxic effects are life-threatening arrhythmias (eg, toxicity is a concern given its narrow therapeutic window, especially in patients with renal dysfunction and perhaps in women. These patients may need a lower oral dose, as may older patients, patients with a low lean body mass, and patients also taking amiodarone. The most important toxic effects are life-threatening arrhythmias (eg,ventricular 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 also occur. If hypokalemia or hypomagnesemia (often due to diuretic use) is present, lower doses and serum levels can still cause toxicity; thus, electrolyte levels should be monitored in patients taking diuretics and digoxin.
Diuretics
While spironolactone is recommended for all patients with While spironolactone is recommended for all patients withHRrEF and used for many with HRpEF, additional diuretics are given to patients with heart failure (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 (1, 2). Chronic diuretics may be scheduled or used as needed by patients based on peripheral edema or changes in weight. Diuretics are a primary therapy in symptomatic HRpEF. They are used with caution in right heart failure, particularly in cor pulmonale, due to sensitivity to small changes in preload.
Loop diuretics should be used initially for control of volume overload, but their dose should be reduced when possible in favor of mineralocorticoid receptor antagonists.
Thiazide diuretics are not normally used alone unless being given as treatment of hypertension; however, a thiazide diuretic may be added to a loop diuretic for additional diuresis and to reduce the loop diuretic dose. Hydrochlorothiazide, metolazone, and chlorthalidone can be used in this manner.are not normally used alone unless being given as treatment of hypertension; however, a thiazide diuretic may be added to a loop diuretic for additional diuresis and to reduce the loop diuretic dose. Hydrochlorothiazide, metolazone, and chlorthalidone can be used in this manner.
Commonly used loop diuretics include furosemide, bumetanide, and torsemide. The starting dose of these medications depends on whether the patient has previously received loop diuretics. Common starting doses are: Commonly used loop diuretics include furosemide, bumetanide, and torsemide. The starting dose of these medications depends on whether the patient has previously received loop diuretics. Common starting doses are:
Furosemide 20 to 40 mg orally once a day or twice a day
Bumetanide 0.5 to 1.0 mg orally once a day
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.
In refractory cases, IV loop diuretics or metolazone 2.5 to 10 mg orally can be used for an additive effect. IV infusion of furosemide (5 to 10 mg/hour) or other loop diuretics may be helpful in selected patients with severe pulmonary edema. A bolus dose of loop diuretic should be given before starting an IV infusion and before each increase in infusion rate. In refractory cases, IV loop diuretics or metolazone 2.5 to 10 mg orally can be used for an additive effect. IV infusion of furosemide (5 to 10 mg/hour) or other loop diuretics may be helpful in selected patients with severe pulmonary edema. A bolus dose of loop diuretic should be given before starting an IV infusion and before each increase in infusion rate.
Loop diuretics (particularly when used in combination with thiazide diuretics) may cause hypovolemia with hypotension, hyponatremia, hypomagnesemia, and severe hypokalemia. The dose of diuretic required acutely can usually be gradually reduced; the target is the lowest dose that maintains stable weight and controls symptoms. When heart failure improves, the diuretic may be stopped if other medications improve heart function and relieve symptoms of heart failure. Using diuretic doses that are larger than required lowers cardiac output, impairs renal function, causes hypokalemia, and increases mortality. Serum electrolytes and renal function are monitored, initially daily (when diuretics are given IV) and subsequently as needed, particularly after a dose increase.
Vasopressin (antidiuretic hormone) receptor antagonists are not frequently used though they may be helpful in cases of severe refractory hyponatremia in patients with heart failure.
Inotropes
Various positive inotropic medications have been evaluated in heart failure but, except for digoxin, they increase mortality risk. These medications can be grouped by mode of action as: have been evaluated in heart failure but, except for digoxin, they increase mortality risk. These medications can be grouped by mode of action as:
Adrenergic (norepinephrine, epinephrine, dobutamine, dopamine)
Nonadrenergic (enoximoneand milrinone [phosphodiesterase type 3 inhibitors], levosimendan [calcium sensitizer])
Inotropic support is important for treatment of acute heart failure with cardiogenic shock. The choice of inotrope depends on availability, local practice, and afterload. For example, in a patient with severely reduced LV ejection fraction, peripheral vasoconstriction, and high or normal blood pressure, initial inotropic support may be combined with an IV vasodilator such as nitroprusside, and then transitioned to milrinone (which has mild vasodilatory effects). On the other hand, a patient with reduced ejection fraction and hypotension with peripheral vasodilation may require an inotrope with vasopressor effects (norepinephrine, high dose epinephrine), or a combination of an inotrope and a pure vasoconstricting agent. Synergy can be obtained by using both an adrenergic and nonadrenergic inotrope.with cardiogenic shock. The choice of inotrope depends on availability, local practice, and afterload. For example, in a patient with severely reduced LV ejection fraction, peripheral vasoconstriction, and high or normal blood pressure, initial inotropic support may be combined with an IV vasodilator such as nitroprusside, and then transitioned to milrinone (which has mild vasodilatory effects). On the other hand, a patient with reduced ejection fraction and hypotension with peripheral vasodilation may require an inotrope with vasopressor effects (norepinephrine, high dose epinephrine), or a combination of an inotrope and a pure vasoconstricting agent. Synergy can be obtained by using both an adrenergic and nonadrenergic inotrope.
In patients with advanced (Stage D) HRpEF refractory to standard therapies, long-term continuous inotropic infusions may be used as a bridge to transplantation or as palliative therapy (2).
Sinus node inhibitors
Ivabradine is an IIvabradine is an If channel (inward "funny" channel in the sinus node) blocker that acts at the sinus node to slow the heart rate. Since these channels are present primarily in cardiac pacemaker cells, these medications are not useful for treatment in patients who are not in sinus rhythm. Ivabradine is recommended for use in patients with HFrEF who have symptomatic heart failure (New York Heart Association Class II or III), normal sinus rhythm, and heart rate > 70 beats/minute despite guideline-directed medical therapy (at target beta-blocker dose or cannot tolerate a further increase in beta-blocker dose) (1, 2).
Initial dose of ivabradine is 2.5 to 5 mg orally twice a day, titrated at 2-week intervals to a heart rate of 50 to 60 beats/minute; maximum dose is 7.5 mg twice a day. Initial dose of ivabradine is 2.5 to 5 mg orally twice a day, titrated at 2-week intervals to a heart rate of 50 to 60 beats/minute; maximum dose is 7.5 mg twice a day.
Soluble guanylate cyclase stimulator
Vericiguat is an oral soluble guanylate cyclase stimulator that enhances the cyclic guanosine monophosphate (GMP) pathway and sensitizes soluble guanylate cyclase to endogenous Vericiguat is an oral soluble guanylate cyclase stimulator that enhances the cyclic guanosine monophosphate (GMP) pathway and sensitizes soluble guanylate cyclase to endogenousnitric oxide, resulting in pulmonary vasodilation. Vericiguat is an option to improve outcomes for patients with HFrEF with worsening heart failure symptoms despite maximal guideline-directed medical therapy, with the potential to reduce mortality or hospitalization.
Vasodilators
Hydralazine and nitrates (such as isosorbide dinitrate) are direct vasodilators, which can improve hemodynamics, reduce valvular regurgitation, and increase exercise capacity without causing significant renal impairment. Hydralazine and nitrates (such as isosorbide dinitrate) are direct vasodilators, which can improve hemodynamics, reduce valvular regurgitation, and increase exercise capacity without causing significant renal impairment.
The combination of hydralazine and isosorbide dinitrate may be considered in patients with The combination of hydralazine and isosorbide dinitrate may be considered in patients withHRrEF who are intolerant of ACE inhibitors or ARBs (usually because of significant renal dysfunction) (1, 2). Additionally, in patients of African ancestry, this combination, when added to standard therapy, may reduce mortality and hospitalization, and improve quality of life.
When used instead of ACE inhibitor or ARB therapy, hydralazine is started at 25 mg orally 4 times a day and increased every 3 to 5 days to a target total dose of 300 mg/day; however, many patients cannot tolerate When used instead of ACE inhibitor or ARB therapy, hydralazine is started at 25 mg orally 4 times a day and increased every 3 to 5 days to a target total dose of 300 mg/day; however, many patients cannot tolerate> 200 mg/day because of hypotension. Isosorbide dinitrate is started at 20 mg orally 3 times a day (with a 12-hour nitrate-free interval) and increased to a target of 40 to 50 mg 3 times a day. When added to ACE inhibitor or ARB therapy, 200 mg/day because of hypotension. Isosorbide dinitrate is started at 20 mg orally 3 times a day (with a 12-hour nitrate-free interval) and increased to a target of 40 to 50 mg 3 times a day. When added to ACE inhibitor or ARB therapy,hydralazine plus nitrate therapy is started at 37.5 mg and isosorbide dinitrate at 20 mg orally 3 times a day, with the maximum dose 75 mg and 40 mg 3 times a day. These doses are also available as a fixed-dose combination. plus nitrate therapy is started at 37.5 mg and isosorbide dinitrate at 20 mg orally 3 times a day, with the maximum dose 75 mg and 40 mg 3 times a day. These doses are also available as a fixed-dose combination.
Nitrates and phosphodiesterase-5 inhibitors have been used to relieve symptoms in patients with HFpEF, but neither is recommended for routine use for these patients (2).
Medication classes references
1. McDonagh TA, Metra M, Adamo M, et al: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 42(36):3599-3726, 2021. doi: 10.1093/eurheartj/ehab368
2. Heidenreich PA, Bozkurt B, Aguilar D, et al: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e895–e1032, 2022, doi: 10.1161/CIR.0000000000001063
