cardiovascular disorders
Drugs for Heart Failure
Classes of Drugs for Heart Failure
 receptor blockers (ARBs). Thus, the aldosterone antagonists (also termed mineralocorticoid receptor antagonists) are often used, particularly for patients with Symptoms and Signs or signs of heart failure. 30% and chronic HF, or acute HF complicating Acute Myocardial Infarction (MI) . 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. Inpatients with HFrEF,an aldosterone antagonist plus either an ACE inhibitor or an ARB is preferred over the combination of an ACE inhibitor and ARB. reduces hospitalization for heart failure and likely reduces cardiovascular mortality ( Drug treatment references ). 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. 250 micromol/L], bilateral Renal Artery Stenosis and Occlusion , renal artery stenosis in a solitary kidney, or previous angioedema due to ACE inhibitors). ACE inhibitors reduce production ofangiotensin IIand 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 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. 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 drugs includeenalapril10 to 20 mg twice a day,lisinopril20 to 30 mg once a day, andramipril5 mg twice a day; there are many others. ), 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 no reason to stop the drug 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 5 to 15% of patients, probably because bradykinin accumulates, but other causes of cough should also be considered. Occasionally, rash or dysgeusia occurs. 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. demonstrated improved exercise capacity. It did not improve survival, although there was a high rate of crossover from placebo to ACE inhibitor in this trial ( Drug treatment references ). 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. Inchronic HFrEF,ACE inhibitors and ARBs are likely equally effective. Usual oral target doses arevalsartan160 mg twice a day,candesartan32 mg once a day, andlosartan50 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 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. ( Drug treatment references ) demonstrated reduced number of hospitalizations for recurrent HF; however, hospitalization was a secondary endpoint. In another trial ( 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. a large randomized, controlled trial ( Drug treatment references ) compared There are 3 strengths ofsacubitril/valsartan: 24/26 mg, 49/51 mg, and 97/103 mg, all are taken orally twice a day. The starting dose 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 mgenalaprildaily) or in those patients who are ACE inhibitor/ARB naive or who have low/borderline blood pressure. ACE inhibitors must be discontinued 36 hours before initiation ofsacubitril/valsartan. Patients previously taking an ARB can simply switch tosacubitril/valsartanwithout a washout period. Complications associated with use of ARNI include hypotension, Hyperkalemia , renal insufficiency, and reduced NTproBNP levels at 12 weeks and left atrial volume at 36 weeks. The PARAGON HF study in a stable population of patients with HFpEF showed a non-significant reduction in death and hospitalization ( Drug treatment references ). However, there may have been lower hospitalization rates—further study is needed. beta-blockers, unless otherwise contraindicated (by Asthma , 2nd- or 3rd-degree 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 Drug treatment references recommend beta-blockade as first-line therapy for conditions where ventricular rate control is indicated (ie, control of ventricular rate with atrial fibrillation). 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 arecarvedilol25 mg twice a day (50 mg twice a day for patients≥85 kg),bisoprolol10 mg once a day, andmetoprolol50 to 75 mg twice a day (tartrate) or 200 mg once a day (succinate extended-release).Carvedilol, a 3rd-generation nonselective beta-blocker, is also a vasodilator with alpha-blocking and antioxidant effects; it is the preferred and most widely studied beta-blocker but is more expensive in many countries. Some beta-blockers (eg, bucindolol, xamoterol) do not appear beneficial and may be harmful. 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. InHFrEF,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. Digoxininhibits the sodium-potassium pump (Na+, K+-ATPase). As a result, it causes 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.Digoxinis excreted by the kidneys; elimination half-life is 36 to 40 hours in patients with normal renal function. Digoxinhas 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,digoxinuse has dropped significantly and is reserved for patients with significant symptoms despite optimal treatment with other mortality lowering medications.Digoxinshould 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.Digoxinis most effective in patients with large LV end-diastolic volumes and a 3rd heart sound (S3). Acute withdrawal ofdigoxinmay 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 withdigoxin0.5 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)digoxinlevel 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,digoxinload) patients with HF. Thus, simply startingdigoxinat 0.125 mg orally once a day (in patients with normal renal function) ordigoxin0.125 mg orally every Monday, Wednesday, and Friday (in patients with abnormal renal function) is sufficient in patients with heart failure. has a narrow therapeutic window. The most important toxic effects are life-threatening arrhythmias (eg, Ventricular Fibrillation (VF) , Whendigoxintoxicity occurs, the drug should be stopped; electrolyte abnormalities should be corrected (IV if abnormalities are severe and toxicity is acute). Patients with severe toxicity are admitted to a monitored unit, anddigoxin immune Fab(ovine antidigoxin antibody fragments) is given if arrhythmias are present or if significant overingestion is accompanied by a serum potassium of>5 mEq/L (> 5 mmol/L).Digoxin immune Fabis also useful for glycoside toxicity due to plant ingestion. Dose is based on the steady-state serumdigoxinlevel or total amount ingested. Ventricular arrhythmias are treated withlidocaineorphenytoin. Atrioventricular block with a slow ventricular rate may require a temporary transvenous pacemaker.Isoproterenolis contraindicated because it increases risk of ventricular arrhythmia. 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. should be used initially for control of volume overload, but their dose should be reduced when possible in favor of Aldosterone antagonists . Commonly used loop diuretics includefurosemide,bumetanide, andtorsemide. The starting dose of these drugs depends on whether the patient has previously received loop diuretics. Common starting doses are:furosemide20 to 40 mg orally once a day or twice a day,bumetanide0.5 to 1.0 mg orally once a day, andtorsemide10 to 20 mg orally once a day. If needed, loop diuretics can be titrated up to doses offurosemide120 mg orally twice a day,bumetanide2 mg orally twice a day, andtorsemide40 mg orally twice a day based on response and renal function.Bumetanideandtorsemidehave better bioavailability thanfurosemide. If patients are switched between different loop diuretics, they should be placed on equivalent doses.Furosemide40 mg is equivalent tobumetanide1 mg, and both are equivalent totorsemide20 mg. In refractory cases, IV loop diuretics ormetolazone2.5 to 10 mg orally can be used for an additive effect. IV infusion offurosemide(5 to 10 mg/hour) or other loop diuretics may be helpful in selected patients with severe 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 withmetolazone) 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 HF improves, the diuretic may be stopped if other drugs improve heart function and relieve HF symptoms. Using larger than required doses of diuretics lowers CO, 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. Analdosterone antagonist,eitherspironolactoneoreplerenone, should be added early to offset the potassium-losing effects of higher-dose loop diuretics. Hyperkalemia may result, especially when ACE inhibitors or ARBs are also taken, so electrolytes must still be monitored, especially during a dehydrating illness that could cause renal dysfunction. Aldosterone antagonists may have particular benefit in chronic right ventricular failure, in which hepatic congestion results in elevated aldosterone levels as aldosterone metabolism is reduced. To reduce the risk of hyperkalemia, aldosterone antagonists should generally be given only to patients whose potassium level is < 5.0 mEq/L (< 5 mmol/L), serum creatinine is < 2.5 mg/dL (< 221 micromol/L), and GFR is > 30 mL/min/1.73 m2. Furthermore, it should be noted that the equivalent dose ofeplerenoneis twice that ofspironolactone(ie,spironolactone25 mg =eplerenone50 mg). Thiazide diureticsare 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, andchlorthalidonecan be used in this manner. 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 (If). Inhibition of this current prolongs the time it takes to achieve critical spontaneous depolarization of pacemaker cells, and thus lowers the heart rate. ) and heart rate > 70 beats/minute who are at target beta-blocker dose or cannot tolerate a further increase in beta-blocker dose ( Drug treatment references ). Initial dose ofivabradineis 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. Ivabradineis currently the only drug in this class. , was shown to improve symptoms and quality of life and decrease hospitalization and mortality in patients with HFrEF when added to standard care in patients with elevated natriuretic peptide levels; benefit was similar in patients with and without diabetes ( Drug treatment references ). In a recent clinical trial, the addition of the SGLT2 inhibitor Dapagliflozinandempagliflozinmay 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 drugs are generally not indicated in patients with type I diabetes, low blood pressure, low eGFR (< 30 mL/min/1.73 m2), or rapidly worsening renal function. Other SGLT2 inhibitors (eg,canagliflozin,ertugliflozin) have not been studied directly in HF, but secondary analysis of studies in diabetes suggest they may also be beneficial. Hydralazineplusisosorbide dinitratemay 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. When used instead of ACE/ARB therapy,hydralazineis 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, although many patients cannot tolerate>200 mg/day because of hypotension.Isosorbide dinitrateis 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. Whether lower doses (frequently used in clinical practice) provide long-term benefit is unknown. In general, vasodilators have been replaced by ACE inhibitors, which are easier to use, are usually better tolerated, and have greater proven benefit. When added to ACE/ARB therapy,hydralazine-nitrate therapy may benefit patients of African ancestry with HFrEF. In this case, the starting dose ishydralazine37.5 mg andisosorbide dinitrate20 mg orally three times a day, with the maximum dose 75 mg and 40 mg three times a day. These doses are also available as a fixed-dose combination. The decision to add or substitutehydralazine-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. spray as needed for acute dyspnea and a transdermal patch for nocturnal or exertional dyspnea. In HFrEF, nitrates are safe, effective, and well tolerated and are particularly helpful in patients with HF and Angina Pectoris . Adverse effects include hypotension and headache. are better tolerated and may be useful for patients with HF and associated angina or Hypertension . Both drugs may cause peripheral edema; rarely, Variouspositive inotropic drugshave been evaluated in heart failure but, except fordigoxin, they increase mortality risk. These drugs can be grouped as adrenergic mode of action (norepinephrine,epinephrine,dobutamine,dopamine) or nonadrenergic (enoximone,milrinone, levosimendan [calcium sensitizers]). Regular outpatient IV infusions of inotropes (eg,dobutamine) were previously tried but found to increase mortality and are not recommended. However, outpatient continuous infusions of inotropes such asdobutamineormilrinonecan be used for palliative purposes in patients with severe HFrEF. ( Drug treatment references ). 1.Pitt B, Pfeffer MA, Assmann SF, et al:Spironolactonefor heart failure with preserved ejection fraction.N Engl J Med370:1383–1392, 2014. doi: 10.1056/NEJMoa1313731 2.Cleland JG, Tendera M, Adamus J, et al: Theperindoprilin elderly people with chronic heart failure (PEP-CHF) study.Eur Heart J27:2338–2345, 2006. doi: 10.1093/eurheartj/ehl250 3.Yusuf S, Pfeffer MA, Swedberg K, et al: Effects ofcandesartanin patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.Lancet362:777, 2003. doi: 10.1016/S0140-6736(03)14285-7 4.Massie BM, Carson PE, McMurray JJ, et al:Irbesartanin patients with heart failure and preserved ejection fraction.N Engl J Med359:2456–2467, 2008. doi: 10.1056/NEJMoa0805450 5.McMurray JJ, Packer M, Desai AS, et al: Angiotensin-neprilysin inhibition versusenalaprilin heart failure.N Engl J Med371:993–1004, 2014. doi: 10.1056/NEJMoa1409077 6.Solomon SD, McMurray JJ, Anand IS, et al: Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.N Engl J Med381:1609–1620, 2019. doi: 10.1056/NEJMoa1908655 7.McMurray JJV, Jackson AM, LAM CSP, et al: Effects ofsacubitril-valsartanVersusvalsartanin women compared with men with heart failure and preserved ejection fraction: Insights From PARAGON-HF.Circulation41(5):338–351, 2020. doi: 10.1161/CIRCULATIONAHA.119.044491 8.Swedberg K, Komajda M, Bohm M, et al:Ivabradineand outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.Lancet376(9744):875–885, 2010. doi: 10.1016/S0140-6736(10)61198-1 9.McMurray JJV, Solomon SD, Inzucchi SE, et al:Dapagliflozinin patients with heart failure and reduced ejection fraction.N Engl J Med381(21):1995–2008, 2019. doi: 10.1056/NEJMoa1911303 10.Anker SD, Butler J, Filippatos G, et al:Empagliflozinin heart failure with a preserved ejection fraction.N Engl J Med385(16):1451-1461, 2021. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189. 11.Redfield M, Anstrom KJ, Levine JA, et al:Isosorbide mononitratein heart failure with preserved ejection fraction.N Engl J Med373:2314–2324, 2015. doi: 10.1056/NEJMoa1510774 12.Armstrong PW, Pieske B, Anstrom KJ, et al:Vericiguatin patients with heart failure and reduced ejection fraction.N Engl J Med382(20):1883–1893, 2020. doi: 10.1056/NEJMoa1915928 