The severity and rapid spread of COVID-19 (caused by SARS-CoV-2) have raised questions about the use of some drugs in patients with the disease and whether currently available drugs could be effective in treating it. Definitive answers are lacking, but some recommendations can be made. For additional information on specific drugs, see our table Some Drugs Being Considered for Treatment of COVID-19.

View the Table: Treatments Considered for COVID-19

The severity and rapid spread of COVID-19 (caused by SARS-CoV-2) have raised questions about the use of some drugs in patients with the disease and whether currently available drugs could be effective in treating it. Definitive answers are lacking, but some recommendations can be made. For additional information on specific drugs, see our table Some Drugs Being Considered for Treatment of COVID-19.

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

View the Expanded Table: Some Drugs for HFrEF

A reader asked whether healthcare providers should avoid prescribing the angiotensin receptor blocker (ARB) olmesartan medoxomil (Benicar, and others) because it can cause severe GI adverse effects.

In 2013, the FDA warned that olmesartan can cause sprue-like enteropathy, a condition characterized by intestinal villous atrophy, severe chronic diarrhea, and significant unintended weight loss. The warning was based on 23 cases of serious sprue-like enteropathy associated with use of olmesartan, some occurring years after starting the drug. All patients improved after stopping olmesartan; 10 had a positive rechallenge.1 A case series describing 22 patients reported similar observations.2

Duodenal biopsies in patients with olmesartan-associated enteropathy have shown elevated CD8+ T cell counts and overexpression of interleukin-15 by epithelial cells, biomarkers similar to those seen after gluten exposure in patients with celiac disease. Mucosal recovery and lower levels of inflammatory biomarkers were observed in biopsies obtained after stopping olmesartan.3

In an observational cohort study including about 4.5 million patients in France who started ARB or angiotensin converting enzyme (ACE) inhibitor therapy over a 6-year period, exposure to olmesartan for >2 years was associated with one additional hospitalization for intestinal malabsorption per 12,550 patients, compared with exposure to another ARB or ACE inhibitor; this difference was statistically significant.4

Isolated cases of enteropathy have been reported with use of other ARBs.5-8

The absolute risk of sprue-like enteropathy with olmesartan is very low, and the effect is reversible. Patients without GI risk factors whose hypertension is well controlled on olmesartan could probably continue taking it. For patients starting antihypertensive therapy and those with GI risk factors, any of the several other ACE inhibitors or ARBs available generically9 might be a better choice. Patients taking any ARB should notify their healthcare provider if they develop severe diarrhea.

1. FDA Drug Safety Communication: FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil. Available at: www.fda.gov. Accessed January 18, 2018.
2. A Rubio-Tapia et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 2012; 87:732.
3. EV Marietta et al. Immunopathogenesis of olmesartan-associated enteropathy. Aliment Pharmacol Ther 2015; 42:1303.
4. M Basson et al. Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. Gut 2016; 65:1664.
5. A Negro et al. A case of moderate sprue-like enteropathy associated with telmisartan. J Clin Med Res 2017; 9:1022.
6. HS Mandavdhare et al. Telmisartan-induced sprue-like enteropathy: a case report and a review of patients using non-olmesartan angiotensin receptor blockers. Intest Res 2017; 15:419.
7. ML Herman et al. A case of severe sprue-like enteropathy associated with valsartan. ACG Case Rep J 2015; 2:92.
8. EY Choi and BJ McKenna. Olmesartan-associated enteropathy: a review of clinical and histologic findings. Arch Pathol Lab Med 2015; 139:1242.
9. Drugs for hypertension. Med Lett Drugs Ther 2017; 59:41.

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

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

The FDA has approved Prestalia (Symplmed), an oral fixed-dose combination of the dihydropyridine calcium channel blocker amlodipine (Norvasc, and generics) and a new salt form of the angiotensin-converting enzyme (ACE) inhibitor perindopril, for treatment of hypertension in patients not adequately controlled on monotherapy or already taking both drugs, and in those just starting therapy who are likely to need multiple drugs to control their blood pressure. The new salt form (perindopril arginine) is more stable and has a longer shelf-life than perindopril erbumine (Aceon, and generics). Two other ACE inhibitor/calcium channel blocker combinations, benazepril/amlodipine (Lotrel, and generics) and trandolapril/verapamil ER (Tarka, and generics), have been available in the US for many years.

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

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

Treatment of migraine in the emergency department, which may involve use of intravenous drugs, is not discussed here.

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

Drugs available in the US for treatment of chronic hypertension, with their dosages and adverse effects, are listed in the tables that begin on page 2. Combination products are listed on page 8. Drugs for treatment of hypertensive emergencies are not discussed here. They were reviewed previously.

The angiotensin receptor blocker (ARB) azilsartan medoxomil (Edarbi – Takeda) was recently approved by the FDA for oral treatment of hypertension, either alone or combined with other drugs. It is the eighth ARB approved for this indication.

Many patients with hypertension require more than one drug to control their blood pressure. Tribenzor (Daiichi Sankyo), recently approved by the FDA for treatment of hypertension, combines the calcium channel blocker amlodipine (Norvasc, and others), the angiotensin receptor blocker (ARB) olmesartan (Benicar)and the most commonly prescribed diuretic, hydrochlorothiazide (HCTZ). Tribenzor is not approved for initial therapy, but is recommended for patients not adequately controlled on any 2-drug combination of a calcium channel blocker, an ARB or a diuretic.

The FDA has approved Twynsta (Boehringer Ingelheim), a fixed-dose combination of the calcium-channel blocker (CCB) amlodipine and the angiotensin receptor blocker (ARB) telmisartan, for treatment of hypertension.

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

Most patients with hypertension require more than one drug to control their blood pressure. Exforge HCT (Novartis) is a new 3-drug fixed-dose combination tablet approved by the FDA for treatment of hypertension. It combines the calcium-channel blocker amlodipine (Norvasc, and others) and the angiotensin receptor blocker (ARB) valsartan (Diovan), which are already available in a combination tablet (Exforge), with the most commonly prescribed diuretic hydrochlorothiazide (HCTZ). Exforge HCT is not approved for initial treatment of hypertension, but rather for patients not adequately controlled on a 2-drug combination of a calcium-channel blocker, an ARB or a diuretic. It can also be substituted for amlodipine, valsartan and HCTZ in patients already taking all 3 of these drugs.

Drugs available in the US for treatment of chronic hypertension, with their dosages, adverse effects and costs, are listed in the tables that begin on page 2. Combination products are listed on page 9. Drugs for treatment of hypertensive emergencies are not discussed here. They were reviewed in Treatment Guidelines (volume 1, page 19, December 2002) and in The Medical Letter (volume 50, page 73, September 22, 2008).

Aliskiren (Tekturna - Novartis), the first direct renin inhibitor for treatment of hypertension, has been approved for use in a fixed-dose combination with the diuretic hydrochlorothiazide (Tekturna HCT - Novartis). Many angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are also available in fixed-dose combinations with hydrochlorothiazide (HCTZ).

Some drugs for treatment of migraine attacks are listed in table 2 on page 18. Drugs for prevention of migraine are listed in table 3 on page 20. Treatment of migraine in the emergency room, which may involve use of intravenous drugs, is not included here.

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

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

Drugs available in the US for treatment of chronic hypertension, with their dosages, adverse effects and costs, are listed in the tables that begin on page 40. Combination products are listed on page 47. Drugs for treatment of hypertensive emergencies are not discussed here.

Angiotensin receptor blockers (ARBs) are widely used as an alternative to angiotensin converting enzyme (ACE) inhibitors for treatment of hypertension because they lower blood pressure without inducing a cough. It has not been established that they provide the same cardiac benefits as ACE inhibitors. Recently, an editorial in the British Medical Journal suggested that ARBs may increase the risk of myocardial infarction.

Drugs for treatment of migraine attacks are listed in the table on page 64. All of the oral drugs are most effective if taken early in an attack when the pain is mild (H Christoph-Diener et al, Neurology 2004; 63:520). Drugs for prevention of migraine are listed in the table on page 65. Treatment of migraine in the emergency room, which may involve use of intravenous drugs, is not included here.

The importance of adequate control of hypertension in preventing organ damage and death is well established, but the choice of drugs is still controversial. Three recent drug trials, one supporting initial therapy with a diuretic, the second favoring an angiotensin converting enzyme (ACE) inhibitor, and the third showing equivalence between a calcium-channel blocker and an angiotensin-receptor blocker (ARB) have intensified the debate.

Eplerenone (e pler' en one; Inspra - Pharmacia), an aldosterone receptor antagonist similar to spironolactone (Aldactone, and others), has been approved by the FDA, but not yet marketed, for treatment of hypertension. It has also been tried for treatment of heart failure.

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

Drugs available in the US for treatment of chronic hypertension, with their dosages, adverse effects and costs, are listed in the table that begins on page 35. Combination products are listed on page 39. Drugs for treatment of hypertensive emergencies were discussed in Treatment Guidelines volume 1, issue 4, page 19, December 2002.

Olmesartan medoxomil (Benicar - Sankyo), a substituted imidazole, is the seventh oral angiotensin II receptor blocker (ARB) approved by the FDA for treatment of hypertension.