Which is more likely to cause a cough, losartan (angiotensin II receptor antagonist) or lisinopril (Angiotensin-Converting Enzyme (ACE) inhibitor)?

From the Guidelines

Lisinopril, an ACE inhibitor, is more likely to cause a cough than losartan, an angiotensin II receptor antagonist. ACE inhibitors like lisinopril commonly cause a dry, persistent cough in approximately 5-35% of patients taking the medication, as they prevent the breakdown of bradykinin, which accumulates in the lungs and stimulates cough receptors 1. This side effect typically develops within weeks to months of starting therapy and resolves within 1-4 weeks after discontinuation. In contrast, losartan and other angiotensin II receptor blockers (ARBs) work through a different mechanism that doesn't affect bradykinin metabolism, making cough a much rarer side effect (less than 1% of patients) 1.

Key Points

• ACE inhibitors, such as lisinopril, are known to cause cough in a significant percentage of patients due to their effect on bradykinin levels.
• ARBs, such as losartan, have a much lower incidence of cough as they do not affect bradykinin metabolism in the same way.
• For patients who need RAAS (renin-angiotensin-aldosterone system) blockade but develop a cough on an ACE inhibitor, switching to losartan or another ARB is often recommended as an effective alternative that provides similar cardiovascular and renal benefits without the cough side effect 1.
• The mechanism of action of ACE inhibitors and ARBs differs, with ACE inhibitors inhibiting the conversion of angiotensin I to angiotensin II and also increasing bradykinin levels, while ARBs block the action of angiotensin II at its receptor, without affecting bradykinin levels.

Clinical Implications

• When considering the use of ACE inhibitors or ARBs, the potential for cough should be taken into account, especially in patients with a history of cough or those who may be more susceptible to this side effect.
• The decision to switch from an ACE inhibitor to an ARB should be based on the individual patient's response to therapy and the presence of side effects such as cough.
• Given the more recent and comprehensive guidelines from 1 and 1, these should be prioritized in clinical decision-making over older studies.

From the FDA Drug Label

The incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy. Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience. Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy Table1: Study 1*HCTZLosartanLisinopril Cough25%17%69% Table1: Study 2 †PlaceboLosartanLisinopril Cough35%29%62%

Lisinopril is more likely to cause a cough than losartan.

• The incidence of cough with lisinopril is 69% and 62% in two studies,
• whereas the incidence of cough with losartan is 17% and 29% in the same studies. 2

From the Research

Comparison of Cough Incidence between Losartan and Lisinopril

• The incidence of cough is significantly lower with losartan compared to lisinopril, as shown in studies 3, 4, 5.
• In a double-blind comparison of losartan, lisinopril, and hydrochlorothiazide, the incidence of cough with losartan (29%) was lower than that for lisinopril (72%, P < 0.01) and similar to that for hydrochlorothiazide (34%) 3.
• Another study found that the incidence of cough with losartan was significantly lower than that for lisinopril, and similar to that for hydrochlorothiazide, in patients with previous angiotensin converting enzyme inhibitor cough 4.

Mechanism of Cough Induction

• ACE inhibitor cough is likely to be related to non-specific kininase II inhibition, which is not a mechanism associated with losartan, an angiotensin II receptor antagonist 3, 5.
• The specific selective AT1 angiotensin II receptor antagonist losartan is significantly less likely than lisinopril to cause cough in patients who previously have had ACE inhibitor cough 3.

Exceptional Cases

• However, there have been reports of losartan-induced cough, which resolved after substitution with an ACE inhibitor, enalapril, in a small number of cases 6.
• This suggests that while losartan is generally less likely to cause cough than lisinopril, there may be individual variations in response to these medications.

Summary of Findings

• The majority of studies suggest that losartan is less likely to cause cough than lisinopril, due to differences in their mechanisms of action 3, 7, 4, 5.
• However, exceptional cases of losartan-induced cough have been reported, highlighting the need for individualized treatment and monitoring 6.