Adverse events in HEAAL: when to hold and when to fold.

This editorial refers to ‘Predicting adverse events during angiotensin receptor blocker treatment in heart failure: results from the HEAAL trial’, by M.S. Kiernan et al., published in this issue on pages 1401–1409. In 2009, the HEAAL investigators 1 reported that losartan 150 mg/ day reduced the rate of death and admissions for heart failure with reduced ejection fraction (HFREF) compared with patients receiving losartan 50 mg/day, the dose previously recommended and evaluated in ELITE II 2 to compare losartan with captopril. This important contribution pointed out the necessity to determine the effective dose of a drug in patients with HFREF rather than relying upon the dose used to lower blood pressure in patients with essential hypertension. In this issue of the journal, the HEAAL investigators 3 report that investigator-reported adverse events (AEs), including kidney impairment, hyperkalaemia, and hypotension, were associated with an increased risk of death compared with those patients who did not experience them, and that these AEs were more frequent in the losartan 150 mg than the losartan 50 mg group. The median serum creatinine on the day of their investigator-reported AE was 1.8 mg/dL, potassium 5.8 mmol/L, and systolic and diastolic blood pressures were 86 and 60 mmHg, respectively. Independent of the dose of losartan, these AEs were more frequent in older patients, those receiving an aldosterone blocker, and in those who reported the incident AE as the reason for intolerance to angiotensin-converting enzyme inhibitor therapy, one of the criteria for treatment with losartan. Baseline levels of serum creatinine were predictive of subsequent renal impairment, while entry levels of serum potassium predicted the occurrence of hyperkalaemia, and baseline systolic blood pressure predicted subsequent hypotension. Diabetes mellitus, baseline haemoglobin, and diuretic use were also predictive of subsequent kidney impairment and hyperkalaemia. However, while these factors were predictive of subsequent AEs, the association between investigator-reported kidney impairment, hyperkalaemia, and hypotension and the excess risk of subsequent death and first hospitalization for HF was independent of these baseline factors. Also of note was the finding that the frequency of these AEs continued to increase over time and was not limited to the period surrounding initiation of therapy with losartan. On the basis of these findings, the HEAAL investigators 3 suggest close monitoring in patients with the baseline risk factors they identified and in patients treated with losartan 150 mg/day. The finding that these AEs were associated with an increase in mortality, while not surprising, is nevertheless of importance and raises the issue of how we can avoid these AEs and how we should respond once they occur. It is important to emphasize that while there were significantly more AEs associated with the use of losartan 150 than 50 mg/day the strategy of losartan 150 mg significantly reduced cardiovascular events in comparison with 50 mg 1 and that the same AEs were associated with an increase in mortality when they occurred in patients on losartan 50 mg. While avoiding these AEs that were associated with an increase in mortality is desirable, it should be pointed out that these AEs are often difficult to predict in an individual patient and may be the cost of some strategies shown to be effective in reducing total mortality in patients with HFREF. One might conclude given the dictum ‘primun non nocere’ that since losartan 150 mg/day is associated with an increase in the incidence of AEs that resulted in an increase in mortality, it is better to avoid this strategy, especially in individuals at high risk for the development of these AEs with losartan such as those with chronic kidney disease, diabetes mellitus, or low haemoglobin, the very old, and those on an aldosterone blocker. These are, however, the very individuals who are at greatest risk and most in need of effective therapy to reduce their cardiovascular risk. Many clinicians have used this reasoning and have, for example, avoided the use of indicated aldosterone blockers in patients with HFREF 4 due to the fear of inducing hyperkalaemia, despite the evidence that aldosterone blockers reduce cardiovascular events even in these high-risk individuals. 5 While close monitoring should be instituted when prescribing losartan or similar agents to patients with the baseline risk factors identified by the HEAAL investigators, 3 the failure to attempt initiation may place the patient at greater risk than that associated with the development of these AEs. A more difficult question is what should one do once these AEs occur in a patient with HFREF. Our initial impulse might be to withhold or reduce the dose of the drug thought to be responsible for