Letter by Barrios et al Regarding Article, “Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial”
To the Editor:
We read with interest the article by Davis et al1 about the risk of hospitalization for heart failure (HF) in the patients included in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In ALLHAT, 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin. The analysis was limited to the sample of 910 patients who had been hospitalized with HF and in whom left ventricular ejection fraction was objectively measured. Interestingly, the results of this analysis showed that chlorthalidone significantly reduced the occurrence of new-onset HF hospitalization compared with amlodipine and doxazosin, regardless of systolic function, Moreover, chlorthalidone provided better protection than lisinopril against new-onset hospitalization caused by HF with preserved ejection fraction.
In the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), the addition of telmisartan to patients with cardiovascular disease or diabetes mellitus with end-organ damage had no significant effect on the primary end point, which included cardiovascular death, myocardial infarction, stroke, or hospitalization for HF.2 Notably, the lack of a significant difference in primary end point was influenced mainly by the similar rates of HF hospitalizations observed in the telmisartan and placebo groups. Surprisingly, the addition of a renin-angiotensin system inhibitor did not prevent hospitalizations for HF. In TRANSCEND, the use of diuretics at baseline was similar in both groups, as expected in a correct randomization. But notably, at study end, the proportion of patients on diuretics was significantly higher in the placebo arm (33.7% versus 40.0%; P<0.0001), and this could reduce a potentially beneficial effect of telmisartan on HF.
On the other hand, most clinical trials usually analyze the incidence of hospitalizations, not the clinical diagnosis of HF. It is likely that patients with mild HF symptoms could be treated with diuretics in outpatient clinics, and this action may prevent hospitalizations. As a result, although in those patients randomized to chlorthalidone in ALLHAT or to placebo in TRANSCEND, the admissions for HF were reduced in the first study and similar to telmisartan in the second one, it is suggestive that in these groups the cases of clinical diagnosis of HF could be superior to those reported exclusively by hospitalizations rates.
Importantly, these data should highlight the clinical relevance of concomitant medication in the randomized controlled trials. When it differs significantly between treatment arms during the study, the outcomes could be biased, and doubts may arise about some end points that could potentially be influenced by medication different from the study drugs. This could be the case for the use of diuretics in the placebo arm of TRANSCEND study and new-onset HF. Moreover, it is of note that the use of diuretics may reduce hospitalizations by masking incipient clinical HF symptoms. Therefore, when concomitant medications vary between groups during the study, some final results could be at least questionable. On the other hand, for future trials, it will be of interest if HF end points include not exclusively hospitalizations but also clinical diagnosis.
Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, Farber MA, Ford CE, Levy D, Massie BM, Nawaz S, for the ALLHAT Collaborative Research Group. Heart failure with preserved and reduced left ventricular ejection fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2008; 118: 2259–2267.
Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008; 9644: 1174–1183.