ACE inhibitors raise stroke outcomes risk by 11 per cent compared to diuretics: JAMA

The study stated that the long-term follow-up supports the main findings that the diuretic group had comparable cardiovascular outcomes and the ACE inhibitor group had greater stroke mortality risk.

The prespecified secondary analysis of outcomes of 32 804 participants in a randomized clinical trial (ALLHAT) and posttrial up to 23 years later, showed no significant difference in mortality due to cardiovascular diseases among the three antihypertensive treatment groups. However, an increased risk was observed for stroke outcomes for ACE inhibitors compared with diuretics, after accounting for multiple comparisons, this increased risk was no longer significant.

ALLHAT was a randomized, multicenter, double-blind, active-controlled clinical trial that compared initial antihypertensive treatment with a calcium channel blocker (amlodipine), an α-blocker (doxazosin), or an angiotensin-converting enzyme inhibitor (lisinopril), all compared with a thiazide-type diuretic (chlorthalidone) for the composite outcome of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI).

The long-term relative risk of antihypertensive treatments for morbidity and mortality is not well understood. Considering this, Jose-Miguel Yamal, The University of Texas Health Science Center at Houston, Houston, and colleagues aimed to determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, CCB, or ACE inhibitor with up to 23 years of follow-up.

For this purpose, the researchers conducted a prespecified secondary analysis of the ALLHAT trial in which they followed up participants aged 55 years or older with a hypertension diagnosis and at least 1 CHD risk factor for up to 23 years from 1994 to 2017. Trial participants were linked with administrative databases for postrial morbidity (n = 22 754) or mortality outcomes (n= 32 804).

Participants were randomly assigned to receive a CCB (n = 8898), a thiazide-type diuretic (n = 15 002), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of about 4 to 8 years and posttrial passive follow-up for up to 23 years.

The study revealed the following findings:

• A total of 32 804 participants (mean age, 66.9 years; 53.1% were men) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean age, 68.7 years; 56.1% women) were followed up for nonfatal or fatal CVD through 2017 (mean follow-up, 13.7 years; maximum follow-up, 23.9 years).
• Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 for CCB vs diuretic; AHR, 1.06 for ACE inhibitor vs diuretic).
• The long-term risks of most secondary outcomes were similar among the 3 groups.
• Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11).

"In this prespecified secondary analysis of an RCT using Medicare billing data to obtain follow-up for up to 23 years after baseline, we found similar results as those found during the ALLHAT," the researchers wrote.

ACE inhibitors were tied to an increased risk of stroke outcomes (11% increased risk of combined fatal and nonfatal hospitalized stroke) compared with diuretics, and this effect persisted well beyond the trial period," they concluded.

Reference:

Yamal J, Martinez J, Osani MC, Du XL, Simpson LM, Davis BR. Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023;6(12):e2344998. doi:10.1001/jamanetworkopen.2023.44998