Thiazides better than ACE inhibitors as first-line antihypertensives, large-scale analysis suggests

Thiazide diuretics are more effective than ACE inhibitors for the first-line treatment of hypertension, according to an analysis of data from almost 5 million patients.

The LEGEND-HTN study attempted to address uncertainty over the real-world comparative effectiveness of common antihypertensive drugs. | GETTY IMAGES
The LEGEND-HTN study attempted to address uncertainty over the real-world comparative effectiveness of common antihypertensive drugs. | GETTY IMAGES

Initiating antihypertensive treatment with a thiazide instead of an ACE inhibitor has the potential to prevent 'many' major cardiovascular events, say the authors of the Large-scale Evidence Generation and Evaluation in a Network of Databases for Hypertension (LEGEND-HTN) study, published in The Lancet.

Novel approach

The researchers used a large-scale systematic approach to compare the cardiovascular outcomes and safety of monotherapy with 5 classes of blood-pressure-lowering drugs: thiazide or thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers.

The analysis included data from 9 observational databases in the US, Japan, South Korea and Germany, covering 4,893,591 patients from July 1996 to March 2018. Using a novel analytical approach, the authors generated 22,000 hazard ratios comparing all classes and outcomes across databases. They say this strategy minimises confounding and avoids the risk of publication bias or over-emphasising the results of a single observational analysis.

Overall, 48% of patients initiated an ACE inhibitor, 17% a thiazide, 16% a dihydropyridine calcium channel blocker, 15% an angiotensin receptor blocker, and 3% a non-dihydropyridine calcium channel blocker. Median overall follow-up time was more than 2 years for most databases, with 25% of patients having more than 5 years of follow-up in each drug class.

Most of the estimates revealed no difference in effectiveness between antihypertensive classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than ACE inhibitors with regard to risk of acute myocardial infarction (hazard ratio [HR] 0.84, 95% CI 0.75–0.95), hospitalisation for heart failure (HR 0.83, 95% CI 0.74–0.95), and stroke (HR 0.83, 95% CI 0.74–0.95) while on initial treatment.

Safety profiles also favoured thiazide or thiazide-like diuretics over ACE inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other 4 classes.

'Substantial effect'

The authors say their analysis is the largest and most comprehensive study ever conducted to provide evidence about the comparative effectiveness and safety of first-line antihypertensives.

'While our results suggest ACE inhibitors have only a modestly less favourable effectiveness profile than thiazide diuretics in magnitude, the effect of favouring thiazides across the whole population could be substantial,' they wrote. 'If the 2.4 million ACE inhibitor new-users we observed had instead chosen a thiazide, over 3,100 major cardiovascular events could potentially have been avoided'.

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