Heart failure

Thiazides should be preferred first line antihypertensive agent

A thiazide diuretic has the best outcomes as monotherapy in hypertension and should be used first line in preference to other agents such as ACE inhibitors and calcium channel blockers, a major study published in The Lancet concludes.

In what is described as the largest and most comprehensive head-to-head comparison study of antihypertensive agents, the retrospective cohort LEGEND-HT study analysed data from 4.9 million patients starting monotherapy for hypertension. The study authors said they had used a novel systematic analytic framework to combine observational data from four different databases and address confounding and residual bias.

With a median follow up of two years, thiazides were found to be more effective than ACE inhibitors for all three primary endpoints of acute myocardial infarction, hospitalisation for heart failure, and stroke.

The event rate for thiazides was about 15% lower overall (acute MI hazard ratio 0·84; hospitalisation for HF 0·83, and stroke 0·83).

There were no significant differences in effectiveness between ACE inhibitors, Angiotensin Receptor Blockers (ARBs), and dihydropyridine Calcium Channel Blockers (CCBs), while non-dihydropyridine CCBs were the least effective agents.

Safety  profiles  also  favoured  thiazide  diuretics  over  other agents. While thiazides had higher risk of hypokalaemia and hyponatraemia compared with other drug classes, ACE inhibitors had higher risk of all-cause mortality, cardiovascular mortality, angio-oedema, TIA, dementia, renal disorders, thrombocytopenia, gastrointestinal side-effects, and cough compared with thiazides.


“This is a remarkable, massive, multinational study that has provided insights that can inform patient choices about hypertension treatment,” said study co-investigator Dr Harlan Krumholz, a Yale University cardiologist.

Dr Krumholz said it was notable that current hypertension guidelines recommend starting antihypertensive therapy with any drug from five different classes of medications, but there was no evidence to support the practice of using ACE inhibitors over the other agents.

In the study, the most commonly initiated antihypertensives were ACE inhibitors (48%), followed by thiazides (17%), dihydropyridine CCBs (16%), ARBs (15%), and non-dihydropyridine CCBs (3%).

“Given that these drugs [thiazides] are inexpensive and have a long track-record, the findings should clearly turn us away from the prevalent practice of starting with ACE inhibitors. These findings support people opting for a thiazide diuretic over an ACE inhibitor for the initial treatment of hypertension,” Dr Krumholz concluded.

Current Australian Heart Foundation guidelines recommend that in patients with uncomplicated hypertension, ACE inhibitors, ARBs, calcium channel blockers and thiazide diuretics are all suitable first line agents – and that beta blockers should not be offered first line.

The study was part-funded by the NHMRC.

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