Thiazides better than ACE inhibitors as first-line antihypertensive?

While effectiveness is generally comparable among the four first-line antihypertensive drug classes, initiating thiazides may be better than the most commonly prescribed class of ACE* inhibitors in reducing primary cardiovascular (CV) outcomes, suggests real-world evidence from the LEGEND-HTN** study.

“Health-care providers faced with the question of which medication to prescribe first for newly diagnosed patients get little help from current hypertension guidelines,” which state that any of the four drug classes — thiazides, ACE inhibitors, ARBs, or CCBs*** — can be used in the first line, noted Drs Christopher Ives and Suzanne Oparil from the University of Alabama at Birmingham in Birmingham, Alabama, US in an accompanying commentary. [Lancet 2019;doi:10.1016/S0140-6736(19)32461-4]

“Which of these medications should be preferentially initiated in newly diagnosed hypertensive patients remains undecided,” they wrote.

Which drug class for first line?

Using nine international health databases, the researchers analysed data of almost 4.9 million patients who started on antihypertensive monotherapy between the period of July 1996 to March 2018. Median follow-up was 2 years, with a quarter of them being followed for >5 years. [Lancet 2019;doi:10.1016/S0140-6736(19)32317-7]

Overall, the effectiveness between drug classes was generally comparable, which the authors said “supports equivalence between drug classes for initiating monotherapy for hypertension — in keeping with current guidelines.”

However, thiazide or thiazide-like diuretics were associated with a significantly lower risk of the three primary endpoints of acute myocardial infarction (hazard ratio [HR] 0.84), stroke (HR, 0.83), and hospitalization for heart failure (HR, 0.83) compared with ACE inhibitors (p=0.01 for all).

There were no significant differences in the three primary CV outcomes among the other three drug classes.

The safety profiles also favoured thiazides over ACE inhibitors — with the risk of CV-related and all-cause mortality, transient ischaemic attack, thrombocytopenia, gastrointestinal side effects, angioedema, dementia, and cough being higher with ACE inhibitors vs thiazides. On the other hand, thiazides were associated with a higher risk of hypokalaemia and hyponatraemia compared with the other drug classes.

“These data provide evidence that thiazides are more effective in preventing health outcomes and are underused given their tolerable side-effect profile,” observed Ives and Oparil.

Based on the analysis, ACE inhibitor (48 percent) was the drug class most commonly used for monotherapy initiation, followed by thiazides (17 percent), dihydropyridine CCB (16 percent), ARB (15 percent), and nondihydropyridine CCB (3 percent).

The implication of the study is huge, the authors noted. “If the 2.4 million ACE inhibitors new users had instead started on a thiazide or thiazide-like diuretic, more than 3,100 major CV events could potentially have been avoided.”

Filling the gap

Current recommendations were largely derived from earlier randomized clinical trials (RCTs), which generally compared between individual drugs rather than drug classes and did not restrict patients to those initiating therapy.

“With LEGEND, we have found a way to fill in the gaps left by RCTs and help guide physicians in their clinical decision making,” said study co-author Dr George Hripcsak of Columbia University Medical Center in New York, New York, US. “These large-scale and unfiltered populations better represent real-world practice than the restricted study populations in … RCTs.”

As BP readings at baseline and after treatment were unavailable in some databases included in the analysis, the researchers acknowledged that this might have resulted in unmeasured confounding by indication since baseline BP may drive the choice of drug class.

Another limitation comes from the fact that the analysis only included data on monotherapy initiation.

“Future analyses should compare initial combination therapies,” suggested Ives and Oparil. “Current hypertension guidelines recommend, on the basis of expert opinion, that combination therapy might be considered if initial blood pressure exceeds a specific threshold.”

Also, some questions remain, they pointed out. “For example, what are the benefits and risks of treating hypertension with medications in patient groups for which there are no or very limited data from RCTs, such as younger people, people at low overall CV disease risk, and people with comorbidities?”