Diuretics effective as second-line therapy for hypertension

Sunday, November 8, 2009

by Lisa Nainggolan

Vancouver, BC - Diuretics, when given as second-line therapy to treat hypertension, reduce blood pressure to about the same extent as when they are used as first-line treatment, a new review shows.

The results also indicate that the BP-lowering effect of diuretics depends on the dose used but is independent of the type of first-line agent used; the latter being an unexpected finding, say Jenny MH Chen (University of British Columbia, Vancouver) and colleagues in a report published October 7, 2009 in the Cochrane Database of Systematic Reviews.

Hydrochlorothiazide (HCTZ) was the diuretic used in 92% of the studies included in this review, and it has recently been the subject of some criticism.

But Chen told heartwire she did not believe this to be warranted: "We believe that the recent criticism of HCTZ is misguided and not an accurate reflection of the evidence. Our review adds to the body of evidence demonstrating that HCTZ is indeed effective in lowering trough blood pressure; it can be given as a single daily pill and is an excellent drug choice for patients as the first or second drug."

Dr Franz Messerli (St Luke's Roosevelt Hospital, New York, NY), the lead author of a recent meta-analysis that concluded that HCTZ is a "paltry" antihypertensive at the usual doses prescribed (12.5-25 mg), told heartwire: "The meta-analysis of Chen et al is thorough and comprehensive, as one expects from this well-experienced team." But, he says, it is outcomes that are important, not merely lowering blood pressure, and there are no outcome data as yet for HCTZ 12.5 to 25 mg. "All outcome data with so-called 'thiazides' are based on chlorthalidone and indapamide."

Better information about BP-lowering effects of diuretics used second-line

Chen and colleagues say diuretics are widely prescribed for hypertension, not only as initial therapy but also as second-line treatment. This new analysis is the first to look at the additional reduction in BP with diuretics when given in combination with other antihypertensive drugs, they explain.

"It is possible for the effect of a diuretic as a second-line drug to be additive, subadditive, or synergistic," they observe. The aims of the review were to quantify the additional BP reduction achieved with a diuretic as a second drug vs placebo and to compare withdrawals due to adverse effects between a diuretic as a second drug and placebo.

"This review should be able to provide clinicians with better information about the magnitude of BP lowering when a diuretic is given as second-line therapy in the management of elevated blood pressure," they note.

There were 53 double-blind, randomized controlled trials evaluating a thiazide in 15 129 hypertensive patients (average baseline BP 156/101 mm Hg) included in the review. HCTZ was the thiazide used in 49 of the 53 (92%) included studies.

Thiazides as a second-line drug reduced BP by 6/3 mm Hg and 8/4 mm Hg at doses of one and two times the manufacturer's recommended starting dose, respectively. The antihypertensive effect was dose related and similar to that obtained when thiazides are used as a single agent.

Adding a thiazide diuretic as a second-line agent in combination resulted in greater reduction in BP compared with monotherapy without a thiazide.

Only three double-blind trials using loop diuretics were identified. This type of diuretic appeared to have a similar BP-lowering dose as thiazides at the recommended starting dose, the researchers say, although they acknowledge the evidence for this particular drug class is "weak." And due to wide confidence intervals, it was not possible to assess how loop diuretics compared with thiazides, they note.

Effect independent of first-line drug, or not?

Chen et al also showed that the BP-lowering effect of thiazides, particularly HCTZ, is independent of the type of first-line drug used, "a finding that was not expected," they say.

Based on the proposed mechanism of action, most doctors believe that adding a thiazide to an ACE inhibitor or an angiotensin receptor blocker (ARB) would have a greater effect than adding it to a calcium-channel blocker (CCB), they explain.

But Messerli says the claim that HCTZ's antihypertensive efficacy as an add-on was independent of the first-line drug used was "only true when 25 mg was given, whereas at lower doses (12.5 mg) the addition of HCTZ elicited a greater response in patients who were taking a renin angiotensin system (RAS) blocker [ACE inhibitor or ARB] than in those on a CCB. The authors shrug off these findings as being due to chance," he observes.

Unable to evaluate long-term side effects

Unfortunately, because of the short duration of trials and lack of reporting of adverse events, this review "does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug," Chen et al say. The trials were also carried out in predominantly white populations; therefore, further research of the BP-lowering effects of thiazides in people of other ethnicities is needed.

Chen commented to heartwire: "We agree that our data were not good at estimating side effects with long-term therapy. They did suggest that diuretics did not increase the rate of withdrawals due to adverse effects in the first three- to 12-week treatment period and thus appear well-tolerated at least for short-term therapy."

But, "Fortunately, there are also long-term trials showing the benefits of first-line thiazides in reducing mortality and morbidity, so we do not think our inability to estimate side effects is an important limitation," she added.

In conclusion, she told heartwire: "Thiazide diuretics are recommended as first-line agents in the treatment of hypertension" because "the evidence for the other classes of drugs such as beta blockers, ACE inhibitors, and CCBs, for example, is less robust."

However, Messerli begs to differ: "The authors get carried away by stating that thiazide diuretics are recommended as first-line agents because the evidence for other drug classes is less robust," but they "seem to forget that there are no outcome data for HCTZ in doses of 12.5 to 25 mg. Most important, we should remember that outcome data comparing combination therapy are scarce.

"The only convincing study is ACCOMPLISH, in which a fixed combination of amlodipine and benazepril was clearly superior to a fixed combination of benazepril and HCTZ with regard to morbidity and mortality. Since BP was lowered to the same extent in both treatment arms, this would indicate that antihypertensive effect per se is of limited value when assessing combination therapy," he concludes.


  1. Chen JMH, Heran BS, Wright JM, et al. Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension. Cochrane Database Syst Rev 2009; 4:CD007187.


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