In the early days of this century, as new antihypertensive medications were seeking their niche, the popular comparator drug was atenolol. The LIFE, ASCOT, and INVEST trials all used atenolol to demonstrate the “power” of their drug. Slowly, however, evidence emerged that atenolol was less effective than alternative antihypertensives. The Cochrane database dealt a blow to the entire beta-blocker class, decreeing that evidence did not support their first-line use for hypertension. Guidelines, influenced by this data and by the massive ALLHAT trial, fell in line. The JNC 7 recommended thiazide-type diuretics as first line, with beta-blockers in the “if necessary” category. The European NICE guidelines were more explicit: “Beta-blockers are no longer recommended for first line therapy as the evidence suggests that they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.” Ouch.

So where to turn? Based on ALLHAT, the first-line treatment recommendations became thiazide-type diuretics. In the US, this became hydrochlorothiazide (HCTZ). In Europe, this was bendrofluazide. The reasons these two drugs became the thiazides-of-choice is not clear. I have asked Google, but if it knows then it’s not telling. Neither was in ALLHAT, which is the study that drove the recommendations–it used chlorthalidone. But then again, I don’t know how atenolol became the beta-blocker-of-choice, either.

Thus, since the fall of atenolol, HCTZ has been the official first-line antihypertensive. As such, it has also been the comparator of choice when conducting new studies. But should it be? Back when I was starting kindergarten, the Multiple Risk Factor Intervention Trial (MRFIT) reported in 1982 a trend toward excess risk of cardiovascular mortality in patients treated for hypertension with thiazide diuretics. In the trial, 6 centers used chlorthalidone, and 9 used HCTZ. After 5 years, investigators noted a 44% increased mortality risk in the group treated with HCTZ versus the “usual care” group. This was not found in the chlorthalidone-using clinics, and all patients were changed to chlorthalidone. At study’s end, after 10.5 years, there was an overall risk reduction of 28%. Although this was a retrospective observation, it is, to say the least, interesting.

In 1995, a study comparing amlodipine to HCTZ found that “the use of HCTZ in doses of up to 25 mg daily is inadequate for ambulatory BP control in the elderly despite official recommendations.” Indeed, the studies showing significant beneficial effect for HCTZ used doses of 25-50mg, even 100mg: the European Working Party study, the MRC Working Party study, the MIDAS study, and the INSIGHT study.

Though guidelines have elevated thiazide diuretics (and thus HCTZ) to first line therapy primarily on the basis of ALLHAT, subsequent studies have exposed some chinks in the ALLHAT armor. The ANBP2 reported better outcomes in elderly patients treated with ACE inhibitors versus those treated with “thiazide diuretics”–that is, HCTZ. Most recently, ACCOMPLISH demonstrated superiority of a CCB+ACEI combination over a ACEI+“thiazide” (HCTZ) combo.

What do these studies mean? Do they suggest that the ALLHAT trial was wrong, or that it is (as I’ve heard it called) “Old Hat”? I recommend an excellent editorial discussing the ACCOMPLISH trial in the context of ALLHAT and other prior research. It suggests, as have others, that the problem is the term “thiazide diuretic,” suggesting all thiazides are alike. As one editorialist put it, if you’ve seen one thiazide diuretic, you’ve seen one thiazide diuretic. Chlorthalidone and HCTZ are actually quite different in their pharmacodynamics. First, chlorthalidone is roughly twice as potent as HCTZ. Second, the half-life of HCTZ is 8-15 hours after long-term use; it is 45-60 hours for chlorthalidone. I would argue that this is likely clinically significant. Chlorthalidone reduces ambulatory blood pressure more than HCTZ, and this is likely due to chlorthalidone’s longer duration of action. Since we tell patients to take their diuretics in the morning, when we check BP in the office it is well within HCTZ’s duration of action; at night, however, BP tends to increase. Is this relevant? Well, we have no prospective head-to-head trial, but as noted above, MRFIT suggests it is quite relevant.

So, does ACCOMPLISH say that ACEI+CCB is superior to ACEI+thiazide diuretic? Do these recent studies suggest that ALLHAT is wrong? I say no. I would argue, on the basis of the above-linked evidence:
        - that ACCOMPLISH reinforces prior evidence that HCTZ is the lesser sibling of chlorthalidone,
        - that ALLHAT is solid evidence that chlorthalidone should be our first-line thiazide,
        - and that no study has come out demonstrating the superiority of any drug over chlorthalidone as first-line treatment of hypertension.