by Dr Geoffrey Modest
A recent meta-analysis assessed 42 trials comparing low-dose (one-quarter dose) antihypertensive therapy versus placebo, finding some efficacy and essentially no adverse events at this low dose (See DOI: 10.1161/HYPERTENSIONAHA.117.09202).
Details:
— 42 trials were identified involving 20,284 participants
— 37 comparisons evaluated quarter-dose therapy versus placebo
— 7 comparisons were of dual quarter-dose therapy versus placebo
— 1 comparison of quadruple quarter-dose therapy versus placebo
— standard full-dose therapy for some of the commonly prescribed medications were:
— atenolol 50 mg
— metoprolol 100 mg
— carvedilol 25 mg
— amlodipine 5 mg
— verapamil 240 mg
— lisinopril 20 mg
— enalapril 20 mg
— valsartan 80 mg
— candesartan 8 mg
— hydrochlorothiazide 25 mg
Results:
— quarter-dose therapy versus placebo led to a 4.7/2.4 mmHg improvement (p<0.001)
— dual quarter-dose therapy was associated with a 6.7/4.4 mmHg improvement versus placebo (p<0.001), as effective as standard-dose monotherapy
— quadruple quarter-dose therapy versus placebo (only one study) found a blood pressure reduction of 22.4/13.1 mmHg (p<0.001)
— adverse events in both the single and dual quarter-dose therapies were not significantly different from placebo and had significantly fewer adverse events compared to standard-dose monotherapy
Commentary:
— the studies used in this meta-analysis were quite old, the average being published to 17 years ago, and 85% had eligibility criteria based on diastolic blood pressure alone.
— It is important to realize that this study only looked at office-based blood pressure targets, not clinical outcomes. For example, beta-blockers are now out of favor because of a few meta-analyses showing little benefit in terms of clinical outcomes. And some commonly used meds are not included (eg losartan).
— Some of the older JNC recommendations, perhaps based on some of these studies, did raise the issue of combining low-dose medications versus increasing a single medication, given the synergy in blood pressure lowering of the combination and the significant decrease in adverse events
— there was also an interesting meta-analysis from 2009 (see Wald DS. Am J Med 2009; 122: 290), looking at 42 trials with 10,968 participants, finding that doubling the dose of thiazides, beta blockers, ACE inhibitors, calcium channel blockers, and the summation of all of these classes of antihypertensives led to only 22% of the equivalent incremental effect of adding a 2nd agent (though calcium channel blockers did a little better than others, especially ACE inhibitors). This study really reinforces my own anecdotal experience, that doubling the dose of lisinopril, amlodipine, etc seems to have much less blood pressure lowering effect than adding a 2nd agent (e.g going from lisinopril 10 mg to 20 mg has pretty consistently a lower incremental value than adding low-dose hydrochlorothiazide to the lisinopril 10 mg, which has the added benefit of being available as a single combination pill). Sort of similar to statins where the most significant cholesterol-lowering is at the lowest dose (I have a patient on 1/3 of atorvastatin 10mg, ie 3.3 mg, with impressive lipid lowering). There was also another study finding that half-dose therapy was about 80% as effective as compared to full standard-dose therapy.
— In a prior blog on the increased efficacy of chlorthalidone over hydrochlorothiazide, I lamented the fact that chlorthalidone was only available as 25 mg in the United States, that that dose was associated with significant hypokalemia, and that the pill was too small to cut easily. One of my readers commented that he actually took one quarter of the pill, did not find it difficult to cut the pill, and his blood pressure was well-controlled with that.
So, I do realize these meta-analyses are based on old studies, but it does seem to have validity, and is reinforced by my own clinical experience. Based on the study comparing doubling the dose versus combination medications, my practice has been to double the dose of the medication only if there is a compelling other reason (such as trying to decrease the level of proteinuria by maximizing ACE inhibitor dose) or if the medication is well-tolerated and the patient is pretty close to the target blood pressure.