Issue 145 Item 6 How Many Drugs, Which Drugs — to Treat Hypertension?

How many drugs does it take to control hypertension? >A possible answer to this question comes this month from the results of a Australian study that compared the 4 main classes of antihypertensive drugs.

The investigators found that the reason most patients need multi-drug therapy to control their hypertension may be because, while some antihypertensive drugs have a consistent effect, others reach maximum effect at different times of the day or night.

It is a well-known tenet of good medical practice that patients with hypertension will probably need a combination of drugs of different classes for effective treatment. The most recent evidence of this was seen in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), in which 63% of the patients enrolled were on 2 or more drugs by the end of the study.[1] Now a possible explanation for why multiple drug therapy is so often necessary to control hypertension has come from a small study in which different classes of drugs were shown to work most effectively at different times of the day.[2]

Researchers from the University of Melbourne, Australia, studied the antihypertensive effects of a beta-blocker, an angiotensin-converting enzyme (ACE) inhibitor, a CCB, and a diuretic in previously untreated patients aged > 65 years with systolic blood pressure (SBP) > 150 mm Hg. Twenty-four patients were randomized in a double-blind, balanced design to atenolol 25 mg, perindopril 4 mg, felodipine 5 mg, hydrochlorothiazide 20 mg, or placebo for 4 weeks. They were then force titrated to double dose, unless contraindicated, and after 1 month at the higher dose, crossed over to the next drug. In total, each patient received 5 treatment regimens over 8 weeks.

Ambulatory blood pressure monitoring (ABPM) was done over 1 hour at monthly visits (clinic SBP) and over 25-26 hours at the end of each 2-month drug treatment period (24-hour mean SBP); pressures were recorded during 3 periods of the day: morning (6:00 AM-9:00 AM), awake (9:00 AM-10:00 PM), and sleep (12:00 AM-6:00 AM). Medication was taken at 9:00 AM.

All 4 classes of drugs significantly lowered clinic SBP (P < .05) and 24-hour mean SBP (P < .05), although the reductions in SBP were greater with the felodipine and hydrochlorothiazide, confirming the results of a larger study performed by the same investigators with the same drugs.[3] However, hydrochlorothiazide and felodipine had a relatively consistent effect on blood pressure compared with the effects of atenolol and perindopril, which were highly dependent on the time of day. Atenolol was more effective during the awake hours, but had no significant effect during the sleep or morning periods. By contrast, perindopril lowered blood pressure more during sleep hours than awake hours, when it was relatively ineffective. The fall in sleep blood pressure produced by perindopril was, however, greater than with the other drugs.

Noting the importance of sleep blood pressure in determining whether end-organ damage, particularly cardiac hypertrophy, occurs, lead researcher Professor Trefor Morgan, MD, suggested that the failure of atenolol to reduce sleep blood pressure might explain why beta-blockers are relatively ineffective at reducing cardiac hypertrophy and in preventing cardiac morbidity and mortality when used as monotherapy for hypertension. He also suggested that the greater effectiveness of perindopril during the night might partly explain why ACE inhibitors are so effective in reducing cardiac hypertrophy and deaths due to coronary artery disease, as demonstrated in the Heart Outcomes Prevention Evaluation (HOPE) trial.