Many patients with hypertension require more than one drug to control their blood pressure. Although evidence from clinical trials indicates that monotherapy with diuretics is as effective as or more effective than monotherapy with the newer classes of drugs for preventing cardiovascular sequelae,1 there are no comparable data from clinical trials regarding combination therapy with drugs from two classes. Thus, the choice of therapy with two drug classes must be guided by data from observational studies. We assessed cardiovascular events in relation to pharmacologic treatment of hypertension among 30,219 postmenopausal women with no previous cardiovascular disease (CVD), who were enrolled in the Women’s Health Initiative Observational Study (WHI-OS), a longitudinal follow-up study that included 93,676 women aged 50 to 79 years.
At the time of enrollment in WHI, the participants responded to a series of questionnaires, and physical tests were performed.2 Trained nurses or technicians measured blood pressure with a conventional sphygmomanometer, and the average of two readings taken at least 30 seconds apart with the participant in a sitting position was used for analyses. Women were considered to be hypertensive if they had elevated blood pressure at the clinic (systolic blood pressure [SBP] ≥ 140 mm Hg or diastolic blood pressure [DBP] ≥ 90 mm Hg, or both), or if they stated that they were taking antihypertensive medication.
At the first visit, participants brought in their medications, and the medication data from the original bottle label were entered into a pharmacy database. The therapy was classified as monotherapy with a diuretic, beta blocking agent, calcium channel blocker, or angiotensin-converting enzyme (ACE) inhibitor, or as two-drug—class therapy with a diuretic combined with a beta blocker, a diuretic combined with a calcium channel blocker, a diuretic combined with an ACE inhibitor, an ACE inhibitor combined with a calcium channel blocker, or any other therapy that may have included different drug classes or other drug combinations. No distinction was made as to which drug was used first or whether therapy was initiated with multiple drugs.
Cardiovascular and other end points were determined yearly by obtaining medical records from physicians and from hospitals for participants who self-reported any hospitalizations. This information was compiled for physician evaluators who ascertained the nature of the event. We assessed myocardial infarction (MI), stroke, and cardiovascular death, which was defined as death due to definite or possible coronary artery disease, pulmonary embolism, cerebrovascular disease, or CVD of unknown type. Patients were followed-up for an average of 5.9 years.
There were 35,920 women classified as having hypertension, of whom 35,198 had information on CVD history (angina, prior MI or stroke, angioplasty, coronary artery bypass graft surgery, or congestive heart failure). Of these, 30,219 did not have a history of CVD. Among the 30,219 women, 19,889 reported receiving antihypertensive medication, of whom 18,969 had their antihypertensive medication recorded in the database; 81.0% of these participants received monotherapy or the two-drug—class combinations of beta blocker, calcium channel blocker, diuretic, or ACE inhibitor. Blacks were more likely to be taking calcium channel blockers or diuretics than were whites.
Among those receiving monotherapy, women taking calcium channel blockers had higher average baseline SBP (139.2 mm Hg) than those taking diuretics (135.5 mm Hg). Duration of use of monotherapy at baseline ranged from 3.6 years (calcium channel blocker) to 7.5 years (diuretic; data not shown). Among those receiving combination therapy, which is the main focus of our report (Table 1), those taking a diuretic plus a calcium channel blocker had a higher SBP (137.9 mm Hg) than those taking a diuretic plus a beta blocker (134.4 mm Hg) or a diuretic plus an ACE inhibitor (133.3 mm Hg). Duration of use of combination therapy ranged from 6.6 years (diuretic plus ACE inhibitor) to 7.2 years (diuretic plus calcium channel blocker) and 8.2 years (diuretic plus beta blocker).
Among the 11,294 patients treated with monotherapy consisting of a diuretic, ACE inhibitor, beta blocker, or calcium channel blocker, those receiving calcium channel blockers experienced the highest cumulative rates of death from CVD, after adjusting for specific patient characteristics, including level of physical activity, use of hormone therapy, diabetes, body mass index, high cholesterol level requiring drug therapy, race/ethnicity, smoking, and age; those taking ACE inhibitors as monotherapy experienced the lowest rates (Figure 1).
Among the 4,004 patients taking a diuretic in combination with a beta blocker, ACE inhibitor, or calcium channel blocker, those receiving a diuretic plus a calcium channel blocker experienced the highest CVD mortality rates, and those taking a diuretic in combination with an ACE inhibitor experienced the lowest rates (Figure 2). We also examined the combination of an ACE inhibitor with a calcium channel blocker, but there were only 477 individuals taking that combination, and the data were not robust.
Figure 2 shows the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD death for patients receiving monotherapy relative to diuretic monotherapy (Figure 2A) and for patients receiving combination therapies relative to diuretic plus beta blocker therapy (Figure 2B), adjusted for multiple covariates; it also shows the HRs excluding patients with diabetes and including those who had their SBP controlled (140 mm Hg) at baseline while taking the particular therapy they were receiving. The HR for CVD death for women taking diuretics plus calcium channel blockers compared with those taking diuretics plus beta blockers was 1.85 (95% CI, 1.02—3.36); for the group without diabetes and who were controlled at baseline, the HR was 2.53 (95% CI, 1.01–6.36).
Although clinical trials are the best method to evaluate the effects of drugs, there have been no clinical trials among uncomplicated hypertensive patients who are receiving combination therapy with a diuretic. Evidence is available from one clinical trial, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial, which indicates that diuretics are as effective as or, in some cases, more effective than ACE inhibitors or calcium channel blockers as first-line therapy.1 In our study, calcium channel blockers as monotherapy were associated with a higher risk of CVD death than diuretics. There have been (or are in progress) a number of trials evaluating various antihypertensive agents in different subgroups of patients taking
calcium channel blockers and ACE
inhibitors.3,4 There is inadequate evidence, however, concerning combination therapy; therefore, observational evidence for comparisons of therapy with a diuretic plus another drug class must be used until comparable trials are completed.
Diuretics were recommended as first-line therapy for uncomplicated hypertensive patients in earlier guidelines (Fifth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC V]5 and JNC VI6) along with beta blockers. In the later guidelines (JNC 7), it was suggested that thiazide-type diuretics, ACE inhibitors, beta blockers, or calcium channel blockers be used as initial therapy.7 Two-drug—class combinations usually consist of a thiazide diuretic along with another drug class. We found that, after a mean of 5.9 years of follow-up, and controlling for multiple potential confounding variables, women who did not have a history of CVD and were receiving diuretics plus calcium channel blockers experienced twice the risk of cardiovascular death compared with patients who were taking diuretics plus beta blockers.
Diuretics correlated with more favorable blood pressure control than ACE inhibitors, beta blockers, or calcium channel blockers in our study, after adjusting for variables possibly related to treatment choice.8 This may have been the reason the outcome was better for patients taking diuretics in our study. In analyses limited to those whose SBP was controlled while receiving treatment, our findings were similar to the overall findings. Thus, in a group of patients who were at low risk by virtue of having no history of CVD or diabetes and who had their blood pressure controlled at baseline on each of the drugs we considered, we found that calcium channel blockers alone or in combination with a diuretic were associated with a higher risk of cardiovascular death than diuretics alone or than diuretics plus beta blockers.
Our study was not a clinical trial; we cannot, therefore, guarantee that we were able to completely control for confounding variables by indication; we did, however, conduct propensity analyses to adjust for the likelihood that a patient was on a particular drug at baseline. We do not know if the diuretic was a first-line or second-line drug. Our study results apply to 50- to 79-year-old postmeno-
pausal women and may not be able
to be generalized to men or younger women. A total of 40 US institutions participated in this study, however, and the women represent a varied population with regard to geographical region, education, income, and race.
Patients taking calcium channel blockers plus diuretics were shown to have a higher risk of CVD mortality than patients who were taking ACE inhibitors plus diuretics or beta blockers plus diuretics in our observational study of postmenopausal women with uncomplicated hypertension.