Is Dual Agent Therapy for Hypertension Superior?


The Problem

A 56-year-old man is referred to you after he was evaluated for enrollment in a smoking cessation clinical trial, but was declined enrollment due to elevated blood pressure (BP). He was unaware of his elevated BP, as he has not interfaced with the medical establishment in over 20 years. He has no significant medical history and he takes no medications. He has a family history of premature coronary artery disease (his father and brother). His BMI is 31 kg/m2 and his BP is 168/96 mm Hg on an average of five readings. You discuss with him that he has hypertension and that you recommend he start therapy.

Your typical approach has been to use hydrochlorothiazide/triamterene, but have had recent difficulty obtaining this combination due to nationwide drug shortages. You have been writing two different prescriptions for many patients, but this patient inquires if he really needs to start two medications. You decide to remind yourself of the literature supporting dual therapy before confidently addressing this question.

By Dr. Jon O. Ebbert and Dr. Eric G. Tangalos

The Question

In patients starting medication therapy for hypertension, is dual therapy better than monotherapy for long-term control?

The Search

Visit PubMed, enter "hypertension" and "combination medication therapy," and limit to randomized controlled trial.

The Evidence

"Combination Therapy as Initial Treatment for Newly Diagnosed Hypertension" (Am. Heart J. 2011;162:340-6).

Design: A cohort study was conducted using data from the Cardiovascular Research Network Hypertension Registry from 2002 to 2007. The Cardiovascular Research Network is a consortium of research organizations sponsored by the National Institutes of Health and includes all adult patients with hypertension at HealthPartners of Minnesota, Kaiser Permanente Colorado, and Kaiser Permanente Northern California.

Participants: Patients entered into the registry if they met at least one of the following criteria: two consecutive elevated BP measurements defined as at least 140 mm Hg systolic blood pressure (SBP) and/or 90 mm Hg diastolic blood pressure (DBP) or at least 130/80 mm Hg in the presence of diabetes mellitus (DM) or chronic kidney disease (CKD); two diagnostic codes for hypertension recorded on separate dates; one diagnostic code for hypertension plus a prescription for an antihypertensive medication; or one elevated BP measurement plus one diagnostic code for hypertension. The current analysis includes 161,585 patients with a new diagnosis of hypertension who were started on a medication. Combination antihypertensive therapy was defined as treatment initiation with two antihypertensive agents for patients with incident hypertension.

Outcomes: BP control at 12 months was the primary outcome of interest. Blood pressure was considered uncontrolled if BP was greater than 140/90 mm Hg (or greater than 130/80 mm Hg in patients with DM or CKD). Systolic and diastolic BP data at 12 months were available for 77% of the cohort. Patients were analyzed by stage of blood pressure, with stage 1 defined as SBP 140-159 mm Hg or DBP 90-99 mm Hg and stage 2 as SBP of 160 mm Hg or DBP of 100 mm Hg.

Results: More patients with stage 2 hypertension (HTN) were treated with a combination than were patients with stage 1 HTN. Among patients with stage 2 HTN, the proportion treated with 2 drugs rose from 22% in 2002 to 45% in 2007. In all, 90% of combination medication prescriptions was accounted for by two combinations: thiazide/potassium-sparing diuretic (48%) and thiazide/ACE inhibitor (41%). Less common combinations included thiazide/B-blocker (5%), ACE-I/B-blocker (3%), ACE-I/loop diuretic (0.54%), thiazide/CCB (0.56%), ACE-I/CCB (0.17%), and thiazide/ARB (0.14%). At 12 months, initial treatment with two drugs was associated with a higher odds of BP control, compared with single agent therapy (odds ratio, 1.16; 95% confidence interval, 1.12-1.20). This was true of both fixed-dose agents (combination pills) or free antihypertensives (two individual drugs). Use of thiazide/ACE-I also was associated with an increased odds of BP control, compared to single-agent therapy (OR, 1.25; 95% CI, 1.10-1.31). No significant differences were observed between the two groups with respect to medication adherence. Patients on combination therapy were less likely to have an increase in the number of classes of antihypertensives used. However, no differences were observed in the number of dose adjustments.

Our Critique

This large, well-conducted study provides important information for the effective treatment of patients with a new diagnosis of hypertension in the clinical setting. The findings support the practice of prescribing two medications as initial treatment for hypertension. The most common medication combinations (thiazide/potassium-sparing diuretic & thiazide/ACE inhibitor) are available in generic form and can be prescribed as combination medications or as free medications.


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