Combination Therapy for Hypertension
Abstract & Commentary
By Michael Crawford, MD
Source: Jamerson, K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359;23:2417-2428; Chobanian A. Does it matter how hypertension is controlled? N Engl J Med. 2008; 359;23:2485-2488.
In order to achieve new aggressive blood pressure goals in hypertensive patients, drug combinations are often used. But which combinations are superior for preventing cardiovascular events? The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial pitted the angiotensin converting enzyme inhibitor (ACE I) benazepril plus diuretic against benazepril plus the calcium blocker amlodipine in a randomized, double-blind trial. The 11,506 patients enrolled with hypertension were considered at high risk for a cardiac event because of evidence of vascular disease, left ventricular hypertrophy (15%), or diabetes (60%). The benazepril dose was up-titrated to 40 mg per protocol. Amlodipine could be increased to 10 mg and hydrochlorothiazide to 25 mg as necessary to control blood pressure. If blood pressure still was not controlled, drugs from other classes, except angiotensin receptor blockers (ARB), could be added (32%). The primary endpoint was a cardiovascular event (myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or cardiac arrest) or death from a cardiovascular cause.
Results: After a mean follow-up of 36 months, blood pressure was reduced similarly in both groups to an average of 132/74 mmHg, and about 75% of both groups achieved the target of < 140/90 mmHg. The study was terminated early because the primary endpoint had occurred in 9.6% of the amlodipine group and 11.8% of the hydrochlorothiazide group (HR 0.80, p < .001). The secondary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 5% of the amlodipine group and 6.3% of the hydrochlorothiazide group (HR 0.79, p = .002). The only secondary endpoint not reduced more, in the amlodipine group, was hospitalization for heart failure. No prespecified subgroup (age, sex, diabetes) failed to demonstrate the overall results. Study drug discontinuation was about 30% in both groups and study withdrawal was similar, at about 15%. The authors concluded that the benazepril-amlodipine combination was superior to benazepril hydrochlorothiazide for reducing cardiovascular events in high-risk hypertensive patients.
There are several unique aspects to this study. First, it is the first comparison of an ACE I-calcium blocker combination to an ACE I diuretic combination. Most previous combination therapy comparison studies involved a beta-blocker combination. Many now believe that beta blockers are generally less effective overall at preventing events in hypertensive patients. In animal studies, the ACE I-dihydropyridine calcium blocker combination showed synergistic effects on vascular nitrous oxide release. Also, this combination reduced atherosclerosis progression in animal models and is additive for reducing left ventricular hypertrophy; none of these effects have been demonstrated for diuretics. Second, despite equivalent blood pressure control, this study showed a difference in cardiovascular endpoints, supporting the concept that this combination has beneficial effects beyond blood pressure control. Most prior studies showed no difference in outcomes if blood pressure was equally controlled. Those few that showed an outcome difference demonstrated a blood pressure difference as well. Third, a remarkable 75% of patients in both treatment groups achieved target blood pressures of < 140/90 mmHg. At baseline, only 37% of the patients were at this target on their pre-study medications; a rate similar to what is achieved in many antihypertensive studies. Fourth, this was a high-risk group of patients. Average age was 68 years; 24% had a previous myocardial infarction; 13% a prior stroke; 36% had coronary revascularization; 74% had dyslipidemia; and a whopping 60% were diabetic.
The major limitation to this study was that there was no washout period, so we do not know how severe the patient's initial blood pressure was. It is understandable why the investigators did not want to wash out these high-risk patients, as they might have events while off medication. Unfortunately, we do not know exactly what stage of hypertension would be best treated with an ACE I-calcium blocker combination. Clearly, anyone with a blood pressure > 20/10 mmHg greater than target would be a candidate for combination therapy, since blood pressure control is unlikely with one agent. The clinical implication of this study is that high-risk vascular disease or diabetic patients are excellent candidates for the ACE I dihydropyridine calcium blocker (DCB) combination as their baseline therapy. Presumably, ARB + DCB could also be effective. Currently, there are several fixed-dose combination pills available of ACEI or ARBs plus calcium blockers. Fixed-dose combinations, as were used in this study, are popular with patients because of reduced cost and increased convenience. Also, they may increase compliance.
Thus, fixed-dose combination therapy is often indicated in moderately severe hypertension patients, and the ACE I plus DCB is particularly efficacious.