William B. White, MD, FASH Professor, Department of Medicine, Chief, Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT
References
Subsequent to ALLHAT, the benefits and safety of calcium antagonists vs a thiazide diuretic combined with an angiotensin-converting enzyme inhibitor (ACEI) were ad-dressed by the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial.33 This study randomized 11,506 patients with a mean BP of 145/80 mm Hg to combination therapy with benazepril (40 mg/d) and amlodipine (5-10 mg/d) or benazepril and HCTZ (12.5-25 mg/d). Other antihypertensive medications could be added to reach a target BP <140/90 mm Hg (130/80 mm Hg in patients with diabetes or renal insufficiency).33 The study was stopped early at 3 years because the primary outcome of CV death, nonfatal MI or stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization occurred in 552 patients in the benazepril-amlodipine group compared with 679 patients in the benazepril-HCTZ group (9.6% vs 11.8%; RR ratio, 19.6%; hazard ratio [HR], 0.80; P < .001). The mechanism for the benefit observed in the benazepril-amlodipine group may relate in part to improved coronary blood flow that occurs with a calcium antagonist (compared with a diuretic) since BP control was virtually the same in both groups.
Another major hypertension study during the same era was the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).32 This study enrolled 19,257 patients in northern Europe with a mean age of 63 years, an untreated baseline BP ≥160/100 mm Hg or a treated mean BP ≥140/90 mm Hg, and 3 or more of 11 prespecified risk factors for CV. Patients were randomized to amlodipine, with or without perindopril, or atenolol, with or without a thiazide diuretic, and were titrated to reach a BP goal <140/90 mm Hg. The study was halted early after a mean follow up of 5.5 years. Although there was no statistically significant difference in the primary events of nonfatal MI plus fatal CHF between the 2 arms, fewer patients randomized to the amlodipine-based regimen experienced a fatal or nonfatal stroke (327 vs 422; HR, 0.77; 95% CI, 0.66-0.89; P=.0003) and total CV events and procedures were lower in patients taking the amlodipine-based regimen than in those taking the atenolol-based regimen (1362 vs 1602; HR, 0.84; 95% CI, 0.78-0.90; P < .0001).32 All-cause mortality was also lower in the amlodipine-based group (738 vs 820; HR, 0.89; 95% CI, 0.81-0.99; P=.025), and significantly fewer patients in this arm developed diabetes (567 vs 799; HR, 0.70; 95% CI, 0.63-0.78; P < .0001).32
Patients with diabetes in ASCOT who were titrated to achieve a target BP <130/80 mm Hg experienced significantly lower mortality and stroke when taking the amlodipine-based regimen than when taking the atenolol-based regimen (HR, 0.86; 95% CI, 0.76-0.98; P=.026).32 In the group taking the atenolol-based regimen, fatal and nonfatal strokes were reduced by 25% (P=.017), peripheral arterial disease by 48% (P=.004), and peripheral revascularization procedures by 57% (P < .001). There were no statistically significant differences in the endpoints of CHD deaths and nonfatal MI in the diabetes subgroup.
Combination therapy and guideline recommendations
By the 1970s, it became clear that combinations of antihypertensive drugs increased BP lowering efficacy through both additive and synergistic mechanisms. These combinations also reduced adverse events because lower doses of each drug could be used, whereas drugs from different classes might offset each other’s adverse effects. In addition, combining antihypertensive drugs could prolong duration of action, possibly providing additional target organ protection.43 Combining drugs from complementary classes has also been shown to increase the likelihood of BP lowering compared with increasing the dose of a single drug, thus reducing the time required to reach BP goal.31,44-46
The 2010 American Society of Hypertension (ASH) position statement on combination therapy in hypertension therapy notes that at least 75% of patients will require combination therapy to reach goal.47 In addition, a meta-analysis of 9 randomized clinical trials found that combination treatment using a thiazide or thiazide-like diuretic as one of the components could provide a significantly greater effect than monotherapy lacking the diuretic, with similar discontinuation rates.48
Government guidelines in the United States, now nearly 10 years old, do not recommend combination therapy as a first-line approach unless patients have stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg). At that point, the guidelines recommend combination therapy with a thiazide or thiazide-type diuretic plus either an ACEI, ARB, beta-blocker, or calcium antagonist.49 More-specific recommendations are provided for patients with compelling indications (eg, HF, ischemic heart disease, chronic kidney disease, recurrent stroke, diabetes, and high coronary disease risk), as shown in TABLE 2.41,49 New recommendations from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) are expected later this year.
