By Michael H. Crawford, MD, Editor

SYNOPSIS: A large regional database study from Italy demonstrated that initial combination therapy for newly diagnosed hypertension results in fewer major adverse cardiovascular events at one year compared to monotherapy.

SOURCE: Rea F, Corrao G, Merlino L, Mancia G. Early cardiovascular protection by initial two-drug fixed-dose combination treatment vs. monotherapy in hypertension. Eur Heart J 2018;39:3654-3661.

Although many guidelines recommend initial treatment of hypertension with two drugs, especially if the systolic blood pressure (BP) is > 160 mmHg, there are little data on whether this approach improves cardiovascular (CV) outcomes.

Investigators from Milan performed an observational study comparing initial use of monotherapy vs. two-drug therapy to determine if CV outcomes were different at one year. A case-controlled model was used to minimize confounding. Subjects were identified in the Lombardy region National Health Service database (which includes more than 5 million individuals) who received at least one new prescription for an antihypertensive medication and no antihypertensive drug prescriptions in the preceding 10 years. Patients were between the ages of 40 and 80 years and were compliant with therapy. Since most combination therapy in Italy used fixed-dose combinations, patients who received multiple individual prescriptions were excluded. Also, none of the combination pills integrated angiotensin modulators and calcium antagonists at the time the initial data were obtained. The primary endpoint was hospitalization for a CV event.

A total of 44,534 patients met inclusion criteria. Of these patients, 83% started therapy on one drug and 17% started therapy on two drugs. Seventy-seven percent of combination therapies were with an angiotensin modulator and a diuretic. The most common monotherapy was with an angiotensin modulator (68%). Adherence to therapy was similar in both groups (about 75%). After adjustment for covariates, there was a significant (21%) reduction in CV events at one year for the combination therapy patients compared to monotherapy (hazard ratio, 0.79; 95% confidence interval [CI], 0.71-0.88; P < 0.01). This difference also was observed for the individual endpoints of ischemic heart disease (-39%) and atrial fibrillation (-37%). In addition, the frequency of CV events in those on monotherapy was highest in the first month after starting therapy, decreasing incrementally until six months. The authors concluded that initial combination therapy is more effective at preventing CV events over one year than initial monotherapy.


Several rationales for using initial combination therapy for hypertension have been demonstrated. First, this approach lowers BP to target more rapidly, which may be important in patients at high risk for CV events. Second, adherence is better with combination therapy, possibly because of the positive feedback of the lower BP. Third, combination therapy has been associated with better BP control for up to one year, probably because it reduces the inertia of titrating monotherapy. Fourth, by using low doses of multiple drugs with different adverse effect profiles, synergistic BP lowering is accomplished without increasing side effects. However, limited data exist on whether initial combination therapy improves outcomes, which was the aim of this Italian study.

There were several strengths to this study. It was conducted in a general population, not selected trial participants. Participants experienced many CV events. The outcomes data were verified three ways: adjusted for comorbidities, case-matched analysis, and a unique technique whereby patients were used as their own controls. The latter involved finding patients who took monotherapy for some period and combination therapy for a different period and experienced at least one CV event. This analysis showed a large CV event incidence ratio reduction (IRR) in favor of combination therapy (IRR, 0.44; 95% CI, 0.40-0.49).

The major weakness of the study was that the data do not tell us why these differences exist. Adherence rates were similar, but no BP data were available from the database used. Also, there were no laboratory data to identify potential drug toxicities. In addition, the newer combination pills with angiotensin modulators and calcium antagonists were not studied. Based on comparison studies, these newer combinations might have provided bigger differences in CV outcomes.

It is noteworthy in this study that only about one in five patients started combination therapy despite previous positive data and the recommendations of national guidelines. Perhaps this was because of the paucity of outcome data and slow acceptance of combination pills by insurers. Hopefully, this study will help eliminate this acceptance gap. In the United States, there are many generic combination pills, so this barrier has been eliminated. All that remains is convincing physicians and patients that the evidence favors initial combination therapy for hypertension.