Dr Elijah Saunders

The design of the open-label study, dubbed INCLUSIVE, is noteworthy for requiring at least 100 patients in each of a variety of subgroups for which achieving BP targets has long been considered a special challenge. Importantly, such patients—including the elderly, African Americans, Hispanics, and those with type-2 diabetes or the metabolic syndrome—achieved significant mean reductions in the primary end point of systolic pressure and generally reached their BP goals at rates similar to the overall group, according to Dr Elijah Saunders (University of Maryland, Baltimore), who reported the study here last week at the American Society of Hypertension 20th Annual Scientific Session.

But, "The fact that one would get a good response in a diverse population with the combination of an ARB and a diuretic was not surprising," Saunders said when presenting the results. "That's supposed to happen. But the magnitude and extent of achieving goal blood pressure," 77% for systolic pressure and 83% for diastolic, Saunders noted, "was somewhat surprising."

The treatment used in INCLUSIVE was a fixed-dose combination of irbesartan and hydrochlorothiazide (Avalide, Bristol-Myers Squibb/Sanofi-Synthelabo).

Dr Keith C Ferdinand

"INCLUSIVE is a real-world study that gives us an opportunity to see how a combination of medicines works in a very heterogeneous population," according to Dr Keith C Ferdinand (Heartbeats Life Center, New Orleans, LA), who comoderated the session that included Saunders's presentation. "Furthermore, it's one of the first large trials to use systolic pressure as a primary end point," he told heartwire. Systolic pressure is more predictive than the diastolic number for CV events in middle-aged and older patients, he said, so "if more trials start to utilize systolic blood pressure as an end point, we may get a better predictor of how different drugs work."

I'm hoping that our colleagues will see this and realize that the use of combination therapy more aggressively and earlier on in the management of hypertension will get many more patients to goal.

In the 119-center INCLUSIVE trial, patients with uncontrolled hypertension on monotherapy were observed during a placebo washout period for at least a month. "Control" meant achievement of systolic-BP goals recommended by the Seventh Joint National Committee (JNC-7), 140 mm Hg for nondiabetic patients and 130 mm Hg for diabetics [1].

The intention-to-treat population of 736 patients then received 12.5-mg/day hydrochlorothiazide alone for two weeks. Those still uncontrolled were put on the irbesartan-hydrochlorothiazide combination (150 mg and 12.5 mg per day, respectively) for another eight weeks, after which patients who hadn't yet achieved their target had their doses doubled in fixed proportion, and all were followed for eight weeks further.

Patients within each predefined subgroup showed "significantly" reduced systolic and diastolic BP, Saunders said, while only the diabetics, whose target numbers are lower than those of nondiabetics, showed a <70% rate of BP control.

Dr Michael A Weber

Saunders called the fixed-dose regimen "well-tolerated" over the 18 weeks of therapy; hypokalemia was rare and didn't force anyone from the trial. One patient left the study due to elevated potassium levels and another left due to high blood-urea concentrations. Although 14% of patients experienced adverse events considered due to drug therapy, they were judged serious in only a handful of cases.

Elsewhere at the ASH meeting, Dr Michael A Weber (State University of New York, Brooklyn) and colleagues reported that outcomes in INCLUSIVE for both systolic and diastolic BP "were not greatly influenced" by the drug class of the patients' prior unsuccessful monotherapy.

Dr Joel Neutel

At a press conference, INCLUSIVE investigator Dr Joel Neutel (University of California, Irvine) called the fixed-dose regimen "a complementary combination of drugs that is much more effective than any monotherapy could be in these patients. . . . What it shows us is what [JNC-7]and other groups have said, that using combination therapy in patients with stage-2 systolic hypertension should be considered even first line, and certainly much earlier in the management of hypertension," Neutel said. "I'm hoping that our colleagues will see this and realize that the use of combination therapy more aggressively and earlier on in the management of hypertension will get many more patients to goal."