Orlando, FL - Substitution of an angiotensin receptor blocker (ARB) for an ACE inhibitor in the stepwise polypharmacy of hypertension made no difference to cardiovascular clinical outcomes in a randomized trial of patients with documented CAD, according a study reported here today at the American Heart Association 2007 Scientific Sessions [1]. Although limited by a design that included open-label drug therapy, the trial produced a few tantalizing secondary results that included signs of a clinical benefit from the ARB-based approach among patients with reduced creatinine clearance and a suggestion that it might protect somewhat against new-onset diabetes.

Dr Hiroshi Kasanuki

The findings "strongly support" the use of ARB-based antihypertensive therapy in patients with both coronary artery disease and mild to moderate chronic renal dysfunction and "justify further exploration in randomized trials," Dr Hiroshi Kasanuki (Tokyo Women's Medical University, Japan) told heartwire.

As Kasanuki observed when presenting the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE), there was no difference between the ARB- and ACE-inhibitor-based strategies over about four years in a composite primary end point consisting of major adverse cardiac events (MACE). Included in the end point were CV death, nonfatal MI, and any of the following requiring hospitalization: unstable angina, heart failure, stroke, or "other CV events."

Among the approximately half of patients who had a creatinine clearance <60 mL/min, however, the MACE risk was reduced by 21% (p=0.039) with the candesartan-based approach and, over the entire study population, the incidence of new-onset diabetes was 63% lower (p=0.04).

Dr Gordon Tomaselli

"With all due caution about subgroup analyses," those secondary findings are "intriguing, particularly with respect to diabetes," Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD), chair of the meeting's program committee, told heartwire. In prediabetic patients, for example, "you might consider utilization of this drug as well as in patients who have chronic renal insufficiency."

The study entered 2049 patients with hypertension (defined as a systolic pressure >140 mm Hg, a diastolic pressure >90 mm Hg, or current antihypertensive therapy) and angiographically defined CAD with preserved LV function; 35% of the patients had acute coronary syndromes and the rest had stable CAD; about a third had a history of MI. It excluded patients with a serum creatinine >2.0 mg/dL.

The patients were randomized to receive standard hypertension therapy that used either candesartan or an ACE inhibitor, when it was decided, on a patient-by-patient basis, to add a blocker of the renin-angiotensin system.

Outcomes in HIJ-CREATE by drug-therapy strategy, median follow-up 4.2 years

End points	Candesartan-based, n=1024 (%)	ACE-inhibitor-based, n=1025 (%)	RR (95% CI), candesartan vs standard	p
MACE*	25.8	28.1	0.89 (0.76-1.06)	0.19
Revascularization	25.0	26.6	0.92 (0.77-1.12)	0.41
New-onset diabetes	1.1	2.9	0.37 (0.15-0.94)	0.04

Kasanuki told heartwire that the trial's participating clinicians followed the typical approach to hypertension management in Japan, which he said tends to start with calcium-channel blockers and follow with beta blockers and then either ACE inhibitors or ARBs until blood-pressure targets are reached. In HIJ-CREATE, the treatment goals were <130 mm Hg for systolic and <85 mm Hg for diastolic pressure.

The ARB-based approach was associated with significantly fewer drug-related adverse events (p=0.027), and fewer patients discontinued the ARB than the ACE inhibitor (p<0.001), Kasanuki said. Not surprisingly, patients in the ARB group had significantly less cough (p<0.001). There were no differences in development of dizziness, hyperkalemia, or liver dysfunction.

Analysis by renal function in HIJ-CREATE, HR (95% CI) for MACE, candesartan-based vs ACE-inhibitor-based approach

Creatinine clearance	HR (95% CI)	p
<60 mL/min	0.79 (0.63-0.99)	0.039
>60 mL/min	1.04 (0.81-1.34)	0.764

Dr Beatriz L Rodriguez

"In a general way, these findings are consistent with the VALIANT study, which was conducted in patients with acute MI and which also concluded that ARBs are at least as effective as ACE inhibitors in reducing cardiovascular events," according Dr Beatriz L Rodriguez (University of Hawaii and Pacific Health Research Institute, Honolulu). The assigned discussant for Kasanuki's presentation, formerly a co-principal investigator with the Honolulu Heart Program, Rodriguez concurred in observing that HIJ-CREATE suggests that the ARB-based approach "may be a preferable treatment for [patients with] coronary disease and hypertension, particularly those with mild to moderate kidney disease and in minority populations at high risk for glucose metabolism abnormalities."

Both Kasanuki and Rodriguez report that they have no relevant conflicts of interest to disclose.