BARCELONA — Add-on valsartan for control of high-risk hypertension resulted in a highly significant 45% reduction in the incidence of the primary cardiovascular end point compared with non–angiotensin receptor blocker add-on therapy in the randomized Kyoto Heart Study.
The estimated number of patients who would need to be treated (NNT) with valsartan (Diovan) instead of an alternative antihypertensive drug for 3.27 years to prevent one additional adverse cardiovascular event was 21, Dr. Hiroaki Matsubara reported at the annual congress of the European Society of Cardiology.
The combined primary end point consisted of stroke, MI, angina, hospitalization for heart failure, coronary revascularization, renal failure, or peripheral artery disease. The overall 45% decrease in the valsartan group was driven chiefly by reductions of 55% in the risk of stroke and 49% for angina, noted Dr. Matsubara of Kyoto (Japan) Prefectural University.
The Kyoto Heart Study randomized 3,042 hypertensive Japanese patients at high cardiovascular risk to open-label add-on valsartan or non-ARB antihypertensive therapy. High risk was defined by the presence of diabetes, ECG evidence of left ventricular hypertrophy, obesity, smoking, or a history of coronary artery disease. With add-on therapy, patients achieved identical blood pressure lowering, going from a mean baseline of 157/88 mm Hg to 133/76 mm Hg. Although the target dose for valsartan was 160 mg/day—the maximum in Japan—the average dose was 88 mg/day.
The trial was halted early, after a median 3.27 years of follow-up, for ethical reasons because the combined primary end point had been reached by 10.2% of control patients, compared with 5.5% of those in the valsartan group.
There were 25 strokes in the valsartan arm, compared with 46 in controls. Moreover, the valsartan group had 22 cases of angina pectoris, as determined by a blinded end point committee on the basis of ECG evidence and confirmatory coronary angiography, compared with 44 cases in controls. The NNT to prevent one stroke was 72; the NNT to prevent one case of angina was 69.
New-onset diabetes, a prespecified secondary end point, occurred in 86 controls, compared with 58 valsartan-treated patients, which was a highly significant difference.
However, rates of MI, heart failure hospitalization, and all-cause mortality were not significantly different in the two treatment arms.
The Kyoto Heart Study was undertaken because of a dearth of clinical trial data on the use of ARBs in Asian patients. For example, Asians comprised less than 4% of participants in the landmark Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) and Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trials, Dr. Matsubara noted.
Cardiovascular disease in the Japanese population differs from that in the United States and Europe. While the prevalence of hypertension is comparable, cardiovascular mortality in Japan is one-third that in the United States, and stroke mortality is at least 50% greater. The Japanese have a lower average body mass index than do Americans, but their salt intake is 2.5-fold greater. Calcium channel blockers account for more than 60% of all antihypertensive prescriptions in Japan.
The Kyoto findings suggest valsartan may be considered a vascular-specific ARB. It has the greatest selectivity of any ARB for the angiotensin type-1 receptor, and it appears to be particularly useful in treating hypertensive patients who have angina or who are at risk for stroke, according to Dr. Matsubara.
Discussant Frank Ruschitzka called the 45% reduction in the combined cardiovascular end point with valsartan “almost too good to be true,” pointing to the lack of benefit shown for acute MIs.
And the 49% reduction in angina was unpersuasive: “Angina is a weak end point … of minor importance,” said Dr. Ruschitzka of the University of Zurich.
He noted that the Kyoto finding that valsartan provided significant protection against stroke but not against MI is consistent with a just-completed meta-analysis he performed with American coinvestigators Dr. Franz H. Messerli and Dr. Sripal Bangalore. The meta-analysis incorporated 26 randomized non–heart failure clinical trials of ARBs totaling roughly 100,000 patients. It showed that ARBs resulted in a significant 13% relative risk reduction for stroke along with a nonsignificant 3% increased risk of MI. In contrast, ACE inhibitors have a well-established protective effect against MI.
“For me, ACE inhibitors and calcium antagonists are my first choice in treating high-risk hypertension. The ARBs are for those who don't tolerate the ACE inhibitors so well, although clearly they're equally effective for blood pressure lowering,” the cardiologist concluded.
A more charitable opinion of ARBs for treatment of hypertension was offered by American College of Cardiology President Alfred A. Bove in an interview.