Since they first became available almost 15 years ago, ARB supporters have tried to fight the impression that the drugs are nothing more than ACE inhibitors without the cough. The latest effort to do this, the KYOTO HEART study, was presented earlier today at the ESC and published simultaneously in the European Heart Journal.
Japanese investigators randomized 3,031 patients with uncontrolled hypertension to either valsartan or non-ARB based optimal therapy. At 3.27 years, the primary endpoint, a composite of fatal and nonfatal cardiovascular events, was reduced from 10.2% in the non-ARB arm (155 patients) to 5.4% (83 patients) in the valsartan arm, a highly significant 45% reduction. Most of the clinical benefit was due to a reduction in stroke and angina. As expected, valsartan was well tolerated by patients. Blood pressure control was similar in both groups.
The KYOTO HEART investigators concluded that valsartan “exerts an overall cardiovascular protective effect in high-risk Japanese hypertensive patients and in particular exerts anti-stroke and anti-angina actions.”
In an EHJ commentary, Franz Messerli, Sripal Bangalore, and Frank Ruschitzka point out that the reduction in stroke may be partly attributable to the higher prevalence of stroke in Asian populations. Angina, they note, is a “rather soft endpoint,” especially in light of open label dosing in the trial. “We find it somewhat difficult to believe that an ARB should be better in preventing angina than a calcium antagonist,” they write.
Messerli et al conclude that ARBs “have come of age” when it comes to safety and antihypertensive efficacy, but remind that blood pressure is still a surrogate endpoint:
The impressive results of the KYOTO study lead to the question of whether ARBs as a class have come of age and should now be considered as preferred or baseline therapy in hypertension. The answer, with regard to safety and efficacy, could be a resounding yes, i.e. if efficacy were defined as blood pressure reduction. However, blood pressure is merely a surrogate endpoint which correlates to some extent with the true endpoint, i.e. heart attack, stroke, and death. As the above meta-analysis demonstrates, ARBs are efficacious and even superior to other drug classes in stroke prevention but their efficacy with regard to coronary events remains uncertain. Thus, if efficacy is defined as reduction in overall cardiovascular events and mortality, the answer, in view of the data in aggregate, remains no, or perhaps, not yet.
Click here to download the KYOTO slides.
Click here to read the EHJ KYOTO paper.
Click here to read the EHJ commentary by Franz Messerli, Sripal Bangalore, and Frank Ruschitzka.
Here is the ESC press release:
Valsartan reduces morbidity and mortality in Japanese patients with high risk hypertension: results from the KYOTO HEART Study
Barcelona, Spain, 1 September 2009: The KYOTO HEART Study, which took place in Japan between January 2004 and January 2009, shows that the addition of valsartan to conventional antihypertensive treatment to improve blood pressure control is associated with an improved cardiovascular outcome in Japanese hypertensive patients at high risk of CVD events.
It remains to be determined whether the evidence found in Western countries for the benefit of blockade of the renin-angiotensin system could be directly applied in East Asian populations, including Japanese, as a long-term strategy. The KYOTO HEART Study was designed to investigate the add-on effect of valsartan (an angiotensin II receptor antagonist, ARB) versus non-ARB optimal antihypertensive treatment on cardiovascular morbidity and mortality in Japanese hypertensive patients with uncontrolled blood pressure and high cardiovascular risks.
The KYOTO HEART Study was a multicentre, prospective, randomised comparison study with a response-dependent dose titration scheme. More than 3000 Japanese patients were assessed for eligibility (43% female, mean age 66 years); all had uncontrolled hypertension and with one or more cardiovascular risk factors (such as diabetes, smoking habit, lipid metabolism abnormality, a history of ischaemic heart disease, cerebrovascular disease or peripheral arterial occlusive disease, obesity (BMI>25) and left ventricular hypertrophy on electrocardiogram). 3031 patients were randomised to receive either additional treatment with valsartan or non-ARB conventional therapies.
The primary endpoint was a composite of defined cardio- or cerebrovascular events such as stroke/transient ischemic attack, myocardial infarction, hospitalisation for heart failure, hospitalisation for angina pectoris, aortic dissection, lower limb arterial obstruction, emergency thrombosis, transition to dialysis, or doubling of serum creatinine levels.
The study was prematurely stopped after a median observation time of 3.27 years. This was for ethical reasons because of unequivocal benefit in the valsartan group.
* Compared with non-ARB arm, fewer individuals in the valsartan arm reached a primary endpoint (83 vs 155; HR 0.55, 95% CI 0.42-072, p=0.00001). This difference in primary endpoint rate was mainly attributable to reduced incidences of angina pectoris (22 vs 44; HR 0.51,95% CI 0.31-0.86, p=0.01), stroke/TIA (25 vs 46; HR 0.55, 95% CI 0.34-0.89, p<0.05).
* Differences in acute myocardial infarction (7 vs 11), heart failure (12 vs 26), arterio-sclerosis obliterance (11 vs 12), and aortic dissection (3 vs 5) were not significant. In addition, rates of all-cause mortality (22 in valsartan arm vs 32 in non-ARB arm) and cardiovascular mortality (8 vs 13) were not significant.
* Blood pressure at baseline was 157/88 mmHg in the both groups. Mean blood pressure during the treatment period was 133.1/76.1 mmHg in the valsartan add-on arm and 133.3/76.0 mmHg in the non-ARB arm.
Says principal investigator Professor Hiroaki Matsubara:
“The KYOTO HEART Study was first designed to evaluate whether the addition of valsartan to conventional antihypertensive treatment to improve blood pressure control influences the cardiovascular outcome in Japanese high-risk hypertensive patients. The study showed that valsartan has the additional benefits of cardiovascular event prevention for hypertensive patients in East Asia with metabolic syndrome or high-risks.”
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