KYOTO HEART Study Not Quite Sufficient to Extend the Role of ARBs to First-Line Therapy

September 01, 2009

September 1, 2009 (Barcelona, Spain) — The addition of the angiotensin receptor blocker (ARB) valsartan (Diovan, Novartis) to therapy in high-risk hypertensive patients prevented more cardiovascular events than conventional non-ARB treatment in the KYOTO HEART study, reported here during a hotline session at the European Society of Cardiology (ESC) 2009 Congress today and published online simultaneously in the European Heart Journal by Dr Takahisa Sawada (Kyoto Prefectural University School of Medicine, Kyoto, Japan) and colleagues [1]. There was no significant difference in blood pressure between the two treatment arms, however, which indicates that this benefit of valsartan could not be entirely explained by its antihypertensive effects, the researchers note.

The 45% reduction in the primary end point was primarily driven by a reduction in stroke and in angina symptoms in the Asian study population. Senior author Dr Hiroaki Matsubara (Kyoto Prefectural University School of Medicine), who presented the findings at the meeting, told heartwire that he believes the main message of the trial is "that in high-risk hypertension patients, valsartan should now be considered a first-line drug." This message applies to Asian patients and "probably" also to Europeans and Americans, he said.

In an editorial accompanying the publication of the study [2], Drs Franz Messerli (St Luke's Roosevelt Hospital, New York, NY), Sripal Bangalore (Brigham and Women's Hospital, Boston, MA), and Frank Ruschitzka (University Hospital, Zurich, Switzerland) say: "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."

Ruschitzka, who was also the discussant for the KYOTO trial at the meeting, said these "wonderful" results "were almost too good to be true." But he noted that there was no effect of valsartan on MI in this study and therefore the "weak end point" of angina is "of minor importance, particularly on a background of no benefit on MI."

If all other studies in this field are neglected, "valsartan should be the number-one therapy out there for all patients at high cardiovascular risk," Ruschitzka said, but he noted, "There is a big brother of KYOTO, and that is VALUE. To play with words, what is the VALUE of KYOTO?" The VALUE results, he reminded the audience, are "diametrically different" from the current findings and showed an increased risk of MI associated with valsartan and even a "tendency toward increased strokes."

I would put my mother on an ACE inhibitor, but valsartan is just good enough for my mother-in-law.

He went on to discuss a meta-analysis he performed with Messerli and Bangalore, which is described in the editorial. This included the most recent ARB trials such as TRANSCEND, PROFESS, CASE-J, HIJ-CREATE, JIKEI-Heart, and KYOTO and showed a 13% reduction in stroke (p=0.022) overall but a trend toward an increased risk of MI, especially when compared with active treatment (p=0.06).

"ARBs fail consistently to prevent MIs, and that's a cautionary tale," stressed Ruschitzka. "For me, the take-home message is that ACE inhibitors and calcium-channel blockers are my number-one choice and ARBs are for those who don't tolerate ACE inhibitors. I would put my mother on an ACE inhibitor, but valsartan is just good enough for my mother-in-law."

Does the "Vascular" Nature of Valsartan Explain the Findings?

The KYOTO HEART researchers explain that cardiovascular-disease incidence in Japan differs from that in Western societies. "Coronary artery disease [CAD] mortality is one-third of that in the USA and cerebrovascular disease mortality is approximately 1.5 times higher." The trial, which was a multicenter, randomized, prospective, open blinded-end-point design, set out to examine whether adding valsartan to conventional antihypertensive treatment would influence cardiovascular events in high-risk Japanese patients with uncontrolled hypertension.

In the trial, 3031 patients with uncontrolled hypertension (systolic BP >140 mm Hg and/or diastolic >90 mm Hg) taking one to two antihypertensive drugs who had one or more risk factors for cardiovascular disease, including a history of MI or stroke, diabetes, obesity, abnormal lipid levels, LV hypertrophy, or current smoking, were randomized to add-on valsartan, titrated up to a maximum of 160 mg per day, or the non-ARB group, which was given other antihypertensives (excluding ACE inhibitors and ARBs). Any patients treated with ARBs before randomization were excluded. With regard to the maximum dose of valsartan used in the study (160 mg/day), Matsubara said this was the highest recommended daily dose in Japan; the mean dose of valsartan actually used in the trial was 88 mg/day.

The median follow-up period was just over three years, and the primary end point was a composite of new onset or recurrence of stroke (including transient ischemic attack [TIA]); new onset or recurrence of acute MI or angina, PCI, or CABG; hospitalization due to heart failure; new onset or recurrence of peripheral arterial disease or aortic dissection; or transition to dialysis or doubling of creatinine levels. Secondary end points included all-cause mortality, new-onset diabetes, and worsening of cardiac function.

The study was stopped early by the data safety and monitoring board because of the remarkable reduction in the primary end point observed. There was a highly significant reduction of the primary end point seen in the valsartan group compared with the non-ARB group (5.5% vs 10.2%; hazard ratio 0.55; p=0.00001), driven by a significant decrease in stroke (1.7% vs 3.1%; HR 0.55; p=0.015), of which less than 10% were TIAs, and angina (1.5% vs 3%, HR 0.51; p=0.011).

There was also a significant reduction in one of the secondary end points, new-onset diabetes, in the valsartan group (p=0.028). This finding was also seen in VALUE and suggests the antidiabetic action of ARBs should be considered when physicians are treating hypertensive patients at high risk of diabetes, say the Japanese doctors.

"These substantial benefits were noted despite a short median follow-up of 3.27 years and with blood-pressure–lowering effects being similar between valsartan add-on treatment and non-ARB groups," they note.

Sawada et al say there have been only three large open trials of this nature in Japanese populations: candesartan (Atacand, AstraZeneca) vs amlodipine in high-risk hypertensive patients in CASE-J, candesartan vs non-ARB therapy in hypertensive patients with CAD in HIJ-CREATE, and add-on effect of valsartan in hypertensive patients with CAD and/or heart failure in the JIKEI-Heart Study.

"Neither CASE-J nor HIJ-CREATE showed that candesartan is superior to either amlodipine-based therapy or the non-ARB therapy in reducing cardiovascular complications," whereas the JIKEI-Heart study findings are more consistent with the present findings, they note, suggesting that the result might be specific to valsartan, which they suggest could be a "vascular" ARB.

Asians May Be More Receptive to Protective Effects of ARBs

The Japanese doctors say the findings of KYOTO HEART are highly relevant to Western populations because the use of ARBs and ACE inhibitors is very high in the US and Europe compared with Japan, where calcium-channel blockers are more frequently employed.

In their editorial, however, Messerli, Bangalore, and Ruschitzka say the reason for the divergence in findings between VALUE and KYOTO could be the study population: "Asians may be particularly receptive to the protective effects of ARBs, as was shown in RENAAL, where most of the benefits occurred in the Asian subpopulation." In VALUE, less than 3.5% of participants were Asian.

Asked by heartwire to comment on KYOTO HEART, president-elect of the European Society of Cardiology, Dr Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), said: "I think that it provides incremental information on the potential benefit of ARBs for preventing some CV outcomes in hypertensive patients from Asia. All epidemiologic studies show that Asian populations are at high risk of stroke events, and I think this is probably the most relevant part of this study." But whether this benefit would translate to Western European or North American populations, who generally have a much higher risk of coronary events than stroke, "is difficult to say," he concluded.

The answer as to whether ARBs should now be considered as preferred or baseline therapy in hypertension "could be a resounding yes if efficacy were defined as blood-pressure reduction," say Messerli, Bangalore, and Ruschitzka in their editorial. "However, BP is merely a surrogate end point that correlates to some extent with the true end point--ie, heart attack, stroke, and death."

ARBs are efficacious and even superior to other drug classes in stroke prevention, but their efficacy with regard to coronary events remains uncertain, they conclude. 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."

No conflicts of interest were reported by the authors or editorialists.