Dr Koon K Teo

Dr Koon K Teo (McMaster University, Hamilton, ON) reported the findings of TRANSCEND at a press conference and a hotline session here at the European Society of Cardiology Congress 2008 today, and the results were published simultaneously in the Lancet [1]. He told heartwire: "It would be nice if we had had a clear benefit, but the benefit [of telmisartan] was modest."

TRANSCEND and its much larger sibling study ONTARGET were designed as the biggest comparisons to date of ARB and ACE-inhibitor therapy in high-risk patients with controlled blood pressure, and the results were expected to contribute significantly to the future treatment of cardiovascular disease. ONTARGET, reported in March of this year, showed that telmisartan was noninferior to ramipril in terms of blood-pressure-independent cardioprotection, but now the results of TRANSCEND appear to throw a wrench in the works, leading at least one cardiologist to question whether ARBs or even ACE inhibitors have a place in cardioprotection unless there are clear indications, such as hypertension or diabetes.

Discussant of TRANSCEND Dr Karl Swedberg (Sahlgrenska University Hospital, Gothenburg, Sweden) said, "The preventive effects of telmisartan are at best modest," and he wondered "how telmisartan can be noninferior to ramipril [based on ONTARGET] but barely better than placebo." The findings, he said, "illustrate the complexity of interpreting different patient populations and trying to come up with a conclusion."

How [can] telmisartan . . . be noninferior to ramipril [based on the recent ONTARGET results] but barely better than placebo?

Accompanying the TRANSCEND paper is a Comment by Drs Toni L Ripley and Donald Harrison (University of Oklahoma College of Pharmacy, Oklahoma City) [2]. They say the failure of telmisartan to reach the primary end point in this study is "unexpected" and that there are several possible reasons for this.

First, the study was "ambitiously powered" they note. Also, it's possible that there is heterogeneity in the ARB class. More data are needed on ARBs, they conclude, and ACE inhibitors "should remain the preferred renin-active agent to prevent vascular events in patients with or at high risk for cardiovascular disease." Nevertheless, the TRANSCEND data, in addition to those from CHARM-Alternative, "support the use of an ARB in those with an intolerance to an ACE inhibitor for reasons beyond cough," they conclude.

The TRANSCEND researchers explain in their paper that the role of ARBs in primary or secondary prevention of cardiovascular disease has been unclear. While it is well established that ACE inhibitors reduce mortality, MI, stroke, and heart failure in patients with cardiovascular disease or high-risk diabetes, up to about 20% of patients—particularly women or Asians—are unable to tolerate an ACE inhibitor, mainly due to cough but also due to hypotension, renal dysfunction, or angioneurotic edema.

The CHARM-Alternative trial and a substudy of Val-HeFT showed that ARBs reduce mortality and rehospitalization for heart failure, compared with placebo, in patients intolerant to ACE inhibitors with low ejection fraction and heart failure, and the LIFE trial showed that they reduce stroke and cardiovascular morbidity compared with beta blockers in those with moderate hypertension and left ventricular hypertrophy.

"However, direct evidence of benefit of an ARB in reducing major cardiovascular events in broader high-risk populations is lacking," they note.

In TRANSCEND, 5926 patients with cardiovascular disease or high-risk diabetes without heart failure who were intolerant to ACE inhibitors were randomized to telmisartan 80 mg per day (n=2954) or placebo (n=2972) in addition to other usual therapies. Compared with similar trials, the patient population in TRANSCEND had more women, more patients with a history of stroke, and more with hypertension, Teo noted.

After a median duration of follow-up of 56 months, there was no difference in the primary composite end point of cardiovascular death, MI, stroke, or admission to the hospital for heart-failure events, which occurred in 465 (15.7%) of patients taking telmisartan and 504 (17.0%) of those on placebo (hazard ratio 0.92; p=0.216).

Those on telmisartan had, on average, a 4-mm-Hg reduction in blood pressure compared with those on placebo.

In their comment, Ripley and Harrison say that TRANSCEND was ambitiously powered to find a 19% relative risk reduction, a more robust effect size than that seen with the ACE inhibitor ramipril in HOPE, so it may be that this is the explanation for the lack of effect. But perindopril reduced cardiovascular death, MI, and cardiac arrest by 20% in EUROPA, "despite the patients being on similar [concomitant] drugs to those in TRANSCEND," they note.

"It is unclear if this result reflects a lesser effect of telmisartan or if the benefit in EUROPA was driven by a sicker population (all had coronary disease in EUROPA vs 75% in TRANSCEND).

The TRANSCEND investigators did find a difference in the prespecified composite secondary outcome of cardiovascular death, MI, and stroke, however, with 384 such events in the telmisartan group (13.0%) vs 440 (14.8%) in those on placebo (hazard ratio 0.87; p=0.048). But this difference became nonsignificant after statistical adjustments were made for multiple comparisons (p=0.068).

Teo stressed in the hotline session that there was a "remarkable and quite strong" trend toward a reduction in MI and stroke among those taking telmisartan, "but the neutral effect on heart-failure events was surprising."

Ripley and Harrison say: "The nonsignificant trend in favor of telmisartan suggests there may be a more modest but significant effect in a trial designed to detect a smaller risk reduction. At present, a statistical and clinical benefit from telmisartan cannot be ruled in or out."

They also stress that the efficacy data from TRANSCEND must not overshadow the safety information. In TRANSCEND, 377 patients had previously had severe reactions to ACE inhibitors that would, "until these data, preclude use of an ARB."

Teo said: "The remarkable tolerability of telmisartan is emphasized by the fact that fewer individuals stopped medication if they were receiving telmisartan compared with placebo." TRANSCEND demonstrates the value of telmisartan in the large proportion of people who are unable to tolerate ACE inhibitors, he added.

The TRANSCEND investigators also performed a prespecified combined analysis stratified by time with data from the PROFESS trial, which was just published August 27, 2008 in the New England Journal of Medicine; the latter also failed to show an effect of telmisartan on hospitalizations from heart failure, a finding they note was "unexpected and puzzling" given the findings with ACE inhibitors from HOPE, PEACE, and EUROPA.

However, the current findings are consistent with data from ONTARGET, they note, in which there were more hospitalizations for heart failure with telmisartan—394 (4.6%)—than with ramipril—354 (4.1%)—for a risk ratio of 1.12.

The time-stratified analysis showed no effect of telmisartan on the composite of cardiovascular death, MI, and stroke in the first six months in both trials, but there was a clear benefit after six months.

"These analyses suggest that there may be a delay of six to 12 months before the benefits of ARBs emerge and that it could take several years of treatment for the full benefits to manifest," they hypothesize.

However, they concede that the results also raise the question of "whether telmisartan is less effective than ACE inhibitors in preventing heart failure."

But other ARBs have been shown to reduce hospitalizations for heart failure, they note. "By contrast with previous trials of ARBs, our patients were not known to have left ventricular systolic dysfunction (heart failure was an exclusion factor), and few had left ventricular hypertrophy at study entry. It is possible that when the absolute risk of heart failure is low, ACE inhibitors and ARBs might not reduce the incidence of heart failure."

Ripley and Harrison say: "Overall, data supporting use of ARBs to prevent vascular events in various cardiovascular groups, other than heart failure, are incomplete. TRANSCEND's results challenge the noninferiority shown in ONTARGET and suggest no more than a modest effect, if any at all. Other evidence on ARBs is also limited.

"ARBs that have been studied in coronary disease are safe but possibly less effective alternatives in patients with intolerance to ACE inhibitors. Although data are too limited to reach definitive conclusions, the clinical effect of ARBs seems less robust than that of ACE inhibitors," they say.

The whole issue of ARBs or even ACE inhibitors in people who haven't got other indications such as hypertension or diabetes has to be brought into question.

In his discussion, Swedberg said the TRANSCEND results make it clear that ACE inhibitors should be used first-line but the question remains as to whether ARBs can be used as alternatives in those who are intolerant of ACE inhibitors.

"TRANSCEND would suggest that if the HOPE criteria apply, it seems reasonable to use telmisartan as an alternative," he noted, "but as the mechanisms are unknown behind the lack of effects on prevention of heart failure, documented ARBs—candesartan and valsartan—should be used in patients who already have heart failure."

Dr Phil Aylward (Flinders Medical Center, Adelaide, Australia) commented to heartwire: "This shows that if you have good background treatment, the ARB effect is not as good as we have seen in the earlier studies. The ACE inhibitors should be what we use first."

But he added, "The whole issue of ARBs or even ACE inhibitors in people who haven't got other indications such as hypertension or diabetes has to be brought into question."