Congress Reports

MedWire - ESC (Munich, Germany), August 31, 2008: This Hot Line Session on the second day of the European Society of Cardiology Congress 2008 featured results of the TRANSCEND (Telmisartan Randomised AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular Disease) study. TRANSCEND is the first trial to examine the cardioprotective potential of an angiotensin receptor blocker (ARB), telmisartan, in high-risk patients who are unable to tolerate standard therapy with angiotensin-converting enzyme inhibitors (ACEIs). Coinciding with today’s presentation, the full study report and an accompanying editorial were published in The Lancet.

TRANSCEND
Dr. Koon Teo, McMaster University, Hamilton, ON, Canada

ACEIs are an established treatment in patients at high risk of cardiovascular (CV) events, but these drugs cannot be tolerated by around 20% of patients. The TRANSCEND study was undertaken to evaluate whether telmisartan, one of a class of related compounds known as ARBs, would be beneficial in patients who are at high risk of CV events but who are unable to tolerate ACEI therapy.

Presenting the study on behalf of his fellow investigators, Dr. Teo said that TRANSCEND included 5926 patients who had CV disease or diabetes, and who also had end-organ damage. None had heart failure (HF). The subjects were recruited from 630 centers in 40 countries, and the study was sponsored by Boehringer Ingelheim, the manufacturers of telmisartan.

Following a 3-week, single-blind, run-in period, patients were randomized in a double-blind manner to receive telmisartan 80 mg/day or placebo and followed up for a median duration of 56 months. Dr Teo said that the study subjects were well treated at baseline, with a high proportion receiving concomitant proven therapies such as statins, antiplatelet agents, diuretics, beta-blockers and calcium channel blockers.

Over the course of the study, telmisartan therapy was associated with a significantly greater fall in blood pressure than was placebo, Dr. Teo said. The mean difference in blood pressure between treatment groups was 4.0/2.2 mm Hg at the end of follow-up. Nevertheless, the study’s primary outcome - a composite of CV death, myocardial infarction, stroke and hospitalization for HF - did not differ significantly between the telmisartan and placebo groups. After adjusting for systolic blood pressure, the hazard ratio (HR) for this composite outcome was 0.92, indicating a 8% risk reduction with telmisartan therapy, albeit a non-significant reduction (p=0.2158). “The curves begin to diverge after around 2 years,” Dr. Teo noted.

When HF hospitalization was omitted from the composite outcome, however, the result favored telmisartan, with an HR of 0.87 after adjustment for systolic blood pressure (p=0.0475 versus placebo). This was the composite outcome used in the landmark HOPE (Heart Outcomes Prevention Evaluation) study, Dr. Teo said. Furthermore, two individual components of the composite endpoint favored telmisartan over placebo - namely, rates of myocardial infarction (MI) (HR=0.79) and stroke (HR=0.83).

Importantly, telmisartan was well tolerated, with no excess of adverse events in comparison with the placebo group.

Dr. Teo also showed a meta-analysis of the two large trials involving telmisartan: PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) and TRANSCEND. Pooled data from these trials indicate that active treatment was associated with a 0.9% absolute reduction in the combined endpoint of CV death, MI, stroke, and HF hospitalization (p=0.026 versus placebo). The meta-analysis also suggested that significant benefits became apparent only after 6 or more months of treatment.

Discussion
Dr. Karl Swedberg, Sahlgrenska Hospital, Gothenberg, Sweden

The discussant for the study was Dr. Swedberg, who called TRANSCEND an “important and impressive” study despite the fact that the primary result was neutral. He said there were various interpretations of the results, including that telmisartan has at best a modest effect on the renin-angiotensin-aldosterone system and that telmisartan might be non-inferior to ramipril but little better than placebo. “Would ramipril have shown a clear benefit in this situation?” he asked. Telmisartan’s lack of benefit on the development of HF contrasts with the effect of other ARBs (e.g. candesartan and valsartan) in patients with diagnosed HF, he added.

Dr. Swedberg said that a recent editorial on the subject of stroke prevention was pertinent to the interpretation of the TRANSCEND results. Writing in the New England Journal of Medicine, Kent et al. [1] noted, “In the era of comparative effectiveness, when multiple agents are pitted against one another, randomized trials often cannot be understood in isolation. Rather, they need to be interpreted in the context of a sometimes complex network of other similar or relevant evidence. The reduction of such complex networks to treatment recommendations is not always straightforward.”

With this in mind, Dr. Swedberg summarized the clinical implications of the TRANSCEND study as follows:

• The effects of ARBs in the primary prevention of vascular disease are at best modest and take time - between 6 months and 1 year - to emerge;
• ACEIs should remain the first-line therapy for vascular protection;
• If the combined endpoint of the HOPE study is applied, it seems reasonable to use telmisartan as an alternative in ACEI-intolerant patients;
• Given that the mechanisms behind the lack of effect of telmisartan on HF prevention are unknown, documented ARBs (e.g. candesartan and valsartan) should be used in patients who already have HF.

Reference

1. Kent DM, Thaler DE. Stroke prevention - insights from incoherence. N Engl J Med 2008;DOI:10.1056/NEJMe0806806