Does the administration of telmisartan in addition to combination treatment with extended-release dipyridamole plus ASA with clopidogrel offer benefit in patients with strokes?

May 2007

Patients presenting with a transient ischemic attack or ischaemic stroke have a high risk of recurrent stroke or death. While acetylsalicylic acid (ASA) is standard therapy in these patients, recent trials demonstrate that a combination of ASA and extended-release dipyridamole (DP) or clopidogrel may be superior to ASA alone. Additionally, it was suggested that the beneficial effects of combination therapy may be increased by administration of angiotensin receptor blockers (ARBs).

To quantify these potential beneficial effects, a substudy of the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) trial will compare the combination of DP and ASA with clopidogrel for secondary stroke prevention and assess the benefits of adding telmisartan, an ARB, to the antiplatelet therapy versus placebo treatment.

"In experiments on animals, administration of ARBs decreased the size of stroke lesions’, neuroprotection, prevention of arthrosclerosis and thrombosis, and improved brain perfusion, but so far no data on its effects in humans have been assessed," Professor Hans-Christoph Diener, one of the chief investigators of PRoFESS, said at the ESC 2007 in Glasgow.

The investigators defined recurrent stroke as the primary outcome of this substudy. The most important secondary outcome is the composite of stroke and myocardial infarction or vascular death. Other secondary outcomes included composite and congestive heart failure, new-onset diabetes, other designated occlusive vascular events such as pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, transient ischaemic attack, cerebral venous thrombosis or retinal vascular accident not classified as stroke, any death, stroke subtype by TOAST criteria, and the Mini Mental State Examination score. Safety will be evaluated by assessing the risk of major haemorrhagic events.

The comparison between ASA + DP and clopidogrel will be based on an initial assessment of noninferiority, followed by evaluation of superiority. The superiority of telmisartan over placebo will be assessed in a time-to-event analysis.

Using this approach, the PRoFESS investigators plan to evaluate protection with telmisartan against end-organ damage, such as new-onset diabetes, kidney failure, new-onset atrial fibrillation and vascular dementia, beyond the usual endpoints of stroke, myocardial infarction and vascular death.

At the ESC in Glasgow 2007, Professor Diener briefly outlined two further trial programmes: ONTARGET, which will compare telmisartan with the ACE inhibitor ramipril and with the combination of these two drugs in 23,400 high risk patients, and the TRASCEND trial programme, which will compare telmisartan with placebo in patients who cannot tolerate ACE inhibitors.

These three trials, PRoFESS, ONTARGET and TRANSCEND represent the largest study programmes ever on the effects of ARBs in primary and secondary prevention of stroke. Their results are expected to provide new insights into optimum stroke prevention and treatment.