After a mean follow-up of 2.5 years, a total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the control group had a subsequent stroke (Figure 1). This difference was not statistically significant (p=0.23).

However, telmisartan showed a positive trend in the reduction of stroke recurrence that was detectable at 6 months and increased over time. A positive trend also emerged after 6 months in the reduction of the two secondary outcomes, major cardiovascular events and new-onset diabetes (Figure 2). In the case of recurrent stroke and major cardiovascular events, the difference in event rates between these two time periods was significant (p=0.04 and p=0.004, respectively).

These results suggest a time-dependent effect of telmisartan treatment and support the possibility that the follow-up period was too short for this effect to reach significance.

 

Telmisartan was shown to be safe and well tolerated in stroke patients. There were no significant differences between the telmisartan group and the control group in the number of patients who died, had a major hemorrhage, had migraine the first 6 months or had headaches the first 7 days.

Significantly more patients in the telmisartan discontinued than patients in the control group. Hypotension and syncope led to study discontinuation significantly more often in the telmisartan group than in the control group.

By the end of the study, the use of diuretics, ACE inhibitors, calcium-channel blockers and beta-blockers was more frequent in the control group than in the telmisartan group.

Telmisartan treatment initiated soon after an ischemic stroke with a mean follow-up of 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events or new onset of diabetes.1 PRoFESS™ also provides further evidence that telmisartan is safe and well tolerated in stroke patients.1,2

The adherence to the telmisartan regimen was lower than in other large trials, such as ONTARGET®. Previous trials of telmisartan have shown it to have a tolerability profile indistinguishable from that of placebo.3 The lower adherence in PRoFESS™ may have been due in part to the fact that patients who had headache caused by aspirin plus extended-release dipyramidole (one of the treatments studied in the antiplatelet part of the factorial design) stopped both sets of blinded medications.

There was a higher than expected rate of events in the first 6 months of the trial, which decreased thereafter. This finding is consistent with the HOPE study of ramipril and the PROGRESS study of perindopril/indapamide, which showed significant prevention of stroke by the end of follow-up but little to no benefit in the first 6 months.4,5

After the first 6 months of treatment, a positive trend in prevention of recurrent stroke, major cardiovascular events and new onset of diabetes was evident in the telmisartan arm.1 The difference in the incidence of recurrent stroke and of major cardiovascular events in the first 6 months versus the last 2 years was significant. This suggests a potential later benefit of telmisartan that increases with time, raising the question of whether these results would have achieved significance had the study continued for a longer time. Indeed, the HOPE study and the PROGRESS study had follow-ups of 4.5 years and 4 years, respectively.4,5

More patients in the control group than in the telmisartan group received non-study blood-pressure-lowering medications (including ACE inhibitors), consistent with the protocol, which strongly emphasized blood-pressure control for all enrolled patients.1 This minimized the blood pressure difference between the telmisartan group and the control group by about one third and may have contributed to a lack of a significant reduction in events.

The ONTARGET^® results also showed a positive trend in the reduction of stroke, although the difference as compared to ramipril was not significant.6 PRoFESS™ supports these results, suggesting a potential long-term benefit of telmisartan treatment in stroke prevention.



References

1. Yusuf S, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225-37.
2. Sacco RL, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238-51.
3. Goebel M, et al. Effective treatment of hypertension by AT(1) receptor antagonism: the past and future of telmisartan. Expert Rev Cardiovasc Ther. 2006;4(5):615-29.
4. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-53.
5. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033-41.
6. The ONTARGET^® Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-59.

Telmisartan is indicated for the treatment of essential hypertension.
The sponsor of PRoFESS™ is Boehringer Ingelheim, the co-funders in selected countries are Bayer Schering Pharma and GlaxoSmithKline