PRoFESS® results announced at XVII European Stroke Conference

Ingelheim/Germany, 14 May 2008 - The World Health Organization estimates that 5.7 million people die from stroke each year.¹ Among people aged 45–64 who have had an ischaemic stroke, 8-12 percent will die within 30 days.² Of those who survived a first stroke, the cumulative risk of a recurrent stroke is 7.7 percent at one year, increasing to 18.3 percent at five years.³

Results from the largest-ever recurrent stroke prevention trial, PRoFESS® (Prevention Regimen For Effectively avoiding Second Strokes), were presented today at the XVII European Stroke Conference (ESC) in Nice, France. PRoFESS® is a double-blind, placebo-controlled clinical trial performed at 695 sites in 35 countries, with 20,332 patients randomised to receive Aggrenox® (extended-release dipyridamole (200 mg) plus ASA* (25mg) given twice daily) or clopidogrel (75mg) once daily, and simultaneous randomisation to 80mg Micardis® (telmisartan) or placebo.⁴

“Given the high prevalence of stroke and recurrent stroke in aging societies, physicians need a range of treatment options so they can offer patients a regimen tailored to their individual needs. Landmark trials like PRoFESS® help clinicians make evidence-based treatment choices and ensure that patients receive optimal therapy for their condition,” said Professor Hans-Christoph Diener, MD, University of Essen, Germany, one of the three principal investigators of the study.

“In this trial, recurrent stroke was the most frequent outcome among stroke survivors. With PRoFESS®, the scientific community has gained valuable information comparing different therapeutic options, which will enable doctors to make informed decisions to ensure their patients receive individualized treatment for preventing post-stroke vascular events,” added Professor Ralph L. Sacco, MD, MS, Department of Neurology, University of Miami, Miami, Florida, U.S.A., also one of the principal investigators of the study.

The full congress press releases published today by the XVII European Stroke Conference in Nice, France are quoted here:

Comparison of a fixed-dose combination of extended-release dipyridamole plus aspirin with clopidogrel for secondary stroke prevention: Results from the PRoFESS® trial
Results from the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS®) trial, presented at the 17th European Stroke Conference in Nice, demonstrate that the risks of recurrent stroke or the composite risk of stroke, myocardial infarction or vascular death are similar with either extended-release dipyridamole (ER-DP) plus aspirin or clopidogrel in 20,332 patients with non-cardioembolic ischaemic stroke.¹ The combination of dipyridamole plus aspirin had shown superiority over aspirin monotherapy in secondary stroke prevention in two independent trials (ESPS2, ESPRIT).^2,3
The primary outcome was first recurrent stroke with a pre-specified non-inferiority margin. Across an average observation time of 2.5 years the rates of first recurrent stroke were similar for the two treatments (9.0% ER-DP plus aspirin, 8.8% clopidogrel; hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.11). Among those with recurrent strokes, there were 25 fewer patients with recurrent ischaemic strokes with ER-DP plus aspirin compared to clopidogrel (7.7% vs 7.9%), but 38 more patients with haemorrhagic strokes with ER-DP plus aspirin compared to clopidogrel (0.8% vs 0.4%). Rates for the main secondary outcome of stroke, myocardial infarction or vascular death were similar (13.1% ER-DP plus aspirin, 13.1% clopidogrel; HR 0.99, 95% CI 0.92-1.07, p=0.83). Although the event rates for both the primary and secondary outcomes were nearly identical with the two antiplatelet regimens, the trial failed to meet the non-inferiority criteria.
Major haemorrhagic events and intracranial bleeds were observed more frequently in the ER-DP plus aspirin group compared with clopidogrel (major haemorrhagic events: 4.1% vs 3.6%; HR 1.15, 95% CI 1.00-1.32, p=0.06). The benefit-risk ratio expressed as the combination of recurrent stroke and major haemorrhage was not significantly different between ER-DP plus aspirin and clopidogrel (11.7% ER-DP plus aspirin, 11.4% clopidogrel; HR 1.03, 95% CI 0.95-1.11, p=0.50). Also the distribution of the functional outcome measured by modified Rankin scale 3 months post-stroke was similar. Drop outs due to headache were more frequent with ER-DP plus aspirin than with clopidogrel and much less frequent than in earlier trials (ESPS2, ESPRIT).^2,3
Stroke is the third leading cause of death in developed countries after coronary heart disease and cancer.⁴ Patients who survive a first stroke are at a high risk of a first recurrent stroke.⁵ PRoFESS® is the first trial to directly compare the efficacy and safety of the two antiplatelet agents, ER-DP plus aspirin and clopidogrel, in the prevention of recurrent stroke after non-cardioembolic ischaemic stroke.
PRoFESS® is the largest secondary stroke prevention trial to date including 20,332 patients with recent ischaemic stroke, from 695 centres in 35 countries, randomised to receive ER-DP (200 mg) plus aspirin (25 mg) given twice daily or clopidogrel (75 mg) once daily and simultaneous randomisation to telmisartan (80 mg/day) or placebo.⁶
References:
1.Sacco R et al. European Stroke Conference, Nice, France, 14 May 2008.
2.Diener HC, Cuhna L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. (planned timing ranged from 1.5 to 4 years).
3.The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665-1673.
4.World Health Organization. WHO Atlas of Heart Disease and Stroke 2004. http://www.who.int/cardiovascular_diseases/en/cvd_atlas_16_death_from_stroke.pdf
5.Hardie K et al.. Ten-year risk of first recurrent stroke and disability after first-ever stroke in Perth Community Stroke Study. Stroke 2004;35:731–735
6.Diener HC, Sacco R, Yusuf S, et al. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens and telmisartan vs. placebo in patients with strokes: the prevention regimen for effectively avoiding second strokes (PRoFESS) trial. Cerebrovasc Dis 2007;23:368-380.

Early initiation of blood pressure lowering with telmisartan after a stroke: Results from the PRoFESS® trial
Elevated blood pressure is the most important modifiable risk factor for stroke and recurrent stroke. Initiation of blood pressure lowering with telmisartan after a stroke, with a relatively short duration of therapy of 2.5 years, does not significantly lower the rate of stroke or other major vascular events compared to placebo, according to results from the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS®) trial, presented at the 17th European Stroke Conference in Nice.1 The PRoFESS® trial is the largest secondary stroke prevention trial to date.2 A total of 20,332 patients with a recent non-cardioembolic ischaemic stroke were randomised to receive telmisartan (80 mg/day) or placebo for a mean duration of 2.5 years, and in a simultaneous randomisation to extended-release dipyridamole (200 mg) plus aspirin (25 mg), given twice daily, or clopidogrel.²
There was no significant difference in the number of patients with stroke in the telmisartan group compared to the placebo group (8.7% vs. 9.2%, respectively; hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.86-1.04, p=0.23).
There was no significant reduction in two secondary outcomes 1.) Major vascular events (cardiovascular death, myocardial infarction, stroke and new or worsening heart failure) with telmisartan compared to placebo (13.5% vs. 14.4%, respectively; HR 0.94, 95% CI 0.87-1.01, p=0.11) or 2.) Rate of new diabetes mellitus (125 in the telmisartan group and 151 in the placebo group; HR 0.82, 95% CI 0.65 to 1.04, p=0.10).
Exploratory analyses suggested that there was no difference in the rates of recurrent stroke or major vascular event in the first 6 months of the trial (number of strokes: telmisartan 3.4% vs. placebo 3.2%; HR 1.07, 95% CI 0.92-1.25, p=0.38; major vascular events: telmisartan 4.7% vs. placebo 4.3%; HR 1.10, 95% CI 0.97-1.26, p=0.14). However, beyond 6 months the number of events were lower in the telmisartan group (number of strokes: telmisartan 5.3% vs. placebo 6.0%; HR 0.88, 95% CI 0.78-0.99, p=0.029; major vascular events: telmisartan 8.8% vs. placebo 10.1%; HR 0.87, CI 0.80-0.95, p=0.0029).
“The trial indicates that a modest blood pressure lowering of a mean of only 3.5 mmHg early after a stroke, with treatment given for about 2.5 years may be of insufficient intensity and duration to reliably evaluate whether blood pressure lowering is of clinical value in post stroke patients” said Professor Salim Yusuf, one of the three Principal Investigators of the study. “We need trials with larger blood pressure reductions and longer durations to test the hypothesis” stated Professor Hans-Christoph Diener. “The question of whether blood pressure lowering in those with moderate elevations of blood pressure and previous stroke is of great public health importance and should be further explored in future trials” said Professor Ralph Sacco.
References:
1.Yusuf S, et al. European Stroke Conference, Nice, France, 14 May 2008.
2.Diener HC, Sacco R, Yusuf S, for the Steering Committee and PRoFESS Study Group. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis 2007;23:368–380.

Functional outcome and cognitive function: Results from the PRoFESS® trial
Results from the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS®) trial, presented at the 17th European Stroke Conference in Nice, show that the functional outcome of recurrent stroke is similar in patients who receive extended-release dipyridamole (ER-DP) plus aspirin compared with clopidogrel, or telmisartan compared with placebo.¹ There is also no difference between these treatment groups for cognitive function in patients with recurrent stroke.¹
PRoFESS® is the largest secondary stroke prevention trial to date. Patients were randomised to receive ER-DP (200 mg) plus aspirin (25 mg) given twice daily or clopidogrel (75 mg) once daily, and telmisartan (80 mg once daily) compared with placebo, using a 2 x 2 factorial study design.² Of the 20,332 patients randomised to treatment 1814 patients suffered a recurrent stroke.
The neuroprotective properties of the antiplatelet agents (aspirin, dipyridamole plus aspirin) have been observed in animal stroke models.^3,4 Similar findings have been observed with angiotensin-1 receptor blockers, such as telmisartan.5 Functional outcome after a recurrent stroke was evaluated using the modified Rankin scale and the Barthel index 3 months after the stroke. There was no difference in functional outcome in patients with recurrent stroke who received ER-DP plus aspirin compared with clopidogrel. Also there was no difference in outcome in patients treated with telmisartan compared with placebo. Similar results were observed with the Barthel Index for all the treatment groups.
No difference was observed among the treatment groups with respect to the proportion of patients who were cognitively impaired (Mini Mental State Examination ≤24). Overall, approximately 18%, 14%, and 15% were cognitively impaired at 1 month, 2 years, and at the penultimate visit, respectively.
PRoFESS® is the largest trial to date to investigate the neuroprotective properties of these agents in recurrent stroke. As functional impairment was similar across all the treatment groups, we conclude that results from animal stroke experiments cannot be extrapolated to human stroke. Telmisartan had no effect on cognitive function. The mean observation time of 2.5 years might have been too short to show effects on cognitive performance.
References:
1. Diener HC, et al. European Stroke Conference, Nice, France, 14 May 2008.
2. Diener HC, Sacco R, Yusuf S for the Steering Committee and PRoFESS Study Group. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis 2007;23:368–380.
3. Zheng Z Schwab S, Grau A, Berger C. Neuroprotection by early and delayed treatment of acute stroke with high dose aspirin. Brain Res 2007;1186:275–280.
4. Aldandashi S, Noor R, Wang CX, Uddin G, Shuaib A. Combination treatment with dipyridamole, aspirin, and tPA in an embolic model of stroke in rats. Exp Neurol 2007;205:563–568.
5. Thöne-Reineke C, Zimmerman M, Neumann C, Krikov M, Li J, Gerova N, Unger T. Are angiotensin receptor blockers neuroprotective? Curr Hypertens Rep 2004;6:257–266.

PRoFESS Steering Committee Co-Chairs on behalf of the PRoFESS Study Group:
Professor Hans-Christoph Diener, MD, Department of Neurology, University of Essen, Essen, Germany.
Professor Ralph L. Sacco, MD, MS, Department of Neurology, University of Miami, Miami, Florida, USA.
Professor Salim Yusuf, MD, DPil, FRCPC, Population Health Research Institute, McMaster University, Ontario, Canada.

Please be advised
This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the U.S.A.

Notes to Editor:
* ASA = acetylsalicylic acid (Aspirin®)

Modified Rankin Scale
The Modified Rankin Scale is a numerical functional assessment scale used to rank levels of disability after stroke. Patients receive a score between 0 and 6, where 0 represents no symptoms at all and higher scores represent increasingly severe disability.⁵

Barthels Index
The Barthels Index measures the extent to which the stroke has led to disabilities affecting the patient’s everyday activities.

About ESPRIT
The ESPRIT trial compared a combination of ASA and dipyridamole with ASA alone. The majority of patients on the combination received a free combination of ASA and extended-release dipyridamole (200mg twice daily); 8 percent of the patients received the fixed-dose combination (200mg extended-release dipyridamole plus 25 mg ASA twice daily, as marketed as Aggrenox® and Asasantin® Retard). Free ASA dosages varied from 30 to 325mg/day.⁶

About ESPS-2
In the ESPS-2 study it was shown that the combination of low dose aspirin plus extended-release dipyridamole (marketed as Aggrenox® and Asasantin Retard®) reduced the risk of recurrent stroke by 37 precent compared to placebo. Stroke risk was reduced by 18.1% in the aspirin-alone group.⁷

About Aggrenox®
Aggrenox® (marketed as Aggrenox® and as Asasantin® Retard) is an antiplatelet agent that combines extended release dipyridamole and ASA. A product of Boehringer Ingelheim`s research and development, it is indicated for the prevention of recurrent stroke and transient ischaemic attack (TIA).⁸

About PRoFESS®
PRoFESS® (Prevention Regimen For Effectively avoiding Second Strokes) is a double-blind, placebo-controlled clinical trial1, and included 20,332 patients from 695 sites in 35 countries, randomised to receive extended-release dipyridamole (200 mg) plus aspirin (25 mg) given twice daily or clopidogrel (75 mg) once daily and simultaneous randomisation to telmisartan (60 mg) or placebo. Trial duration was approximately 4.5 years.

PRoFESS® is a collaborative effort between academia and the sponsor Boehringer Ingelheim. Co-funders of the telmisartan arm of the study in selected countries are Bayer Schering Pharma and GSK.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 135 affiliates in 47 countries and 39,800 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2007, Boehringer Ingelheim posted net sales of 10.9 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development.