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Two Secondary Stroke Prevention Treatments Head to Head: safety and efficacy

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In 1997, the largest study on stroke incidence to date estimated that Australians were experiencing 40,000 – 48,000 strokes per year1; 72.5% of which were ischaemic.2 Eleven years on, in the midst of an obesity epidemic and a larger aging population, the estimate has raised to 60,000 strokes per year.3 This estimate includes the incidence of recurrent stroke which is the most common cardiovascular event to occur in stroke patients4, approximately 12,000 per year.1 Preventing the occurrence of a secondary stroke is therefore an essential component of treatment for all stroke victims, highlighting the necessity to determine the most efficacious and safe treatment options.

In approximately one-third of stroke patients aspirin is used as the primary therapy for secondary stroke prevention yet aspirin treatment is only found to be modestly effective.5 Studies have shown that using more potent antiplatelet inhibitors in concurrence with aspirin are substantially more effective in stroke prevention.6

Professor Graeme Hankey, Consult Neurologist and Head of Stroke unit at Royal Perth Hospital, said stroke patients would be “significantly less likely to suffer a subsequent TIA or stroke if they were treated with newer antiplatelet therapies.”

These new antiplatelet therapies include clopidogrel (Plavix or Iscover) and extended release (ER)-dipyridamole (Persantin) co-treated with aspirin. In Australia there is currently a pre-combined ER-dipyridamole and aspirin pharmaceutical on the market, Asasantin SR.7

The Prevention Regime for Effectively Avoiding Second Strokes (PRoFESS) aimed to determine the most effective treatment in preventing secondary stroke in patients who had recently (within 120 days) suffered from an ischaemic stroke.4 The trial concluded this year after four and a half years comparing two known effective antiplatelet treatments; clopidogrel (Plavix or Iscover), a potent non-selective platelet inhibitor and extended release (ER)-dipyridamole/aspirin (Asasantin SR) a specific platelet inhibitor.8 The results indicated that on direct comparison of clopidogrel and ER-dipyridamole co-administered with aspirin there is no significant difference in safety or efficacy between the drugs. These results present flexibility and choice in prescribing, both for physicians and patients, in terms of cost, medical scheduling and side-effect prevention.4,5

The need for this direct comparison arose after a number of trials were conducted that showed the benefit of co-treating aspirin with the more potent antiplatelet drug ER-dipyridamole. Co-treatment with aspirin and ER-dipyridamole showed significant reduction of secondary stroke compared to ER-dipyridamole alone.9 The combination of clopidogrel and aspirin compared to clopidogrel alone had not yet been conclusively investigated. Originally, therefore, PRoFESS aimed to compare clopidogrel/aspirin to ER-dipyridamole/ aspirin treatment but in 2004 a study was published that confirmed the increased likelihood of bleeding when aspirin is co-treated with clopidogrel.10 At this point in the trial the clopidogrel/ aspirin group were taken off the aspirin and continued the trial with clopidogrel alone. Still, “dipyridamole/aspirin and clopidogrel are significantly more effective than aspirin – 18 per cent and 9 per cent respectively – in the prevention of recurrent stroke and other serious vascular events” said Professor Hankey.

The major aim of the trial was to assess both drug treatments in terms of efficacy in prevention of the primary outcome; a secondary stroke. The trial also aimed to determine the efficacy of each drug in terms of occurrence of a secondary outcome; any or all of a combination of vascular events such as myocardial infarction, stroke or death. The side effect profiles of the drugs and how they compared to one another were assessed. PRoFESS also aimed to investigate the effect of blood pressure on secondary stroke and other vascular events by treating half the participants from each drug group with angiotension II receptor antagonist, telmisartan (Micardis). Any positive or negative interaction effects between telmisartan and either of the antiplatelet regimes were also assessed.4

20,332 patients from 35 different countries participated in the randomised, double-blind comparison of clopidogrel (n = 10,151) and ER-dipyridamole/aspirin (n = 10,181). From each antiplatelet drug group participants were also randomised into the telmisartan or placebo condition. The major preventative outcome that was monitored was the occurrence of a second stroke. Other vascular events such as myocardial infarction were the secondary preventative outcome monitored. The participants were followed up one week, one month, three months then six months after the start of treatment then every six months after that. The participants were monitored for the primary and secondary events as well as any minor or major hemorrhagic event.4

Covariates used in this trial were age, diabetes status, use of ACE inhibitors and the Rankin scale. Baseline characteristics that could possibly increase the chance of stroke were calculated in order to determine a stroke risk score for the participant and were matched between the groups.4

On statistical analysis of the primary preventative outcome, a second stroke, no significant difference between the two groups were found; indicating that both treatments are equally effective in stroke prevention. The two treatments cannot be classed as statistically non-inferior due to lack of power of the sample.4

The most common event that occurred in the stroke victims across both drug conditions was secondary stroke. The significant differences between the groups existed in the types of secondary stroke and the side effects associated with the treatment. Although the two groups had very similar rates of incidence of stroke the ER-dipyridamole/aspirin group had a greater proportion of strokes due to intracranial haemorrhage than the clopidogrel group which had a higher proportion of secondary ischaemic stroke.4

The ER-dipyridamole/aspirin group reported significantly higher incidence of headaches and the headaches started earlier on in the course of treatment as compared to those experienced by the clopidogrel group.4

There was no difference between the telmisartan group and placebo group in recurrence of second stroke however the telmisartan did significantly lower blood pressure in this group. There were no interaction effects of telmisartan with clopidogrel or ER-dipyridamole/ aspirin.4

Professor Hankey said “this research – the first head-to-head comparison of these drugs – confirms there are two equally effective and safe options for long-term antiplatelet therapy in the prevention of recurrent stroke.”

This study provides a valid and reliable direct comparison of two stroke prevention treatments that, due to its large scale nature, can be generalised to most situations. The major finding indicates there is no difference in risk of second stroke with ER-dipyridamole/ aspirin or clopidogrel treatment. The secondary preventative outcomes also came up as non-significant between the groups.4 This means that “prescribers will now need to choose between these two therapies (sustained release ER-dipyridamole/aspirin and clopidogrel) based on factors other than efficacy and safety, such as cost, patient preference, potential adverse events and PBS criteria” said Professor Hankey.

The side effect profile in the ER-dipyridamole/aspirin group was larger than the clopidogrel group mainly due to headache. This suggests that when assessing patients for treatment it would be wise to query their headache profile; how often and how prone to headaches they are. For patients that do experience headaches on initial Assantin-SR treatment it is suggested that they switch to one capsule at bedtime and a lower dose (75-150 mg) in the morning.11 Once their headaches have become managable it is recommended that they build up to the normal dose as soon as possible.11 It is also important to note that the use of titrated doses in combination with patient conselling in the present study reduced headache due to withdrawal compared to previous studies.3

The ER-dipyridamole/aspirin regime is substantially less expensive than clopidogrel treatment5; government subsidisation means costs are $36.76 and $84.29 respectively.12

ER-dipyridamole/aspirin has the additional inconvenience of twice daily dosing.5 Accordingly, people in the clopidogrel group showed better medication adherence (76.8%) than the ER-dipyridamole/ aspirin group (69.6%).4 This is another factor to keep in mind when prescribing for older clients who already may have a confusing medication schedule.

The lower blood pressures resulting from telmisartan treatment may have a positive long term effect on stroke prevention however this needs to be investigated over a longer period than the current study.5

Not only does this trial indicate that neither treatment is more effective in preventing second stroke but it also highlights the importance of direct comparisons between drugs. Indirectly inferring statistics from two separate trials is not reliable or valid.


  1. AIHW: Incidence and Prevalence of Chronic Diseases [online]. 2007 [cited 2008 Oct 25]. Available from: URL:
  2. Thrift A, Dewey H, Macdonell R, McNeil J, Donnan G. Incidence of the Major Stroke Subtypes: Initial Findings From the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke. 2001; 32:1732-1738.
  3. What is a Stroke? Facts Figures and Stats [online]. 2008 [cited 2008 Sept 10] Available from: URL:
  4. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release ER-dipyridamole vs clopidogrel for recurrent stroke. The New England Journal of Medicine. 2008; 359:1-14
  5. Hankey GJ. What do the results of the PRoFESS trial teach us? Published Online. 2008; DOI:10,1016/51474-4422(08)70198-4
  6. Cannon C (on behalf of the CAPRIE investigators). Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial). The American Journal of Cardiology. 2002; 90.
  7. Hervey PS, Goa KL. Extended-release ER-dipyridamole/ Aspirin. Drugs. 1999; 58(3):469-475.
  8. Jennings LK, Saucedo JF. Antiplatelet and anticoagulant agents: key differences in mechanisms of action, clinical application, and therapeutic benefit in patients with non-ST-segment-elevation acute coronary syndromes. Current opinion in cardiology. 2008; 23(4): 302-308.
  9. Müller TH, Su CAPF, Weisenberger H, et al. ER-dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. Br J Clin Pharmacol 1990; 30: 179-86.
  10. Diener HC, Bogousslavsky  J. Brass LM et al. Aspirin and clopidogrel compared to clopidogrel alone after recent ischaemic attack in high-risk patients (MATCH): rendomised, double-blind, placebo-controlled trial. Lancet. 2004; 364:331-337.
  11. Assantin SR: Product Information. Boehringer Ingelheim Pty Limited, New South Wales. 2008
  12. PBS For Consumers [online]. 2008 [cited 2008 Oct 16]. Available from: URL:
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Posted On: 26 September, 2008
Modified On: 19 March, 2014


Created by: myVMC