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What is the role of dipyridamole in long-term secondary appear to affect blood pressure.2

prevention after an ischemic stroke or transient ischemic Evidence from randomized
attack? trials
focus on the evidence for use of dipyri-

F or over a decade there has been
clear evidence for the benefits
of antiplatelet treatment in the
prevention of stroke, myocardial in-
farction and death in patients at high
damole, either alone or in combination
with ASA, as alternatives to ASA alone
for the secondary prevention after an
ischemic stroke or TIA.
The most recent systematic review by
the Antithrombotic Trialists’ (ATT) Col-
laboration1 of randomized trials of anti-
platelet treatments for the prevention of
death, myocardial infarction and stroke
risk of serious vascular events, includ- Mechanisms of action in high-risk patients included all data
ing people with a history of ischemic that were available by September 1997.
stroke or transient ischemic attack ASA exerts its antiplatelet effect by ir- Although almost a decade has since
(TIA), with treatment-related reduc- reversibly inhibiting the enzyme cyclo- passed and more antiplatelet trials have
tions of about 20%–25% in the relative oxygenase. This causes decreased emerged, no further randomized trials
risk of serious vascular events.1 Most production of the platelet agonist have been completed comparing dipyri-
of the randomized evidence relates to thromboxane A 2. damole (either alone or in combination
ASA, the most widely available and Dipyridamole is a pyrimidopyridine with ASA) against ASA alone. The
cheapest of all the antiplatelet drugs.1 derivative with antiplatelet and vaso- ATT’s meta-analysis of direct random-
Randomized trials comparing the dilator properties. Its mechanism of ac- ized comparisons between dipyrida-
beneficial effects and hazards of differ- tion on platelets remains a subject of mole alone and ASA alone in high-risk
ent ASA doses have shown that daily controversy. Several possible antiplate- patients found no significant difference
doses of 75–150 mg are as effective as let actions have been observed in vitro, in effect on serious vascular events, in-
higher doses and are associated with including inhibition of platelet phos- cluding stroke, myocardial infarction or
fewer adverse effects. Data on ASA phodiesterase, direct stimulation of vascular death (odds ratio [OR] 1.02,
doses under 75 mg/d are still limited. prostacyclin release from endothelial 95% confidence interval [CI] 0.85–
Direct and indirect comparisons of the cells and inhibition of adenosine uptake 1.21).1 Since the largest body of evi-
benefits of different doses have not by platelets. All of these putative mech- dence for the use of any single anti-
shown clear differences, but the data anisms result in an increase in intra- platelet drug is that for ASA, and the
are insufficient to conclude that those platelet adenosine 3',5'-cyclic mono- wide confidence interval includes the
under 75 mg/d are definitely as effec- phosphate (cyclic AMP), which inhibits possibility that dipyridamole is less ef-
tive as dosages of 75 mg/d or more.1 the mobilization of free calcium, cen- fective than ASA, this implies that dipyr-
An ASA dose of 75–150 mg/d is there- tral to platelet activation. Although di- idamole alone should not generally be
fore generally seen as the standard pyridamole is widely accepted to be an considered as an alternative to ASA.
against which other antiplatelet regi- antiplatelet drug, none of these actions Dipyridamole plus ASA was com-
mens should be compared. has been demonstrated in vivo at the pared with ASA alone in 25 trials in the
The past decade has also seen the doses of dipyridamole used in clinical ATT overview; overall (Fig. 1), the com-
emergence of several large trials com- practice. bination produced a nonsignificant
paring alternative antiplatelet regimens Dipyridamole is also a vasodilator, reduction in serious vascular events (OR
with ASA. These trials have adopted 2 and its coronary dilating effect is the 0.94, 95% CI 0.83–1.06). When the sep-
strategies: comparing another anti- reason for its use in diagnostic stress arate components of the composite out-
platelet drug with ASA, or comparing echocardiography and thallium imag- come were assessed, the combination
ASA plus a different antiplatelet drug ing. During rapid intravenous adminis- appeared to be particularly effective in
with ASA alone. Alternatives to ASA tration in these procedures it tends to reducing nonfatal stroke (OR 0.76,
that have now been directly compared cause blood pressure to drop, but in a 95% CI 0.62–0.92), but not nonfatal
with ASA for long-term secondary pre- randomized comparison of ASA versus myocardial infarction (OR 1.13, 95% CI

vention in randomized trials involving ASA plus 400 mg of dipyridamole 0.89–1.44) or vascular death (OR 1.03,
several thousand high-risk patients in- orally (given daily to about 600 patients 95% CI 0.76–1.46; Fig. 1).
clude dipyridamole alone or in combi- with recent cerebral ischemia of arterial The nonfatal stroke result was de-
nation with ASA, ticlopidine alone, origin, who were followed for an aver- rived mainly from one large study, the
clopidogrel alone or in combination age of 15 months), the long-term oral second European Stroke Prevention
with ASA, and triflusal. In this article I administration of dipyridamole did not Study (ESPS-2),3 in which about 3000

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© 2005 CMA Media Inc. or its licensors

patients with a previous ischemic duce the risk of recurrent stroke and mole is, however, associated with other
stroke or TIA were randomly allocated vascular events in patients with a prior adverse effects, diarrhea and headache
to groups given ASA (50 mg) daily ischemic stroke or TIA, in my view this in particular. In the largest randomized
either with modified-release dipyrida- remains uncertain. trial assessing the combination of
mole (400 mg) or alone. 3 The other The nonsignificant trend toward an dipyridamole plus ASA versus ASA
studies found no difference in nonfatal increased risk of nonfatal myocardial alone,3 more premature cessations of
stroke outcomes between the com- infarction with the combination of di- study treatment occurred owing to ad-
bined drugs and ASA alone. 1,3 The pyridamole and ASA (compared with verse effects with the combination
favourable results for stroke from the ASA alone; see Fig. 1) has made some (262/1650 = 15.9%) than with ASA
ESPS-2 trial could be explained by clinicians anxious about using the drug alone (141/1649 = 8.6%).
chance (since the number of patients combination in patients with ischemic
and relevant outcome events was rela- stroke and TIA who also have a history What should clinicians do?
tively small), the dose of ASA used of ischemic heart disease and may be at
(since 50 mg might be less effective high risk of subsequent infarction. Additional evidence on the effectiveness
than 75 mg or more daily) or the partic- Some reassurance is available from an- of the combination of dipyridamole and
ular dose and preparation of dipyrida- alyses restricted to trials among pa- ASA will be available in a few years,
mole used. Analyses that included only tients with ischemic stroke or TIA, and from the ongoing European–Australian
trials with ischemic stroke and TIA pa- from a post hoc subgroup analysis of Stroke Prevention in Reversible Ischae-
tients, or that considered only the patients with prior ischemic heart dis- mia Trial (ESPRIT), in which some
ESPS-2 trial (the only study to use the ease in the ESPS-2 trial: in neither case 3000 patients with a prior ischemic
modified-release preparation of dipyri- did the combination increase the risk stroke or TIA are being randomly as-
damole), suggest that the combination of myocardial infarction over that of signed to receive ASA alone or in com-
reduces vascular events compared with ASA alone.4,5 bination with dipyridamole (400 mg)
ASA alone,3,4 but since these results are daily (see
also dominated by the stroke outcomes Adverse effects /TrialDetail.aspx?tid=16). Until then,
in the ESPS-2 study, they are also sub- recommendations for the routine use,
ject to the possible effects of chance The ATT overview found no evidence after an ischemic stroke or TIA, of mod-
and the very low dose of ASA. So, al- that the combination of ASA and dipyr- ified-release dipyridamole plus ASA
though the addition of modified- idamole caused major hemorrhage any rather than ASA alone (75–150 mg/d)
release dipyridamole to ASA may re- more than did ASA alone.1 Dipyrida- (e.g., as per the guidelines at www.nice from
the United Kingdom’s National Insti-
No. of No. of dipyridamole, ASA, tute for Health and Clinical Excellence)
Outcome trials patients % % Odds ratio (95% CI) seem to me to go beyond what is justi-
fied by the current evidence.
Vascular Some stroke physicians may favour
events 25 10 404 11.8 12.5 0.94 (0.83–1.06) adding modified-release dipyridamole
to ASA if the patient experiences an is-
chemic cerebrovascular event while al-
infarction 21 9 353 3.2 2.9 1.13 (0.89–1.44) ready taking ASA, on the basis that
these patients are likely to be at particu-
Nonfatal larly high risk and it seems more rea-
stroke 20 8 851 4.1 5.4 0.76 (0.62–0.92) sonable to do something than nothing.
In my view, this reaction is rarely justi-
fied. No randomized trial addressing
death 25 10 404 5.5 5.4 1.03 (0.87–1.22) this specific issue has been completed,
and the effect of adding another med-
ication of uncertain additional benefit
0 0.5 1 1.5 2
may simply be to reduce compliance
ASA + dipyridamole better ASA better with those already prescribed.
It is far more important to ensure
that the diagnosis is really correct and,
if so, that such patients really are taking
Fig. 1: Meta-analysis of randomized trials of dipyridamole in combination with ASA versus
daily ASA (or an oral anticoagulant, if
ASA alone in high-risk patients, using data from the Antithrombotic Trialists’ Collaboration1
for the effects on vascular events, combined and separately. Odds ratios are shown as
atrial fibrillation is present and there
squares of a size proportional to the inverse variance of the odds ratio for that outcome; the are no contraindications), along with
95% confidence interval (CI) for each vascular outcome is indicated by a horizontal bar. an appropriate dose of a statin and ade-
quate blood-pressure–lowering treat-

CMAJ • October 25, 2005 • 173(9) | 1025

ment; that they have made appropriate
modifications to their lifestyle (espe- with modified-release dipyridamole or clopidog- Collaboration steering committee and was previ-
rel. Despite the joint support of the United King- ously assistant coordinator of the collaboration.
cially cessation of smoking); and, if ap- dom Medical Research Council, the US Depart- I am a recently signed-up member of the No
propriate, that they undergo an ade- ment of Veterans Affairs and the Canadian Institute Free Lunch movement (
quate and timely assessment of their of Health Research, further funding was required.
Boehringer Ingelheim initially showed substantial
suitability for carotid endarterectomy. interest; however, it became clear that the company
was only willing to help fund the trial if we made REFERENCES
Cathie Sudlow important modifications to the protocol, including
1. Antithrombotic Trialists’ Collaboration. Collabor-
Clinical Senior Lecturer and Honorary abandoning the ASA-only arm. The planning com- ative meta-analysis of randomised trials of anti-
Consultant Neurologist mittee held to the opinion that any industrial spon- platelet therapy for the prevention of death myo-
sor should have no influence over the trial’s design cardial infarction, and stroke in high risk patients.
Division of Clinical Neurosciences or conduct, and the trial did not go ahead. BMJ 2002;324:71-86.
University of Edinburgh I was involved in producing the technology 2. EL De Schryver for the ESPRIT study group. Dipyri-
Western General Hospital assessment report commissioned by the Health damole in stroke prevention: effect of dipyrida-
Technology Assessment Programme on behalf of mole on blood pressure. Stroke 2003;4:2339-42.
Edinburgh, Scotland 3. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P,
the National Institute for Health and Clinical
Lowenthal A. European secondary prevention study.
Exellence (an independent organization provid- 2. Dipyridamole and acetylsalicylic acid in the second-
ing guidance to the National Health Service in ary prevention of stroke. J Neurol Sci 1996;143:1-13.
England and Wales) on the clinical and cost- 4. Leonardi-Bee J, Bath PM, Bousser MG, Davalos A,
This article has been peer reviewed. effectiveness of clopidogrel and modified-release Diener HC, Guiraud-Chaumeil B, et al. Dipyrida-
dipyridamole in the secondary prevention of oc- mole for preventing recurrent ischemic stroke and
Competing interests: A few years ago, I was a clusive vascular events. other vascular events: a meta-analysis of individual
member of the planning committee for a proposed In 1998 I received fees from Sanofi for speak- patient data from randomized controlled trials [re-
view]. Stroke 2005;36:162-8.
large, international, multicentre, randomized trial ing on the Antithrombotic Trialists’ Collabora-
5. Diener HC, Darius H, Bertrand-Hardy JM, Humph-
involving patients with a previous ischemic stroke tion results at an educational meeting for general reys M, for the European Stroke Prevention Study
or transient ischemic attack. The aim was to practitioners. 2. Cardiac safety in the European Stroke Prevention
compare ASA alone with ASA in combination I am a member of the Antithrombotic Trialists’ Study 2 (ESPS2). Int J Clin Pract 2001;55:162-3.

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