Metaanalysis on Dipyridamole for Preventing Recurrent Ischaemic Stroke and Other Vascular Events

BACKGROUND AND PURPOSE

Results from 7 randomised controlled trials and 1 controlled clinical study of dipyridamole, given with or without aspirin, for secondary prevention after ischaemic stroke or transient ischaemic attack (TIA) have given conflicting results. The authors performed a meta-analysis using invididual patient data from relevant randomised controlled trials.

METHODS

Randomised controlled trials involving dipyridamole in patients with previous ischaemic stroke or TIA were sought from searches of the Cochrane Library, other eletronic databases, reference lists, earlier reviews, and contact with the manufacturer of dipyridamole. Individual patient data were merged from 5 of 7 relevant trials involving 11459 patients. Results were adjusted for age, gender, qualifying event, and history of previous hypertension.

RESULTS

When assessed using a multivariate intention-to-treat analysis adjusting for age, gender, and qualifying event, patients receiving dipyridamole had a 18% lower risk of stroke than those randomised to control (P = 0.046). Similarly, those taking the combination of aspirin and dipyridamole had 22, 26, and 39% lower risks of stroke as compared with those receiving aspirin alone, dipyriamole alone, or control, respectively.

Relationship Between Treatment and Risk of Stroke Recurrence, Myocardinal Infarcton, Death, and Vascular Events

		Odds Ratio (95% CI)
	Events	D/C	AD/C	AD/A	AD/D
Subjects		4,913	6946	6123	5341
Stroke, all	1187	0.82 (0.68, 1.00)	0.61 (0.51, 0.71)	0.78 (0.65, 0.93)	0.74 (0.60, 0.90)
Stroke, non-fatal	803	0.75 (0.59, 0.94)	0.59 (0.49, 0.72)	0.73 (0.59, 0.90)	0.80 (0.63, 1.02)
Myocardinal infarction, all	245	0.97 (0.66, 1.42)	0.67 (0.48, 0.95)	0.95 (0.66, 1.37)	0.70 (0.47, 1.04)
Vascular death	614	1.08 (0.82, 1.42)	0.91 (0.73, 1.12)	1.02 (0.81, 1.29)	0.84 (0.64, 1.10)
Vascular event	1657	0.86 (0.83, 1.03)	0.66 (0.57, 0.75)	0.84 (0.72, 0.97)	0.76 (0.64, 0.90)
Relationship between treatment group and outcome adjusted for age, gender, and qualifying event. The composite outcome of vascular event consists of nonfatal stroke, nonfatal myocardinal infarction, and vascular death. Odds ratio (OR) and 95% confidence intervals (95% CI) less than unity indicate a reduced risk in the event in the patients receiving the first specified treatment group in the table. Bold figures indicate a significant result (P<0.05). A indicates aspirin; D, dipyridamole; C, placebo/control

In the analysis of subgroups and sources of heterogeneity, the effect of dipyridamole in reducing stroke was independent of prognostic factors. Recurrent stroke was reduced by dipyridamole as compared with control (OR, 0.82; 95% CI, 0.68 to 1.00), and by combined aspirin and dipyridamole versus aspirin alone (OR 0.78; 95% CI, 0.65 to 0.93), dipyridamole alone (OR, 0.74; 95% CI, 0.60 to 0.90), or control (OR, 0.61; 95% CI, 0.51 to 0.71). The point estimates obtained for the comparisons of aspirin and dipyridamole versus control (OR, 0.63; significant) or versus aspirin (OR, 0.88; nonsignificant) were similar if the data from the largest trial, ESPS 2 (which provided 57% of data), were excluded. Similar findings were observed for nonfatal stroke.

Unadjusted Comparison of Dipyridamole versus Control/Placebo on Stroke

The combination of aspirin and dipyridamole also significantly reduced the composite outcome of nonfatal stroke, nonfatal myocardinal infarction, and vascular death as compared with aspirin alone (OR, 0.84; 95% CI, 0.72 to 0.97), dipyridamole alone (OR, 0.76; 95% CI, 0.64 to 0.90), or control (OR, 0.66; 95% CI, 0.57 to 0.75). Vascular death was not altered in any group.

Unadjusted Comparison of Combined Aspirin and Dipyridamole versus Aspirin on Stroke

Sensitivity Analysis

The crude odds reductions seen for stroke were broadly similar in each risk group and not different from the overall OR.

No. of Risk Factors	0	1	2	3	All
Subjects	1094	4016	2941	2496	10,547
Risk of stroke in control group (%)	5.8	8.8	13.3	17.6	12.1
Dipyridamole vs control	1.96 (0.70, 5.53)	0.62 (0.37, 1.06)	0.94 (0.71, 1.25)	0.77 (0.56, 1.05)	0.82 (0.68, 1.00)
Aspirin + dipyridamole vs aspirin)	0.57 (0.28, 1.14	0.87 (0.59, 1.27)	0.85 (0.65, 1.12)	0.60 (0.43, 0.83)	0.78 (0.65, 0.93)
Odds ratio (95% CI) for stroke stratified by number of risk factors (0-3) comprising age 65 years and older, stroke as a qualifying event, and a previous history of hypertension. * Over ≈ 27 months.

Dropouts and Adverse Events in Patients Randomised to Dipyridamole-Based Therapy and Aspirin-Based Therapy

Patients were more likely to drop-out of trials or have a significant headache develop if they received dipyridamole (with or without aspirin) as compared with aspirin alone or control. In contrast, bleeding rates were highest with aspirin therapy (with or without dipyridamole).

	C	D	A	AD	χ2 and P
Dropouts	1094	2941	4016	2496	10,547
Headache*	5.8	8.8	13.3	17.6	12.1
Bleeding, any*	1.96 (0.70, 5.53)	0.62 (0.37, 1.06)	0.94 (0.71, 1.25)	0.77 (0.56, 1.05)	0.82 (0.68, 1.00)
*ESPS, ESPS II No (%) given, comparison by χ� test. A indicates aspirin; D, dispyridamole; C, placebo/control.

CONCLUSIONS
Dipyridamole, given alone or with aspirin, reduces stroke recurrence in patients with previous ischaemic cerebrovascular disease. The combination of aspirin and dipyridamole also reduces the composite of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone.

PubMed Abstract

Reference:
Leonardi-Bee et al. Stroke 2005; 36 (1): 162-168.