P.H.A. Halkes

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (23)126.89 Total impact

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    ABSTRACT: The combination of low-dose aspirin and dipyridamole is more effective than aspirin alone in reducing the risk of recurrent stroke and other major cardiovascular events in patients with a recent transient ischemic attack or minor stroke. It is unknown whether this also applies to patients with a disabling stroke. We reanalyzed the data of 5700 patients from ESPRIT and ESPS-2 to study the effect of aspirin and dipyridamole according to modified Rankin scale (mRS) score at baseline. Primary outcome was vascular events (stroke, myocardial infarction, or vascular death). We used proportional hazards regression to estimate the treatment effect across mRS strata at baseline, and we tested for interactions with treatment. In total, 426 patients (7.5%) had mRS score of 4 or 5 at baseline. The risk of an outcome event increased with mRS score. The relative risk associated with the combination of aspirin and dipyridamole compared to aspirin alone in patients with mRS score 0 to 5 was 0.79 (95% confidence interval, 0.69-0.91). The relative risk according to mRS subcategory score 0 to 4 at baseline varied between 0.73 and 0.96 for vascular events and between 0.62 and 0.96 for stroke. The number of patients with mRS score 5 was too small for reliable estimates, but the data suggest a beneficial effect. There was no evidence of interaction between treatment effect and mRS score at baseline. The beneficial effect of the combination of low-dose aspirin and dipyridamole was present in all subcategories of the mRS score.
    Stroke 09/2010; 41(11):2684-6. · 6.16 Impact Factor
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    ABSTRACT: A considerable proportion of patients discontinue dipyridamole therapy because of headache. Risk indicators for the development of dipyridamole induced headache were identified by means of an exploratory analysis of data from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and the Second European Stroke Prevention Study (ESPS 2). In ESPRIT, dipyridamole induced headache was significantly associated with female sex, absence of hypertension and non-smoking (area under the receiver operator characteristic (ROC) curve 0.63 (95% CI 0.58 to 0.68)) and in ESPS 2 with female sex and absence of ischaemic lesions on imaging (area under the ROC curve 0.64 (95% CI 0.59 to 0.69)).
    Journal of neurology, neurosurgery, and psychiatry 05/2009; 80(4):437-9. · 4.87 Impact Factor
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    ABSTRACT: To study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischaemic attack (TIA) or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A+D. The previously published meta-analysis of individual patient data was updated with data from ESPRIT (n = 2,739); trials without data on the comparison of A+D versus ASA were excluded. Review A meta-analysis was performed using Cox regression, including several subgroup analyses and following baseline risk stratification. A total of 7612 patients (five trials) were included in the analyses, 3800 allocated to A+D and 3812 to ASA alone. The trial-adjusted hazard ratio (HR) for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval (CI) 0.72 to 0.92). HRs did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischaemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. A+D were also more effective than ASA alone in preventing recurrent stroke; HR 0.78 (95% CI 0.68 to 0.90). The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischaemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. This superiority was found in all subgroups and was independent of baseline risk.
    Journal of neurology, neurosurgery, and psychiatry 07/2008; 79(11):1218-23. · 4.87 Impact Factor
  • A Algra, E L L M De Schryver, P H A Halkes
    Nederlands tijdschrift voor geneeskunde 06/2008; 152(20):1179; author reply 1180.
  • The Lancet Neurology 04/2008; 7(3):198-9; author reply 199. · 23.92 Impact Factor
  • E L L M De Schryver, P H A Halkes
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    ABSTRACT: The 'European/Australasian stroke prevention in reversible ischaemia trial' (ESPRIT) aimed to determine whether oral anticoagulation of moderate intensity (target international normalised ratio (INR): 2.0-3.0) is more effective than acetylsalicylic acid in preventing future vascular events in patients with transient ischaemic attack (TIA) or minor stroke of arterial origin. International, multicentre randomised clinical trial. Patients were randomised within 6 months of TIA or minor stroke of arterial origin to oral anticoagulants (target INR: 2.0-3.0; n = 536) or acetylsalicylic acid (30-325 mg daily; n = 532). The primary endpoint was a composite of vascular death, non-fatal stroke, non-fatal myocardial infarction or major bleeding complications. In a post hoc analysis, the efficacy of anticoagulants was compared with that of the combination of acetylsalicylic acid and dipyridamole (200 mg twice daily), a third arm of ESPRIT. Treatment was unblinded, but auditing of endpoints was blinded. Data were analysed on an intent-to-treat basis. The comparison of anticoagulants and acetylsalicylic acid was stopped prematurely because the combination of acetylsalicylic acid and dipyridamole was found to be more effective than acetylsalicylic acid alone. The mean duration of follow-up was 4.6 years (SD: 2.2). The mean INR was 2.57 (SD: 0.86; nearly 70% of the time within target range). The primary endpoint occurred in 99 patients (19%) in the anticoagulation group and 98 patients (18%) in the acetylsalicylic acid group (hazard ratio: 1.02; 95% CI: 0.77-1.35). The hazard ratio was 0.73 (95% CI: 0.52-1.01) for ischaemic events and 2.56 (95% CI: 1.48-4.43) for major bleeding complications. The hazard ratio for the primary outcome event comparing anticoagulants with the combination of acetylsalicylic acid and dipyridamole was 1.31 (95% CI: 0.98-1.75). Oral anticoagulants (target INR: 2.0-3.0) were not more effective than acetylsalicylic acid in the secondary prevention of vascular events following TIA or minor stroke of arterial origin.
    Nederlands tijdschrift voor geneeskunde 03/2008; 152(8):445-53.
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    P.H.A. Halkes
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    ABSTRACT: 1. We compared 120 patients who had had a large subcortical infarct with 324 who had had a small deep infarct and with 211 who had had a cortical infarct from the same cohort. We found no differences in risk factor profiles between the three groups, nor a difference in stroke recurrence rate. 2. We demonstrated, by means of a questionnaire filled in by 29 neurologists with special interest in stroke, that there is very little agreement on the classification of cause of death in patients who die after a stroke in the setting of a clinical trial. We developed guidelines for the classification of the cause of death after stroke, with the criteria ‘interval between stroke and death’ (cutoff point at 1 month) and ‘best Rankin grade after stroke’ (cutoff at 3). 3. The results of the first part of the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) are described, in which patients who suffered a Transient Ischaemic Attack (TIA) or non disabling ischaemic stroke of presumed arterial origin were randomized between the combination therapy of aspirin plus dipyridamole (n=1363) and aspirin alone (n=1376). Less patients assigned to the combination therapy (173, 13%) than to aspirin alone (216, 16%) suffered the primary outcome event, which was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. The corresponding hazard ratio was 0.80 (95% confidence interval 0.66-0.98). 4. The results of the second, prematurely halted, part of ESPRIT are presented. In this part a comparison was made between medium intensity oral anticoagulants (aimed international normalized ratio (INR) 2.0-3.0) and aspirin in the secondary prevention after TIA or non disabling ischaemic stroke of arterial origin. There was no difference in the incidence of the primary outcome event (99 of 536 patients, 19% versus 98 of 532, 18%). There were, however, more major bleeding complications in patients assigned to anticoagulation (45 vs. 18, hazard ratio 2.56 (95% confidence interval 1.48-4.43). 5. The results of an individual patient data based meta-analysis of all trials that compared the combination therapy of aspirin plus dipyridamole with aspirin alone in the secondary prevention after TIA or stroke of arterial origin are presented. Data from 7612 patients (3800 allocated to aspirin plus dipyridamole and 3812 to aspirin alone) were available for this analysis. The hazard ratio for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% CI 0.72-0.92). Hazard ratios did not differ in subgroup analyses based on patient characteristics, nor across baseline risk strata as assessed with two different risk scores. 6. We did an exploratory analysis on data from ESPRIT and from the Second European Stroke Prevention Study (ESPS 2), with the aim to identify risk factors for the development of headache during treatment with dipyridamole. The factors we found to be associated with discontinuation of dipyridamole because of headache were female sex, no (relevant) ischemic lesion on brain imaging and not smoking.
    01/2008;
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    ABSTRACT: Oral anticoagulants are better than aspirin for secondary prevention after myocardial infarction and after cerebral ischaemia in combination with non-rheumatic atrial fibrillation. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) aimed to determine whether oral anticoagulation with medium intensity is more effective than aspirin in preventing future vascular events in patients with transient ischaemic attack or minor stroke of presumed arterial origin. In this international, multicentre trial, patients were randomly assigned within 6 months after a transient ischaemic attack or minor stroke of presumed arterial origin either anticoagulants (target INR range 2.0-3.0; n=536) or aspirin (30-325 mg daily; n=532). The primary outcome was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever occurred first. In a post hoc analysis anticoagulants were compared with the combination of aspirin and dipyridamole (200 mg twice daily). Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov (NCT00161070). The anticoagulants versus aspirin comparison of ESPRIT was prematurely ended because ESPRIT reported previously that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4.6 years (SD 2.2). The mean achieved INR was 2.57 (SD 0.86). A primary outcome event occurred in 99 (19%) patients on anticoagulants and in 98 (18%) patients on aspirin (hazard ratio [HR] 1.02, 95% CI 0.77-1.35). The HR for ischaemic events was 0.73 (0.52-1.01) and for major bleeding complications 2.56 (1.48-4.43). The HR for the primary outcome event comparing anticoagulants with the combination treatment of aspirin and dipyridamole was 1.31 (0.98-1.75). Oral anticoagulants (target INR range 2.0-3.0) are not more effective than aspirin for secondary prevention after transient ischaemic attack or minor stroke of arterial origin. A possible protective effect against ischaemic events is offset by increased bleeding complications.
    The Lancet Neurology 03/2007; 6(2):115-24. · 23.92 Impact Factor
  • P H A Halkes, A Algra
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    ABSTRACT: In this paper, an overview is given of trials with oral anticoagulants and dipyridamole in the secondary prevention after transient ischaemic attack or minor stroke. In patients with atrial fibrillation, the secondary preventive treatment of first choice is oral anticoagulation with an aimed international normalised ratio between 2.0 and 3.0. In patients without a cardiac source of embolism, a combination therapy of low-dose aspirin and dipyridamole 200 mg twice daily is the treatment of choice. These treatment strategies do however not prevent all recurrent strokes or vascular complications, and research for more effective strategies is warranted.
    Cerebrovascular Diseases 02/2007; 24 Suppl 1:107-11. · 2.81 Impact Factor
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    ABSTRACT: In this study we compared risk factors, clinical features, and stroke recurrence in a large series of patients with large subcortical, cortical, or small deep infarcts. Patients with a transient or minor ischemic attack (modified Rankin Scale grade of < or =3) who had a single relevant supratentorial infarct of presumed noncardioembolic origin on CT were classified as suffering from a large subcortical (n=120), small deep (n=324), or cortical (n=211) infarct. Mean follow-up was 8 years. Rates of recurrent stroke were compared with Cox regression. The clinical deficits caused by large subcortical infarcts resembled either those of a cortical or those of a small deep infarct. Risk factor profiles were similar in the 3 groups. The rate of recurrent stroke in patients with a large subcortical infarct (25/120; 21%) did not differ from that of patients with a cortical infarct (46/211; 22%) or with a small deep infarct (60/324; 19%). After adjustment for age, sex, and vascular risk factors, hazard ratios for recurrent stroke of large subcortical and cortical infarcts were 1.05 (95% CI, 0.65 to 1.70) and 1.17 (95% CI, 0.79 to 1.73), respectively, compared with small deep infarcts. Clinical features, risk factor profiles, and stroke recurrence rate in patients with a large subcortical infarct only differ slightly from those in patients with small deep or cortical infarcts.
    Stroke 08/2006; 37(7):1828-32. · 6.16 Impact Factor
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    ABSTRACT: Classification of outcome events is essential in clinical research. The Executive Committee of the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), a secondary prevention trial in patients with cerebral ischemia, repeatedly encountered problems in classifying the cause of death after a stroke if the interval between these events was relatively long. We aimed to develop guidelines for classifying such events. Twenty-nine neurologists with a special interest in stroke filled out a questionnaire and audited 5 case vignettes. On the basis of this information, we developed a proposal for classifying causes of death after stroke. This proposal was evaluated in an interobserver analysis in which 10 neurologists or residents in neurology assessed 20 of 100 case vignettes. Initially, there was great variation in classifications of the case vignettes, mainly because the correspondents strongly disagreed about the relative importance of the interval between stroke and death, the degree of disability after stroke, the discharge destination (home or institutional care), and the coexistence of infection. In the new proposal, the main criteria were "interval after stroke" (cutoff point at 1 month) and "best Rankin grade after stroke" (cutoff at 3). In the interobserver analysis, good agreement was obtained among the 5 pairs of neurologists who assessed the 20 case vignettes (kappa 0.80 95% CI, 0.68 to 0.92). In the absence of guidelines, neurologists show striking variation in the classification of causes of death in patients who die after a stroke. With precise rules, agreement in the classification of death after stroke strongly improved.
    Stroke 07/2006; 37(6):1521-4. · 6.16 Impact Factor
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    ABSTRACT: Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent. Our aim was to resolve this uncertainty. We did a randomised controlled trial in which we assigned patients to aspirin (30-325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. Our primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with (NCT00161070). Mean follow-up was 3.5 years (SD 2.0). Median aspirin dose was 75 mg in both treatment groups (range 30-325); extended-release dipyridamole was used by 83% (n=1131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66-0.98; absolute risk reduction 1.0% per year, 95% CI 0.1-1.8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0.82 (95% CI 0.74-0.91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache. The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin.
    The Lancet 06/2006; 367(9523):1665-73. · 39.06 Impact Factor
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    ABSTRACT: Unruptured intracranial aneurysms can be preventively treated by surgical clipping or endovascular coiling. We determined in detail the costs of these treatments. We included patients who were treated for an unruptured aneurysm between 1997 and 2003. Patients coiled in this period were matched with clipped patients according to the year of treatment, age and gender. Considering clipping and coiling, we compared all pre-admission costs of diagnostic procedures, all costs of treatment, and costs during follow-up including standard angiographic control examinations at 6 and 18 months after coiling. Costs were calculated as the product of the used resources and the costs of these resources. The mean price for clipping was EUR 8,865.42 and that for coiling EUR 10,370.29. The difference was mainly determined by the higher material costs of coiling (EUR 5,300) compared with clipping (EUR 690). Costs of clipping were mainly determined by the need for intensive care facilities (1.2 days after clipping and 0 days after coiling) and the length of hospital stay (10.5 days after clipping and 3.4 days after coiling). After bootstrapping the data, costs of coiling were on average EUR 1,553 (95% confidence interval: EUR 1,539-1,569) higher than those of clipping. For unruptured intracranial aneurysms, direct in-hospital costs of coiling are on average higher than those of clipping, mostly because of the more expensive coils.
    Cerebrovascular Diseases 02/2006; 22(1):40-5. · 2.81 Impact Factor
  • 01/2006;
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    P H A Halkes
    Stroke 06/2005; 36(5):933. · 6.16 Impact Factor
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    01/2005;
  • P.H.A. Halkes, A. Algra, Group ESPRIT Study
  • P.H.A. Halkes, A. Algra, Group ESPRIT Study

Publication Stats

395 Citations
126.89 Total Impact Points

Institutions

  • 2010
    • Erasmus MC
      • Department of Neurology
      Rotterdam, South Holland, Netherlands
  • 2006–2009
    • University Medical Center Utrecht
      • Department of Neurology
      Utrecht, Provincie Utrecht, Netherlands
  • 2007
    • Netherlands Institute for Neuroscience
      Amsterdamo, North Holland, Netherlands