SummaryOral anticoagulant therapy has been shown to be effective for scveral indications. The optimal intcnsity of anticoagulation for each indication, howcver, is largely unknown. To determinc this optimal intensity, randomiscd clinical trials are conducted in which two target levcls of anticoagulation are compared. This approach is incfficicnt, since the choice of the target levels will bc arbitrary. Moreover, the achieved intcnsity is not taken into account.Wc propose a mcthod to determine the optimal achieved intensity of anticoagulation. This method can bc applied wilhin a clinical trial äs an "efficacy-analysis", but also on data gathered in day-to-day paticnt carc.In this method, INR-specific incidence ratcs of events, either thromboembolic or hemorrhagic, are calculated. The numerator of the incidence rate is based on data on the INR at the time of the cvent. The denominator consists of the pcrson-time at each INR value, summed over all patients, and is calculated from all INR measurements of all patients during the follow-up interval. This INR-specific person-time is calculated with the assumption of a linear incrcase or decreasc between two consecutive INR determinations. Since the incidence rates may bc substratificd on covariates, efficient assessmcnt of the effects of other factors (e. g. agc, scx, comedication) by multivariale regression analysis bccomes possiblc.This method allows the determination of the optimal pharmacological effects of anticoagulation, which can form a rational starting point for choosing the target levels in subscquent clinical trials.

These data provide a reference for future studies and give adequate risk estimates for clinical decision making.

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We studied the nature and extent of comorbidity of chronic frequent headache (CFH) in the general population and the influence of CFH and comorbidity on quality of life. Subjects with CFH (headache on >14 days/month) were identified in a general health survey. We sent a second questionnaire including questions on comorbidity and quality of life to subjects with CFH and subjects with infrequent headache (IH) (1-4 days/month). We recoded comorbidity by using the Cumulative Illness Rating Scale (CIRS) and measured quality of life with the RAND-36, a Dutch version of Short Form-36. CFH subjects (n = 176) had higher comorbidity scores than the IH subjects (n = 141). Mean CIRS scores were 2.94 for CFH and 1.55 for IH [mean difference 1.40, 95% confidence interval (CI) 0.91, 1.89]. The mean number of categories selected was 1.92 in CFH and 1.10 in IH (mean difference 0.82, 95% CI 0.54, 1.11). Fifty percent of CFH subjects had a comorbidity severity level of at least 2, indicating disorders requiring daily medication, compared with 28% of IH subjects (mean difference 22%, 95% CI 12, 33). CFH subjects had more musculoskeletal, gastrointestinal, psychiatric and endocrine/breast pathology than IH subjects. Quality of life in CFH subjects was lower than that of IH subjects in all domains of the RAND-36. Both headache frequency and CIRS score had a negative influence on all domains. We conclude that patients with CFH have more comorbid disorders than patients with infrequent headaches. Many CFH patients have a comorbid chronic condition requiring daily medication. Both high headache frequency and comorbidity contribute to the low quality of life in these patients. ᮀ Chronic daily headache, comorbidity, headache, medication overuse, quality of life

Summary. Background: Oral anticoagulant therapy (OAT) implies frequent blood checks and dose changes to prevent thromboembolic or hemorrhagic complications. This may interfere with patients' social and working circumstances in addition to the possible stress caused by the condition necessitating this treatment. We studied whether patient selfmanagement could be a way to improve quality of life in these patients. Methods: Within a multicenter randomized study performed by two Dutch anticoagulation clinics, designed to study the effect on treatment quality (time within target range) of different modalities of patient self-management, we looked at the effect of increased patient education (n ¼ 28), self-monitoring of the International Normalized Ratio (INR) (n ¼ 47) and full patient self-management (INR monitoring and dosing of the OAT) (n ¼ 41) on the quality of life of the patients. This was done with the aid of a written questionnaire (32 questions, minimum score ¼ 1, maximum score ¼ 6) at baseline (n ¼ 163), and after 26 weeks (n ¼ 118). We compared the results after 26 weeks with those at baseline, as well as between groups. Results: General treatment satisfaction was already high under routine care (5.11 on a scale of 1-6) and increased further through self-monitoring of the INR (+0.19) and full self-management (+0.32). Distress ()0.44), perceived daily hassles ()0.31) and strain on the social network ()0.21) were reduced through full self-management. Improved patient education was associated with increased distress (+0.33) and perceived daily hassles (+0.23). Comparison at 26 weeks between groups showed similar improvements on these outcomes for self-monitoring and self-management vs. routine care after education.

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Article abstract-Background: The use of oral anticoagulant therapy for the prevention of arterial thromboembolism in patients who have had ischemic stroke is controversial. Coumarins may increase the bleeding risk in patients with cerebral ischemia of arterial origin. Objectives: 1) To calculate incidence rates of bleeding and thromboembolic events in patients with noncardiac cerebral ischemia who were treated routinely in an anticoagulation clinic. 2) To assess which factors contribute to the occurrence of events. 3) To determine the optimal intensity of oral anticoagulant therapy in these patients. Methode: The authors studied all patients treated for noncardiac cerebral ischemia at the Leiden anticoagulation clinic between 1993 and 1998. Outcome events were major hemorrhage, major arterial thromboembolism, and death. Results: The authors observed 356 patients for 644 patient-years. The incidence of major hemorrhage was 3.9 per 100 patient-years (95% CI, 2.5 to 5.7) and that of thromboembolism was 3.0 per 100 patient-years (95% CI, 1.8 to 4.6). The incidence of hemorrhage varied with the duration of treatment (relative risk [RR] of the first versus the second half-year, 3.8; 95% CI, 1.9 to 7.6), age (RR for age >65 years, 3.7; 95% CI, 1.1 to 12.3), and the intensity of oral anticoagulation (RR, 1.8 for each 0.5 international normalized ratio [INR] unit increase; 95% CI, 1.5 to 2.3). The optimal intensity of oral anticoagulant therapy was 2.5 to 3.5 INR; the best target value was 3.0 INR. Conclusion. The risk of hemorrhage with anticoagulant therapy is high in patients with ischemic stroke of arterial origin but is mainly confined to early use and elderly patients. NEUROLOGY 2001;57· 1993-1999 Patients with atrial fibrillation 1 or myocardial infarction 2 4 benefit from treatment with coumarins; however, treatment introduces a moderate annual bleeding risk of 2% to 3%. A study of coumarins in patients with atrial fibrillation and recent nondisabling cerebral ischemia showed a 65% reduction of recurrent strokes with an accompanying annual bleeding risk of less than 3% percent. 5 These results suggest that oral anticoagulation may prevent stroke in a wider ränge of indications.To investigate whether coumarins also could improve the outcome for patients with stroke of noncardiac origin, the Stroke Prevention in Reversible Ischemia Trial (SPIRIT) was designed. SPIRIT was an open, multicenter clinical trial in which patients with cerebral ischemia of presumed arterial origin were randomized between low-dose aspirin (30 mg daily) and full-dose anticoagulation (international normalized ratio [INR], 3.0 to 4.5). 6 The trial was prematurely terminated after the first interim analysis revealed an excessive rate of bleeding complications (7% per year) in patients randomized to oral anticoagulation. Subsequent analyses revealed differences between patients that might help to explain the observed risks; high INR levels äs well äs the presence of leukoaraiosis appeared to be related to the bleeding risk in particular. 6 7 ...