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