Prevalence of genetic polymorphisms of CYP2C9 and VKORC1 - implications for warfarin management and outcome in Croatian patients with acute stroke.

BACKGROUND: Data on the prevalence of CYP2C9 and VKORC1 genes and their influence on anticoagulant effect and warfarin dose in stroke patients are scarce. The aim of this study was to determine the occurrence and significance of these gene polymorphisms and to establish pharmacogenetic algorithm to estimate the dose of introduction. Also, the goal was to determine tailored safety and intensity of anticoagulation response depending on the allelic variants and their impact on the clinical outcome in acute stroke patients in Croatia. METHODS: A total of 106 consented acute stroke patients were tested for CYP2C9 2, 3 and VKORC1 1173C>T gene polymorphisms. We estimated the dose of introduction and monitored anticoagulant effect obtained by INR values, time to reach stable dose, stable maintenance dose, time spent within the therapeutic/supratherapeutic INR range, occurrence of dosage side effects and clinical outcome depending on genotypes. RESULTS: We found that 83% of stroke patients in our study were carriers of multiple allelic variants. The predicted initial dose correlated with the stable warfarin maintenance dose (p=0.0311) and we correctly estimated the dose for 81.5% of 61.3% of study patients who required higher/lower doses than average. Warfarin dosage complications were slightly more frequent among the carriers of CYP2C9 2, 3 compared to the carriers of VKORC1 1173T alleles (68. 9% versus 62.5%), but their occurrence did not affect the final clinical outcome. CONCLUSION: Our data indicated rapid and safe anticoagulation achieved by using pharmacogenetically-predicted warfarin dose in high-risk acute stroke patients without increasing the risk of warfarin dosage complications in an elderly population.

Assessment of prevalence and pathological response to orthostatic provocation in patients with multiple sclerosis.

OBJECTIVE: The aim of this study was to determine the prevalence of pathologic response to orthostatic challenge in patients with relapsing remitting multiple sclerosis (RRMS) and the difference of the response in patients in relapse and remission. PATIENTS AND METHODS: We included 112 RRMS patients; group 1 included 53 patients in a relapse and group 2, 59 patients in remission. The head up tilt table test was used to provoke an orthostatic reaction. RESULTS: 71 (63%) patients (60.4% and 66% of relapse and remission subjects respectively) had a pathological response to orthostatic provocation. Syncope was found in 9 (17%) patients in group 1 compared to 22 (37.3%) in group 2 (p=0.014). Postural orthostatic tachycardia syndrome (POTS) was found in 17 (32%) patients in group 1 compared to 4 (6.8%) in group 2 (p=0.001). There was a significantly negative correlation between the Expanded Disability Status Scale (EDSS) and POTS (-0.201; p=0.034) and a positive correlation between the EDSS and syncope (0.190; p=0.044). CONCLUSION: The prevalence of distinct types of orthostatic autonomic dysfunction in different phases of RRMS seems to be in direct correlation with the EDSS. Furthermore, certain autonomic dysfunctions of orthostasis, more specifically syncope and POTS, tend to be increased in remission and relapse respectively.