Estimation of the warfarin dose with clinical and pharmacogenetic data.
Estimation of the warfarin dose with clinical and pharmacogenetic data.
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DOI：
10.1056/nejmoa0809329
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发表时间：
2009-02-19
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影响因子：
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通讯作者：
Johnson JA
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作者：
International Warfarin Pharmacogenetics Consortium;Klein TE;Altman RB;Eriksson N;Gage BF;Kimmel SE;Lee MT;Limdi NA;Page D;Roden DM;Wagner MJ;Caldwell MD;Johnson JA
患者之间的遗传变异性在确定开始口服抗凝治疗时华法林的使用剂量方面起着重要作用，但在多样且大量的人群中，利用遗传信息的实用方法尚未得到评估。我们开发并使用了一种算法来估算合适的华法林剂量，该算法基于广泛人群的临床和遗传数据。
利用4043名患者的临床和遗传数据创建了仅基于临床变量的剂量算法以及将遗传信息添加到临床变量中的算法。在1009名受试者的验证队列中，我们通过计算华法林预测剂量在实际稳定治疗剂量的20%以内的患者百分比来评估每种算法的潜在临床价值；我们还评估了其他临床相关指标。
在验证队列中，药物遗传学算法比临床算法更准确地识别出每周需要21毫克或更少华法林以及每周需要49毫克或更多华法林以达到目标国际标准化比值的更大比例的患者（在每周需要≤21毫克的患者中，分别为49.4%对33.3%，P<0.001；在每周需要≥49毫克的患者中，分别为24.8%对7.2%，P<0.001）。
使用药物遗传学算法来估算华法林的合适初始剂量所产生的建议，比从临床算法或固定剂量方法得出的建议更接近所需的稳定治疗剂量。在46.2%的需要每周21毫克或更少华法林或每周49毫克或更多华法林进行治疗性抗凝的人群中观察到最大的益处。
Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring ≤21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring ≥49 mg per week). The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.