数学模型模拟高血压患者对降压药物收缩压反应的探索研究

Modeling of systolic blood pressure reaction to antihypertensive agents in people with hypertension

目的 运用建立数学模型的方法,探讨高血压患者对于降压药物收缩压反应的协同影响因素.方法以MRC35-64、MRC65-74、STEP及SYST-EU四个随机口服降压药治疗高血压研究为数据库,患者接受口服利尿剂、β受体阻滞剂或钙通道阻滞剂单种类药物治疗,对照组服安慰剂.分析年龄、性别、身高、体重、吸烟、基础收缩压、舒张压、总胆固醇水平、既往心肌梗死病史等指标,应用SAS（R）及R两种软件建立数学模型,获得药物治疗的协同影响因素.结果共纳入31 140例原发性高血压患者,年龄（60±11）岁,男性47%.降压药是收缩压降低的直接影响因素.（1）利尿剂组年龄、基础收缩压和舒张压为正协同于收缩压下降值的影响因素（β值依次为0.17、0.09、0.14）;（2）β受体阻滞剂组：基础收缩压正协同于药物降压疗效,年龄负协同于药物降压疗效,非吸烟者治疗后血压下降较吸烟者明显（β值依次为-0.17、0.37、-2.07）;（3）钙通道阻滞剂组：基础收缩压与体重为正协同于收缩压下降的影响因素（β值依次为0.18、0.06）.除钙通道阻滞剂组体重（P=0.050）外,P值均为0.000.结论运用数学模型研究方法预测降压药物血压反应是可行的.

Objective We used the individual patient data from clinical trials, pooled in the INDANA data set, to explore whether blood pressure reduction was related to the baseline individual characteristics, and quantify the potential associations. Methods We used the data from 31 140 patients with essential hypertension recruited in four randomized placebo-controlled clinical trials, MRC35-64,MRC65-74, STEP and SYST-EU. Thiazide diuretics, β-blocker, and calcium channel blocker, three of six major BP lowering drugs were analyzed. Patients were all with the same first dosage of the drug in each trial.Age, body weight, height, level of total cholesterin （TC）, systolic blood pressure （SBP） and diastolic blood pressure （DBP） when initialed and at first visit of follow-up, pharmacological treatment, gender,status of smoking, history of myocardium infarction were factors taken into model. Data were managed by software SAS（R）. Statistical analyses were performed with SAS（R） and R. Model was developed to evaluate the relationship between decrease of SBP and characteristics of patients. Results Initial SBP is the only modifier of treatment effect on SBP response in the 3 BP lowering drug classes （β = 0.09, 0.37 and 0. 18,respectively）. Age and initial DBP were factors significantly correlated with SBP fall for diuretic （β =0. 17and 0. 14）, and age was one of factors significantly correlated with SBP fall for β-blocker （ β = -0. 17）.Smokers would receive less SBP fall compare to non-smokers in β-blocker active treated group （β =-2. 07）. There is converse effect of age between the diuretic and β-blocker; older people seem sensitive to diuretic, while young people are sensitive to β-blocker. As to calcium channel antagonist class, body weight is another modifier （ β = 0. 06） （ All P value are 0. 000 except 0. 050 for body weight in calcium channel antagonist class）. Conclusion We identified 5 significant modifiers （baseline SBP and DBP, age, smoking status and body weight） for SBP response to treatment effect, while gender, TC and history of myocardial infarction are not modifiers for SBP response to treatment effect.