Analysis of the reactivity and safety of different doses of clopidogrel and ticagrelor in elderly patients
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摘要: 目的 观察老年患者服用不同剂量氯吡格雷或替格瑞洛的反应性及出血事件的发生。方法 入选2018年1月—2020年1月在北京大学第一医院老年科住院并服用不同剂量氯吡格雷或替格瑞洛的老年患者296例。用光比浊法检测二磷酸腺苷诱导的血小板聚集率(ADP-Ag)，观察氯吡格雷或替格瑞洛不同剂量组ADP-Ag水平及影响因素，并观察12个月内的出血情况。结果 服用氯吡格雷75 mg/d和≤50 mg/d的患者ADP-Ag分别为(42.96±14.20)%和(45.27±14.18)%，组间差异无统计学意义；服用替格瑞洛180 mg/d和≤135 mg/d患者的ADP-Ag分别为(24.17±10.65)%和(25.99±8.84)%，替格瑞洛组ADP-Ag水平低于氯吡格雷组(P< 0.05)。氯吡格雷75 mg/d和≤50 mg/d患者ADP-Ag>46%的比例分别为43.54%和42.31%，服用替格瑞洛的患者ADP-Ag均 < 46%，服用替格瑞洛180 mg/d和≤135 mg/d的患者ADP-Ag < 19%的分别占31.25%和15.56%，高于氯吡格雷75 mg/d(4.78%)和≤50 mg/d(3.84%)的患者。氯吡格雷联用质子泵抑制剂(PPIs)的老年患者ADP-Ag更高[(45.99±12.42)% vs(41.33±14.86)%，P=0.023]，替格瑞洛联用PPIs对ADP-Ag无显著影响。BMI与替格瑞洛治疗的ADP-Ag水平呈正相关(r=0.454，P=0.008)。12个月随访期内，服用氯吡格雷的老年患者发生出血事件5例(2.13%)，服用替格瑞洛的老年患者发生出血事件5例(8.20%)，差异有统计学意义(P＝0.035)。结论 老年患者服用氯吡格雷或替格瑞洛治疗后血小板反应性存在个体差异，氯吡格雷治疗后血小板高反应性比例高，替格瑞洛治疗后血小板低反应性比例高。替格瑞洛减量后仍可降低ADP-Ag，同时减少出血。Abstract: Objective To observe the reactivity of elderly patients taking different doses of clopidogrel or ticagrelor and the correlation with bleeding events.Methods A total of 296 elderly patients treated with clopidogrel or ticagrelor in the Department of Gerontology, Peking University First Hospital from January 2018 to January 2020 were enrolled. ADP-Ag was detected by Light Transmittance Aggregometry(LTA). The levels of ADP-Ag and its influencing factors were observed, and the bleeding events within 12 months were followed-up.Results The average values of ADP-Ag were(42.96±14.20)% and(45.27±14.18)% in patients taking clopidogrel 75 mg/d and ≤50 mg/d, respectively, and there was no statistical difference between the two groups. The average values of ADP-Ag were(24.17±10.65)% and(25.99±8.84)% in patients taking ticagrelor 180 mg/d and ≤135 mg/d, respectively, which lower than those in the clopidogrel group(P< 0.05). The proportion of ADP-Ag>46% in patients with clopidogrel 75 mg/d and ≤ 50 mg/d was 43.54% and 42.31%, respectively; ADP-Ag was < 46% in all doses of ticagrelor, and ADP-Ag < 19% were 31.25% and 15.56% in patients taking ticagrelor 180 mg/d and ≤135 mg/d, respectively, which were higher than that of clopidogrel 75 mg/d(4.78%) and ≤ 50 mg/d(3.84%). The ADP-Ag in elderly patients taking clopidogrel combined with proton pump inhibitors(PPIs) was higher[(45.99±12.42)% vs. (41.33±14.86)%,P=0.023], but the combination of PPIs had no significant effect on ADP-Ag. BMI was positively correlated with ADP-Ag after ticagrelor treatment(r=0.454,P=0.008). During the 12-month follow-up, there were 5 cases(2.13%) that occurred bleeding events in patients taking clopidogrel and 5 cases(8.20%) in patients taking tiacagrelor, the difference between the two groups has statistical significance(P＝0.035).Conclusion The platelet reactivity exists individual differences in elderly patients undergoing treatment with clopidogrel or ticagrelor. The proportion of high platelet reactivity is higher in patients taking clopidogrel, while the proportion of low platelet reactivity is higher in patients taking ticagrelor. Lowering the dose of ticagrelor can still stably and effectively inhibit platelet aggregation as well as reduce bleeding events.
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Key words:
- clopidogrel /
- ticagrelor /
- elderly /
- reactivity /
- bleeding
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表 1 研究人群的基线资料
Table 1. General data
例(%), X±S 项目 氯吡格雷 替格瑞洛 75 mg/d(209例) ≤50 mg/d(26例) 180 mg/d(16例) ≤135 mg/d(45例) 年龄/岁 75.81±8.90 78.69±7.90 71.56±7.551) 74.91±8.57 男性 177(84.7) 20(76.9) 16(100.0)1) 40(88.9) BMI/(kg·m-2) 24.41±3.10 24.66±3.49 25.45±3.63 24.11±2.67 危险因素 吸烟 31(14.8) 2(7.7) 1(6.3) 10(22.2) 高血压 157(75.1) 21(80.8) 14(87.5) 32(71.1) 糖尿病 91(43.5) 11(42.3) 10(62.5) 16(35.6) 冠心病 198(94.7) 20(76.9)1) 16(100.0) 45(100.0) 冠心病介入史 175(83.7) 13(50.0)1) 14(87.5) 43(95.6) 出血史 10(4.78) 0 0 0 合并用药 阿司匹林 172(82.3) 12(46.2)1) 15(93.8) 40(88.9) 他汀类药物 198(94.7) 25(96.2) 15(93.8) 43(95.6) CCBs 78(37.3) 13(50.0) 7(43.8) 15(33.3) PPIs 73(34.9) 7(26.9) 5(31.3) 22(48.9) 实验室检查 PLT/(×109·L-1) 183.86±53.44 172.62±47.54 164.44±48.45 190.16±51.51 Cr/(μmol·L-1) 93.63±29.35 88.12±21.83 94.63±17.29 99.38±23.50 eGFR/[mL·min-1·(1.73m2)-1] 68.92±17.17 68.08±15.14 71.16±14.86 65.50±15.15 FBG/(mmol·L-1) 6.90±2.36 6.78±2.34 6.30±2.09 7.41±5.13 hs-CRP/(mg·L-1) 3.38±12.08 1.00±0.75 2.14±4.33 1.87±3.33 HbA1c/% 6.34±0.89 6.55±1.32 6.76±1.33 6.45±1.26 FIB/(g·L-1) 3.01±0.53 2.87±0.43 2.94±0.51 3.03±0.50 CCBs：钙拮抗剂；Cr：血肌酐；eGFR：估测肾小球滤过率；FBG：空腹血糖；HbA1c：糖化血红蛋白；FIB：血浆纤维蛋白原。与其他3组比较，1)P < 0.05。 
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表 2 氯吡格雷和替格瑞洛治疗后ADP-Ag水平
Table 2. ADP-Ag levels after treatment with clopidogrel and ticagrelor
例(%), X±S 组别 ADP-Ag/% ADP-Ag>46% ADP-Ag＜19% 替格瑞洛 180 mg/d(16例) 24.17±10.65 0 5(31.25) ≤135 mg/d(45例) 25.99±8.84 0 7(15.56) 氯吡格雷 75 mg/d(209例) 42.96±14.20 91(43.54) 10(4.78) ≤50 mg/d(26例) 45.27±14.18 11(42.31) 1(3.84)
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表 3 氯吡格雷75 mg/d组及替格瑞洛90 mg/d组患者基线情况比较
Table 3. Baseline data of patients with clopidogrel 75 mg/d and ticagrelor 90 mg/d
例(%), X±S 项目 氯吡格雷
75 mg/d
(209例)替格瑞洛
90 mg/d
(33例)P 男性 177(84.7) 30(90.9) 0.320 吸烟 31(14.8) 5(15.2) 0.715 高血压 157(75.1) 22(66.) 0.315 糖尿病 91(43.5) 11(33.3) 0.496 冠心病 198(94.7) 32(97.0) 0.559 介入治疗 175(83.7) 31(94.0) 0.093 阿司匹林 172(82.3) 27(81.2) 0.770 他汀类药物 198(94.7) 31(94.0) 0.583 CCBs 78(37.3) 7(21.2) 0.078 PPIs 73(34.9) 13(39.4) 0.543 年龄/岁 75.81±8.90 74.58±8.65 0.459 BMI/(kg·m-2) 24.41±3.10 24.24±2.66 0.753 PLT/(×109·L-1) 183.86±53.44 194.24±52.16 0.299 Cr/(μmol·L-1) 93.63±29.35 99.01±20.92 0.320 eGFR/[mL·min-1·(1.73m2)-1] 68.92 ±17.17 65.35±13.75 0.142 FBG/(mmol·L-1) 6.90±2.36 8.05±5.88 0.485 hs-CRP/(mg·L-1) 3.38±12.08 2.17±3.81 0.937 HbA1c/% 6.34±0.89 6.65±1.47 0.628 FIB/(g·L-1) 3.01±0.53 3.16±0.46 0.134
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表 4 氯吡格雷75 mg/d患者ADP-Ag影响因素分析
Table 4. Influencing factors of ADP-Ag in patients with clopidogrel 75 mg/d
X±S 项目 例(%) ADP-Ag/% 因素存在 因素不存在 男性 177(84.7) 42.76±13.91 44.05±15.92 年龄≥75岁 120(57.4) 43.07±14.46 42.82±13.92 BMI≥28 kg/m2 32(15.3) 43.26±14.02 42.91±14.27 吸烟 37(17.7) 39.44±14.51 43.72±14.06 糖尿病 91(43.5) 43.30±13.15 42.69±15.01 阿司匹林 172(82.3) 43.24±13.77 41.68±16.21 他汀类药物 198(94.7) 42.91±14.44 43.76±9.32 CCBs 78(37.3) 42.49±14.48 43.24±14.08 PPIs 73(34.9) 45.99±12.42 41.33±14.861) 1)P < 0.05。
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表 5 氯吡格雷75 mg/d患者ADP-Ag与部分指标的相关性分析
Table 5. Correlation between ADP-Ag and indexes in patients with clopidogrel 75 mg/d
项目 r P 年龄 0.010 0.881 BMI 0.074 0.286 PLT 0.155 0.025 Scr -0.010 0.885 eGFR 0.017 0.812 hs-CRP 0.213 0.002 HBA1c -0.012 0.869 FBG 0.044 0.619 FIB 0.120 0.085
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表 6 替格瑞洛90 mg/d患者ADP-Ag影响因素分析
Table 6. Influencing factors of ADP-Ag in patients with ticagrelor 90 mg/d
X±S 项目 例(%) ADP-Ag/% 因素存在 因素不存在 年龄≥75岁 18(54.5) 25.55±9.17 26.16±7.39 BMI≥28 kg/m2 3(9.10) 28.45±7.65 25.57±8.42 未戒烟 5(15.2) 29.12±5.74 25.24±8.61 糖尿病 10(30.3) 22.71±9.93 26.61±12.31 阿司匹林 27(81.8) 26.83±7.94 22.73±9.32 CCBs 7(21.2) 28.22±6.54 25.62±8.57 PPIs 13(39.4) 29.32±8.01 24.05±7.72
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表 7 替格瑞洛90 mg/d患者ADP-Ag与部分指标的相关性分析
Table 7. Correlation between ADP-Ag and indexes in patients with ticagrelor 90 mg/d
项目 r P 年龄 -0.036 0.841 BMI 0.454 0.008 PLT 0.060 0.741 Scr -0.043 0.817 eGFR 0.066 0.717 hs-CRP -0.111 0.545 HBA1c -0.018 0.926 FBG -0.071 0.759 FIB 0.284 0.115
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表 8 药物种类调整对ADP-Ag的影响
Table 8. Effects of drug adjustment on ADP-Ag
X±S 调整方式 ADP-Ag/% 调整前 调整后 氯吡格雷→替格瑞洛(16例) 51.18±8.79 23.53±8.75 75 mg/d→180 mg/d(6例) 56.26±3.50 21.45±11.33 75 mg/d→135 mg/d(2例) 35.90±6.60 18.77±5.73 75 mg/d→90 mg/d(6例) 50.65±7.41 26.55±5.65 75 mg/d→45 mg/d(2例) 52.79±7.71 25.44±5.70 替格瑞洛→氯吡格雷(5例) 17.44±8.38 43.37±4.77 180 mg/d→75 mg/d(4例) 19.43±7.42 43.21±5.33 90 mg/d→75 mg/d(1例) 9.47 43.96
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表 9 不同剂量替格瑞洛与氯吡格雷出血事件发生率比较
Table 9. Incidence of bleeding events in groups with different doses of ticagrelor and clopidogrel
例(%) 项目 氯吡格雷
75 mg/d
(235例)替格瑞洛
180 mg/d
(16例)替格瑞洛
90 mg/d
(45例)无出血 205(98.01) 13(81.25) 43(95.56) 发生出血 5(2.13) 3(18.75)1) 2(4.44) 与其他2组比较，1)P < 0.05
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