NEJM：阿奇霉素与心血管原因死亡风险增加无关

在基线高危患者中，阿奇霉素的使用与心血管原因的死亡危险升高相关。在未经选择的普通人群中，阿奇霉素是否引起同样的危险尚不清楚。丹麦哥本哈根市国家血清研究所流行病学研究科Henrik Svanström博士等人展开了相关研究，他们发现在青年和中年人的普通人群中，阿奇霉素使用与心血管原因死亡危险升高无关。研究成果日前发表于国际权威杂志NEJM在线版。

研究人员以丹麦成年人（年龄18～64岁）为样本进行了一项全国范围的历史性队列研究，链接了1997-2010年期间有关处方取药、死亡原因和患者特征的注册数据。研究人员估算了心血管因素死亡发生率比值，对1102050次阿奇霉素用药与未使用抗生素（根据倾向评分，按1:1的比例匹配，共2204100次）的情况进行比较，还对1102419次阿奇霉素用药与7364292次青霉素Ⅴ（一种适应证相似的抗生素）用药进行了比较，校正倾向评分后进行分析。

结果显示，与未使用抗生素相比，正在使用阿奇霉素（定义为一个为期5天的治疗事件）的心血管因素死亡危险显著升高（发生率比值为2.85，95%可信区间（CI）为1.13～7.24）。与一个抗生素使用组进行比较的相关分析包括了17例发生在正在使用阿奇霉素患者中的心血管原因死亡（粗死亡率为1.1例/1000人-年）和146例发生在正在使用青霉素Ⅴ患者中的心血管原因死亡（粗死亡率为1.5例/1000人-年）。研究发现，在校正倾向评分后，与青霉素Ⅴ相比，正在使用阿奇霉素与心血管原因死亡危险的升高无关（比值比为0.93。95% CI为0.56～1.55）。与青霉素Ⅴ相比，经校正的正在使用阿奇霉素的绝对危险为-1例心血管死亡（95% CI为-9～11）/100万次治疗事件。

研究人员由此得出结论，在青年和中年人的普通人群中，阿奇霉素使用与心血管原因死亡危险升高无关。

与阿奇霉素相关的拓展阅读：

• FDA警告：阿奇霉素有致命的心脏风险
• Lancet：阿奇霉素防止非囊性纤维化支气管扩张症病情恶化
• FDA审核阿奇霉素的心血管危险
• NEJM：阿奇霉素轻微增加心血管死亡风险
• JAMA：阿奇霉素的治疗可维持肠道长期较低的带菌率
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Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial.
Abstract
IMPORTANCE: Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible.
OBJECTIVE: To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses.
DESIGN, SETTING, AND PATIENTS: Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%).
INTERVENTION: Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES: Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months.
RESULTS: The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36.
CONCLUSIONS AND RELEVANCE: Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended.