NEJM：阿奇霉素轻微增加心血管死亡风险

根据5月17日的《新英格兰医学杂志》上的一篇报道，在疗程5天的阿奇霉素治疗中，心血管(CV)死亡风险小幅增加。并且，10%的CV疾病最高危患者风险增加最显著(N. Engl. J. Med. 2012;366:1881-90)。

有报告指出“阿奇霉素对心脏的毒性作用相对较小”，但阿奇霉素与红霉素、克拉霉素的关系非常密切，而已知后两者可增加严重室性心律失常和心源性猝死的风险。并且，已有心律正常患者在接受阿奇霉素治疗期间发生心律失常相关不良事件的孤立报告，在向美国食品药品管理局(FDA)提交的报告中包括20个室性心律不齐的病例。

为了验证接受阿奇霉素治疗的患者CV死亡(尤其是心源性猝死)发生率是否将高于未接受抗生素治疗和接受其他抗生素治疗的患者，田纳西州纳什维尔市Vanderbilt大学药物流行病学系的Wayne A. Ray博士及其同事进行了一项回顾性队列研究。

研究者分析了1992(阿奇霉素首次引入美国的时间)~2006年间田纳西州医疗补助计划中30~74岁患者的数据。将347,795 个阿奇霉素5日疗程中的CV死亡和全因死亡事件数与未接受抗生素治疗的1,391,180个匹配对照时期进行了比较。为了校正治疗适应证的潜在混淆作用，研究者纳入第二个对照组，包括1,348,672次阿莫西林处方、264,626次环丙沙星处方和193,906次左氧氟沙星处方。阿奇霉素和阿莫西林最常见的适应证为耳鼻咽喉感染和支气管炎。

结果显示，与未接受抗生素治疗相比，使用阿奇霉素与CV死亡率增高相关(每100万阿奇霉素疗程中发生85.2例CV死亡，每100万无治疗时期中发生29.8例CV死亡)。与未接受抗生素治疗相比，阿奇霉素治疗疗程中的CV死亡风险率为2.88。相似的，使用阿奇霉素治疗较阿莫西林治疗的CV死亡风险增高，阿莫西林治疗中每100万疗程中发生31.5例CV死亡。“与阿莫西林相比，每100万阿奇霉素治疗疗程中将增加47例CV死亡；对于基线CV疾病风险处于最高十分位数的患者，每100个疗程中将增加245例心源性死亡。”

与其他CV死亡风险相同，阿奇霉素也增加心源性猝死的风险。当将阿奇霉素与环丙沙星进行比较时，发现与上述结果相似，但阿奇霉素与左氧氟沙星的死亡风险无显著差异。左氧氟沙星有公认的致药物性心律失常可能，并且既往研究显示这种药物治疗与CV死亡风险增高相关。尽管治疗后数日内阿奇霉素在组织中的浓度仍保持较高水平，但在5日疗程结束之后，死亡风险不再增高。原因可能为药物血清浓度的降低更为迅速，在完成治疗疗程后的“24 h内降至谷浓度”。

该研究由美国国立心肺血液研究所和美国医疗保健研究与质量管理局资助。Ray医生报告与信利保险公司之间存在关于结合雌激素的利益关系，并在涉及唑来膦酸的法律诉讼中提供专家证词。

A small absolute increase in the risk of cardiovascular death occurs during a 5-day course of azithromycin therapy, according to a report in the May 17 issue of the New England Journal of Medicine.

This rise is most pronounced among the 10% of patients who are already at highest risk for cardiovascular disease, said Wayne A. Ray, Ph.D., of the division of pharmacoepidemiology at Vanderbilt University in Nashville, Tennessee, and his associates.

Azithromycin “has been reported to be relatively free of cardiotoxic effects,” but it is closely related to erythromycin and clarithromycin, which are known to raise the risk of serious ventricular arrhythmias and sudden cardiac death. In addition, there have been isolated reports of patients with normal heart rhythms developing arrhythmia-related adverse events while taking azithromycin, including 20 cases of torsades de pointes reported to the U.S. Food and Drug Administration.

Dr. Ray and his colleagues performed a retrospective cohort study testing their hypothesis that patients taking azithromycin would show a higher rate of cardiovascular death – particularly sudden cardiac death – than would people who were not taking antibiotics and people who were taking different antibiotics.

The researchers analyzed data from the Tennessee Medicaid program on patients aged 30-74 years in 1992 (when azithromycin was first introduced in the United States) through 2006. They compared cardiovascular mortality and all-cause mortality during 347,795 5-day courses of azithromycin vs. 1,391,180 matched-control periods with no antibiotic treatment.

To control for possible confounding by treatment indication, the investigators included a second control group of 1,348,672 prescriptions for amoxicillin; 264,626 for ciprofloxacin; and 193,906 for levofloxacin. The most common indications for both azithromycin and amoxicillin were ear, nose, or throat infections and bronchitis.

Compared with no antibiotic treatment, the use of azithromycin was associated with an increased rate of cardiovascular death (85.2 CV deaths per million courses with azithromycin vs. 29.8 per million courses with no treatment). The hazard ratio for cardiovascular death was 2.88 during a course of azithromycin, compared with no antibiotic therapy.

Similarly, the use of azithromycin was associated with an increased risk of cardiovascular death, compared with amoxicillin treatment, for which the rate was 31.5 CV deaths per million courses.

“As compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million courses of azithromycin therapy; for patients in the highest decile of baseline risk of CV disease, there were 245 additional cardiac deaths per 1 million courses,” Dr. Ray and his associates said (N. Engl. J. Med. 2012;366:1881-90).

Azithromycin raised the risk of sudden cardiac death as well as that of other cardiovascular deaths.

The findings were similar when azithromycin was compared with ciprofloxacin, but mortality risks did not differ significantly between azithromycin and levofloxacin. Levofloxacin “has [a] recognized proarrhythmic potential” and has been linked to increased risk of cardiovascular death in previous studies, Dr. Ray and his associates said.

These increased mortality risks did not persist beyond the 5-day course of treatment, even though concentrations of azithromycin remain elevated in tissue for several more days. This may be because serum concentrations of the drug decline more rapidly, “falling to trough levels within 24 hours” of completing the course of therapy.

“Although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism,” they added.

This study was supported by the U.S. National Heart, Lung, and Blood Institute and the U.S. Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics. Dr. Ray reported ties to XL Insurance regarding conjugated estrogens, and providing expert testimony in litigation involving zoledronic acid.