NEJM述评：阿奇霉素和其他抗菌药的心血管风险

根据IMS健康研究公司数据，2011年全美约4.3千万（约1/8人口）服用过门诊处方药中的大环内脂类抗生素阿奇霉素。鉴于其心血管疾病风险，这一年，我们在美国食品和药物管理局（FDA）重审了阿奇霉素及其他已批准的大环内酯类抗菌药的标签说明，从发表的研究报告及上市后监测报告来看，这种风险已变得相当明显。在重审的基础上，考虑其所致的QT间期延长和与之相关的尖端扭转型室速，FDA批准了对阿奇霉素标签说明的修改。修订后的标签说明不建议对已知危险因素的患者使用阿奇霉素，如QT间期延长，低钾血症，低镁血症，心动过缓，或使用某些抗心律失常药物，包括IA类（如奎尼丁，普鲁卡因胺）和三类可以延长QT间期的药物（如，多非利特，胺碘酮，索他洛尔）。在2013年3月为反映一项临床研究结果：阿奇霉素可以延长矫正的QT间期，FDA宣布，对阿奇霉素标签说明已作进一步的修订。

在2012年一项纳入田纳西州医疗补助病人的观察性研究中，Ray 等人量化了与阿奇霉素关联的心血管原因死亡风险并将其与使用其他的抗菌药或不使用相比。研究表明，无论是从任一原因还是心血管疾病原因看，与阿奇霉素关联的死亡的风险都大于阿莫西林。每21000个使用阿奇霉素的门诊病人中就有一人发生心血管死亡，超过那些使用阿莫西林的同数量门诊病人。根据心血管疾病的危险因素，阿奇霉素较阿莫西林过高的风险因素很杂，研究人员估计，在高心血管风险患者中每4100使用阿奇霉素的患者中就有超过一个死于心血管因素，而在低心血管风险患者中死亡率不到1/100,000。

这项由Ray等人进行的研究有一定的局限性，它只是一种内在的观察，而非随机性的临床研究。特别是，非随机性研究不能排除的可能性就是与控制用药患者相比，一些未经评估的患者以一些重要但未被发现的方式服用药物，从而导致结果偏差。这种混杂可能是比较偏差所致，不仅存在于服用抗菌药及未服用抗菌药患者间，也存在于服用不同的抗菌药患者之间。虽然Ray等人使用了适当的分析方法以处理潜在的混杂，但我们无法确信这些方法是否十分有效。通过分析不同的数据组重复作者的结果，将为服用阿奇霉素的患者增加心血管疾病的死亡率这一发现提供更多的可信度。

尽管有这样的告诫，由雷等人给出的结果值得重视。该结果的着重点是风险的时间限制模式：因任何原因与心血管病因与阿奇霉素相关的死亡率增加时间跨度时间为1?5天，反映了典型的阿奇霉素5天给药使用期（例如，希舒美Z-PAK）。在6至10天，心血管原因死亡的风险升高不再出现。此模式与阿奇霉素血药浓度达峰时间及随之而来的QT间期延长风险是一致的。不管是否将使用阿奇霉素治疗与阿莫西林及与不使用抗菌药物相比，升高风险都有显著的统计学意义。此外，观察到的过高死亡率仅来源于心血管疾病死亡，尤其是心脏猝死;虽然心脏性猝死可以是心律失常以外的其他原因引起，在此类别中死亡率增加预想类型一般为心律失常事件与 引起QT间期延长的药物。此外，存在心血管疾病患者与阿奇霉素相关的风险更高且构成药物相关性心律失常。

由Svanstrom和他的同事（在1704至1712页）使用丹麦国家保健数据进行的一项新研究发现，使用阿奇霉素和青霉素V在5天内的心血管死亡风险并无差别（相对风险，0.93;95％可信区间[CI]，0.56至1.55）。然而，在95％的置信区间的上限，不排除风险将增至55％。如Svanstrom等人所说，在死亡基线风险和心血管疾病危险因素方面，他们研究的人口不同于Ray等人。总体来看，丹麦的患者比田纳西州的医疗补助患者有着更好的心血管健康。对存在心血管疾病史的患者进行亚组分析时，阿奇霉素vs青霉素V的风险比大于1，但该差异无统计学意义（相对危险度为1.35，95％CI，0.69 - 2.64）。 svanstrom等人总结道：他们的结果与Ray等人的结果并不冲突。相反，对心血管疾病死亡率的影响可能仅限与患有心血管疾病的患者。

当然，我们必须对临床获益与任何观察到的药物相关性风险进行衡量，因此，对并未反映在 Ray等人分析的风险数据中的阿奇霉素确切获益的可能应进行适当考虑。例如，其他研究表明，大环内酯类药物在社区获得性肺炎治疗中就总体生存期而言优于其他抗菌药。在加拿大最近的一项观察性研究中，研究人员跟踪调查了2973个社区获得性肺炎的门诊病人，与那些接受氟喹诺酮类药物病人相比接受大环内酯类药物患者30天死亡率显着降低（校正比为0.28，95％CI，0.09?0.86）。最近的对观测研究的一项荟萃分析表明：在社区获得性肺炎住院患者中应用大环内酯类药物相对于应用非大环内酯类药物患者在死亡率上存在着25％显著统计学差异。这些研究结果，应考虑其观测研究的限制性，不一定与Ray等人的结果相矛盾。抛开5天的与阿奇霉素相关的心血管疾病死亡风险，这种药物可能会减少因肺炎所致的长期死亡率（例如，超过30天）。在田纳西州医疗补助的病人应用阿奇霉素治疗肺炎不是常规的做法。

临床医生须考虑到不仅阿奇霉素，其他备选抗菌药也有潜在的致心律失常作用。先前的研究表明：红霉素的使用和心源性猝死之间存在关联，与细胞色素P-4503A同工酶（代谢红霉素）抑制剂同用时会增强。红霉素和克拉霉素标签说明警告包括QT间期延长和心律失常。所有氟喹诺酮类产品的标签说明同样有关于QT间期延长的警告，格帕沙星就是因为这种风险从市场上撤回。最近的一项关于加拿大魁北克省老年居民观察性研究显示：门诊氟喹诺酮类药物的使用和严重心律失常（定义为出院诊断为室性心律失常、突然或自发的死亡）存在关联。虽然雷等人的发现：阿奇霉素心血管疾病死亡风险比环丙沙星更大，他们发现使用左氧氟沙星与阿奇霉素的风险相似。作者用证据解释了这种相似性，左氧氟沙星可致心律失常，然而，左氧氟沙星致心律失常与加拿大的研究没有关联性通过分析从2002年到2011年十年间约3200门诊医生进行的一项Encuity研究的数据，我们调查了门诊阿奇霉素最常见的适应症。在所有年龄组的患者中，阿奇霉素最常见的两种适应症为慢性鼻窦炎和支气管炎。表中显示了在美国对于这些适应症的最常用抗菌药物。在此期间阿奇霉素是门诊治疗支气管炎的首选药物（即使阿莫西林与阿莫西林-克拉维酸联合）。对于慢性鼻窦炎，阿奇霉素的使用仅次于阿莫西林排名第二。由于适应症由处方医师报告，这些数据使我们无法评估诊断确定且正在接受治疗的感染。

在决定处方时应该考虑到抗菌药治疗的风险和获益。药理和流行病学数据指出：使用阿奇霉素，大环内酯类，氟喹诺酮类所致的QT间期延长的一个潜在后果就是致命性心律失常。这种可能性使医生在考虑使用抗菌药处方时，尤其是对已存在心血管危险因素或临床症状，使用抗菌药物治疗的获益有限的患者，应暂时停用。
与阿奇霉素相关的拓展阅读：

• NEJM：阿奇霉素与心血管原因死亡风险增加无关
• 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 更多信息请点击：有关阿奇霉素更多资讯

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs
In 2011, approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin, according to IMS Health. During that year, we at the Food and Drug Administration (FDA) reviewed the labels of azithromycin and other approved macrolide antibacterials in view of cardiovascular risks that had become evident from published studies and reports emerging through postmarketing surveillance. On the basis of its review, the FDA approved revisions to azithromycin product labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes. The revised labels advise against using azithromycin in patients with known risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of certain antiarrhythmic agents, including class IA (e.g., quinidine and procainamide) and class III (e.g., dofetilide, amiodarone, and sotalol) — drugs that can prolong the QT interval. In March 2013, the FDA announced that azithromycin labels had been further revised to reflect the results of a clinical study showing that azithromycin can prolong the corrected QT interval.

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In a 2012 observational study involving Tennessee Medicaid patients, Ray et al.1 quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antibacterial drugs or nonuse. The study showed that the risks of death, both from any cause and from cardiovascular causes, associated with azithromycin were greater than those associated with amoxicillin. For every 21,000 outpatient prescriptions written for azithromycin, one cardiovascular death occurred in excess of those observed with the same number of amoxicillin prescriptions. The excess risk over amoxicillin varied considerably according to cardiovascular risk factors; the researchers estimated that there was one excess cardiovascular death per 4100 prescriptions among patients at high cardiovascular risk but less than one per 100,000 among patients with lower cardiovascular risk.

The study by Ray et al. has limitations that are intrinsic to observational, nonrandomized clinical studies. In particular, nonrandomized studies cannot exclude the possibility that patients receiving a drug under evaluation differ from control patients in some important but undetected way, causing bias in the results. Such confounding may bias comparisons not only between patients receiving antibacterial drugs and those receiving no antibacterials but also between patients receiving different antibacterials. Although Ray et al. used appropriate analytic methods to address potential confounding, we cannot know for certain whether these methods were fully successful. Replication of the authors' results, through analysis of a distinct data set, would provide more confidence in the finding of increased cardiovascular mortality among patients receiving azithromycin.

Despite such caveats, the results presented by Ray et al. warrant serious attention. A chief strength of the results is the time-limited pattern of the risk: the azithromycin-associated increase in the rates of death from any cause and from cardiovascular causes spanned days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak). On days 6 through 10, an elevated risk of death from cardiovascular causes was no longer detected. This pattern is consistent with the timing of peak plasma azithromycin concentrations and the concomitant risk of QT-interval prolongation. The elevated risk was statistically significant, regardless of whether azithromycin treatment was compared with amoxicillin or with nonuse of an antibacterial drug. Furthermore, the observed excess mortality was attributable solely to cardiovascular deaths and, in particular, to sudden cardiac death; although sudden cardiac death can result from causes other than arrhythmias, an increase in deaths in this category would be the pattern expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.

A new study by Svanström and colleagues (pages 1704–1712), using Danish national health care data, found no difference between azithromycin and penicillin V in the 5-day risk of cardiovascular death (relative risk, 0.93; 95% confidence interval [CI], 0.56 to 1.55). However, the upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%. As Svanström et al. point out, the population they studied differed from that studied by Ray et al. with respect to the baseline risk of death and cardiovascular risk factors. Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients. In a subgroup analysis of patients with a history of cardiovascular disease, the risk ratio for azithromycin versus penicillin V was greater than 1, though the difference was not statistically significant (relative risk, 1.35; 95% CI, 0.69 to 2.64). Svanström et al. conclude that their results do not conflict with those of Ray et al. Rather, the effect on cardiovascular mortality may be limited to patients with cardiovascular disease.

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One must, of course, weigh any observed drug-associated risk against clinical benefits, so it's appropriate to consider the possibility that certain offsetting benefits of azithromycin may not have been reflected in the risk data analyzed by Ray et al. For example, other studies have suggested that macrolides have an advantage over other antibacterial agents in terms of overall survival from community-acquired pneumonia. In a recent Canadian observational study, researchers followed 2973 outpatients with community-acquired pneumonia and found significantly lower 30-day mortality among patients receiving macrolides than among those receiving fluoroquinolones (adjusted odds ratio, 0.28; 95% CI, 0.09 to 0.86).2 A recent meta-analysis of observational studies showed a statistically significant 25% difference in mortality among hospitalized patients with community-acquired pneumonia favoring macrolides over nonmacrolide antibacterials.3 Such findings, which must be considered with due regard for the limits of observational studies, do not necessarily contradict the results of Ray et al. Past the 5-day period of risk of azithromycin-associated cardiovascular death, the drug might reduce the longer-term (e.g., more-than-30-day) rate of death due to pneumonia. Pneumonia was an uncommon indication among the Tennessee Medicaid patients treated with azithromycin.

Clinicians must consider the arrhythmogenic potential not only of azithromycin but also of potential alternative antibacterial drugs. An earlier study showed an association between the use of erythromycin and sudden cardiac death, augmented by concomitant use of inhibitors of the cytochrome P-450 3A isozymes that metabolize erythromycin.4 Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias. All labels for fluoroquinolone products similarly have warnings regarding QT-interval prolongation, and grepafloxacin was withdrawn from the market because of that risk. A recent observational study of elderly residents of Quebec, Canada, showed an association between outpatient fluoroquinolone use and serious arrhythmias (as defined by hospital discharge diagnoses of ventricular arrhythmia or sudden or unattended death).5 And although Ray et al. found the risk of cardiovascular death to be greater with azithromycin than with ciprofloxacin, they found the risk with levofloxacin similar to that with azithromycin. The authors interpreted this similarity as evidence that levofloxacin may be proarrhythmic; however, levofloxacin was not implicated as proarrhythmic in the Canadian study.

We investigated the most common ambulatory indications for azithromycin by analyzing data from a survey conducted by Encuity Research of approximately 3200 office-based physicians for the decade from 2002 through 2011. Across all age groups of patients, the two most common indications for azithromycin were chronic sinusitis and bronchitis. The table

The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they're considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.