阿奇霉素心血管风险可能仅见于亚组患者

丹麦一项大型全国数据研究显示，使用阿奇霉素并不显著增加心血管风险，这与近期一项促使美国食品药品管理局(FDA)加强对该抗生素警告的研究结果存在不一致，原因可能在于两项研究的人群不同。

在这项丹麦研究中，哥本哈根Statens血清研究所的统计学家Henrik Svanström及其同事采用多个丹麦全国数据库1997~2010年的数据进行了两项比较：一是比较1,102,050次阿奇霉素用药与相同数量匹配患者的非抗生素治疗，二是比较1,102,419次阿奇霉素用药与7,364,292次青霉素V用药(N. Engl. J. Med. 2013;368:1704-12)。

结果显示，非抗生素治疗组有7例心血管死亡，5天阿奇霉素治疗组有17例心血管死亡，青霉素V组有146例心血管死亡，这3组的心血管死亡率分别为0.4/1,000患者-年、1.1/1,000患者-年和 1.5/1,000患者-年。校正的绝对风险差异为，阿奇霉素每治疗1百万次引起的心血管死亡比青霉素V引起的心血管死亡少1例。

研究者表示，与青霉素V相比，阿奇霉素未导致心血管死亡风险显著增加，这一结果表明与未使用抗生素者相比，在阿奇霉素使用者中观察到的心血管死亡的增加并非由该药引起，而是完全归因于急性感染或其他正治疗的健康问题所引起的死亡风险。

一项事后分析还对使用阿奇霉素的患者与使用阿莫西林的匹配患者进行了比较，结果显示阿奇霉素未导致心血管死亡风险显著增加。

亚组分析显示，与未使用阿奇霉素且无心血管疾病史者相比，使用阿奇霉素且有心血管疾病史的患者的心血管死亡风险增加，心血管死亡率分别为1/1,000患者-年和10/1,000患者-年，但差异无统计学显著性。

FDA最近发布警告称，使用阿奇霉素可能导致致死性心律失常风险增加，并强调了目前该药标签上有关QT间期延长和尖端扭转性室性心动过速风险的警告。最高危者为具有已知危险因素的患者，这些危险因素包括当前QT间期延长、血钾或镁水平低、心率慢于正常、或使用某种药物治疗心律失常。促使FDA采取这一举措的是一项有关美国田纳西医疗补助计划(Medicaid)患者的回顾性队列研究。该研究分析的数据为1992~2006年的347,795次阿奇霉素用药、140万次匹配的非抗生素治疗和130次阿莫西林用药。该研究显示，阿奇霉素组心血管死亡风险有轻微绝对增加，阿奇霉素每治疗1百万次引起的死亡为85.2例，而非抗生素组为29.8例/百万次，阿莫西林组为31.5例/百万次。在10%的已具有最高心血管疾病风险的患者中，心血管死亡的风险最大(N. Engl. J. Med. 2012;366:1881-90)。

考虑到这两项研究在患者人群和基线死亡风险方面的显著差异，丹麦研究应被视为对美国研究的具有临床意义的补充，而不是相互矛盾。

本项研究由丹麦医学研究理事会资助。Svanström先生及其同事均声明无经济利益冲突。

随刊述评：对高危患者使用抗生素须三思

FDA药品评价和研究中心监测与流行病学办公室的Andrew D. Mosholder博士及其同事表示，药理学和流行病学证据显示，大环内酯类抗生素(包括阿奇霉素)和氟喹诺酮类可延长QT间期及导致致死性心律失常，因此临床医生在处方这些药物前应三思，特别是在治疗获益有限或患者具有心血管危险因素的情况下(N. Engl. J. Med. 2013;368:1704-12)。

在丹麦研究中，95%置信区间的上限较高(上限为风险增加55%)，并未完全排除阿奇霉素增加心血管风险的可能性。而且丹麦研究受试者的总体健康程度优于美国田纳西研究受试者。

FDA警告称红霉素、克拉霉素和氟喹诺酮类均可延长QT间期，并且美国田纳西研究发现左氧氟沙星的心脏死亡风险与阿奇霉素的心脏死亡风险相似。2011年有超过4千万美国人接受阿奇霉素治疗。田纳西研究显示，门诊每处方21,000次阿奇霉素引起的心血管死亡比处方阿莫西林多1例。在处方阿奇霉素或其替代抗生素时，应权衡潜在的心血管风险和获益。

Mosholder博士及其同事均声明无经济利益冲突。

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By: SHERRY BOSCHERT, Cardiology News Digital Network

A large study of Danish national data found no significantly increased cardiovascular risk from taking azithromycin, results that are different from, but perhaps not contradictory to, a recent report that prompted the Food and Drug Administration to beef up warnings about the antibiotic.

The discordance may be attributable to the different populations in the two studies. The earlier study found a doubled or tripled risk of cardiovascular-related death in a higher-risk U.S. cohort of Medicaid recipients while taking azithromycin, compared with no antibiotic or amoxicillin. The current study found a tripled risk of cardiovascular-related deaths in a lower-risk, young- to middle-age Danish cohort while on azithromycin, compared with no antibiotic use, but there was no increased risk from azithromycin use, compared with taking penicillin V, an antibiotic with similar indications.

Clinicians should find the Danish study "reassuring" because it appears that any cardiovascular risk from azithromycin is not generalizable to all patients seen in office practices, Henrik Svanström and his associates concluded.

They analyzed data from multiple Danish national databases from 1997 through 2010 to conduct two comparisons: one of 1,102,050 episodes of azithromycin use, compared with the same number of matched patients on no antibiotics; and a comparison of 1,102,419 episodes of azithromycin use and 7,364,292 episodes of penicillin V use.

There were 6 deaths from cardiovascular causes while on no antibiotics, 17 while on a 5-day course of azithromycin, and 146 while on penicillin V, which translated into cardiovascular death rates of 0.4/1,000 patient-years on no antibiotics, 1.1/1,000 patient-years on azithromycin, and 1.5/1,000 patient-years on penicillin V, reported Mr. Svanström, a statistician at the Statens Serum Institut, Copenhagen, Denmark.

The adjusted difference in absolute risk was one less cardiovascular death per 1 million treatment episodes of azithromycin, compared with penicillin V, the investigators calculated (N. Engl. J. Med. 2013;368:1704-12).

The lack of any significantly increased risk on azithromycin compared with penicillin V suggests that the increase in cardiovascular deaths on azithromycin, compared with no antibiotics, was not attributable to the drug but was entirely brought about by mortality risks from the acute infections or other health problems being treated, Mr. Svanström suggested.

A post hoc analysis also compared episodes of azithromycin use with matched patients given amoxicillin and found no significantly increased risk of cardiovascular death from azithromycin, he reported.

In subgroup analyses, the risk of cardiovascular death appeared to be increased in patients on azithromycin who’d had cardiovascular disease, compared with patients on the drug with no history of cardiovascular disease (rates of 10 and 1 cardiovascular death per 1,000 patient-years, respectively), but the difference did not reach statistical significance.

The FDA recently issued a warning of increased risk for fatal arrhythmia associated with azithromycin use and strengthened the existing warning on the drug’s label about the risk of QT interval prolongation and torsades de pointes. The people at greatest risk are those with known risk factors such as existing QT interval prolongation, low blood levels of potassium or magnesium, a slower-than-normal heart rate, or use of certain drugs to treat abnormal heart rhythms or arrhythmias, the FDA said.

The FDA action followed a retrospective cohort study of Tennessee Medicaid patients from 1992 through 2006, including 347,795 episodes of azithromycin use, 1.4 million matched episodes with no antibiotics, and 1.3 million prescriptions for amoxicillin. That study found a small absolute increase in the risk of cardiovascular death while on azithromycin: 85.2 deaths per million courses of azithromycin, compared with 29.8 per million periods with no antibiotics and 31.5 per million with amoxicillin. The risk was most pronounced among the 10% of patients who already were at highest risk for cardiovascular disease (N. Engl. J. Med. 2012;366:1881-90).

Considering the "profound differences" between the two studies’ patient cohorts and their baseline risks of death, the Danish study should be considered "a clinically relevant complement to, rather than a contrast with," the U.S. study, Mr. Svanström suggested.

The Danish Medical Research Council funded the study.

Mr. Svanström and his associates reported having no financial disclosures.