Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death.

PURPOSE: Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODS: We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days. RESULTS: During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82). CONCLUSIONS: Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias.

OBJECTIVE: To describe effect sizes of single-arm clinical trials that supported AA approvals. STUDY DESIGN AND SETTING: We reviewed all the single-arm approvals granted by the FDA-AA pathway between June1992 to December2020. Two independent reviewers identified single-arm studies and extracted data from FDA Full-Medical Reviews. We performed a meta-analysis to estimate the effect sizes and compared it between studies that met post-approval FDA requirements for RCTs with those that did not. RESULTS: From the total of 254 approvals, single arm clinical trials describing effects of 54 drugs for 72 clinical indications were evaluated. The effect size estimated was OR:2.22(CI95%:1.76-2.81) [relative risk (RR) = 1.63(95CI% 1.38-1.92)]; 53% of treatments had a lower 95% CI bound crossing the null effect. Effect size did not differ between the treatments that met the FDA requirement for conducting post-approval RCTs. CONCLUSIONS AND RELEVANCE: Treatment effects observed in the FDA AA single-arm studies was modest and can be to ascribed to bias.

Angiotensin receptor blockers and risk of prostate cancer among United States veterans.

To address concerns regarding increased risk of prostate cancer (PrCA) among angiotensin receptor blocker (ARB) users, we used national retrospective data from the Department of Veterans Affairs (VA) through the Veterans Affairs Informatics and Computing Infrastructure. We identified a total of 543,824 unique Veterans who were classified into either ARB treated or not-treated in 1:15 ratio. The two groups were balanced using inverse probability of treatment weights. A double-robust cox-proportional hazards model was used to estimate the hazard ratio for PrCA incidence. To evaluate for a potential Gleason score stage migration, we conducted weighted Cochrane-Armitage test. Post weighting, the rates of PrCA in treated and not-treated groups were 506 (1.5%) and 8,269 (1.6%), respectively; representing a hazard ratio of (0.91, p-value .049). There was no significant difference in Gleason scores between the two groups. We found a small, but statistically significant, reduction in the incidence of clinically detected PrCA among patients assigned to receive ARB with no countervailing effect on degree of differentiation (as indicated by Gleason score). Findings from this study support Food and Drug Administration's recent conclusion that ARB use does not increase risk of incident PrCA.

Angiotensin receptor blockers: are they related to lung cancer?

INTRODUCTION: Angiotensin receptor blockers (ARBs) are commonly used antihypertensive medication with several other additional proven benefits. Recent controversy on association of lung cancer and other solid malignancy with the use of ARBs is concerning, although the follow-up studies have shown no such association. METHODS: We used data from the Department of Veterans Affairs electronic medical record system and registries to conduct a retrospective cohort study that compared first-time ARB users with nonusers in 1:15 ratio, after balancing for many baseline differences using inverse probability of treatment weights. We conducted time-to-event survival analyses on the weighted cohort. RESULTS: Of the 1 229 902 patients in the analytic cohort, 346 (0.44%) of the 78 075 treated individuals had a newly incident lung cancer and 6577 (0.57%) of 1 151 826 nontreated individuals were diagnosed with lung cancer. On double robust regression, the weighted hazard ratio was 0.74 (0.67-0.83, P < 0.0001), suggesting a lung cancer reduction effect with ARB use. There was no difference in rates by ARB subtype. CONCLUSION: In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs.

Caveat oncologist: clinical findings and consequences of distributing counterfeit erythropoietin in the United States.

PURPOSE: Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. MATERIALS AND METHODS: Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration's (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book "Dangerous Doses," LexisNexis (search terms "counterfeit" and "erythropoietin") and the FDA database. RESULTS: Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products were then sold via the pharmaceutical "gray market" to wholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61-year-old patient with breast cancer experienced loss of efficacy after receiving counterfeit erythropoietin. CONCLUSION: Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.