Comparative Safety of BNT162b2 and mRNA-1273 Vaccines in a Nationwide Cohort of US Veterans.

Importance: The risk of adverse events has been found to be low for participants receiving the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna Inc) vaccines in randomized trials. However, a head-to-head comparison of their safety for a broader range of potential adverse events over longer follow-up and in larger and more diverse populations is lacking, to our knowledge. Objective: To compare the head-to-head safety in terms of risk of adverse events of the BNT162b2 and mRNA-1273 vaccines in the national health care databases of the US Department of Veterans Affairs, the largest integrated health care system in the US. Design, Setting, and Participants: In this cohort study, the electronic health records of US veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and September 20, 2021, were used. Recipients of each vaccine were matched in a 1:1 ratio according to their risk factors. Exposures: Vaccination with either the BNT162b2 vaccine, with a second dose scheduled 21 days later, or the mRNA-1273 vaccine, with a second dose scheduled 28 days later. Main Outcomes and Measures: A large panel of potential adverse events was evaluated; the panel included neurologic events, hematologic events, hemorrhagic stroke, ischemic stroke, myocardial infarction, other thromboembolic events, myocarditis or pericarditis, arrhythmia, kidney injury, appendicitis, autoimmune events, herpes zoster or simplex, arthritis or arthropathy, and pneumonia. Risks over 38 weeks were estimated using the Kaplan-Meier estimator. Results: Among 433 672 persons included in the matched vaccine groups, the median age was 69 years (IQR, 60-74 years), 93% of individuals were male, and 20% were Black. Estimated 38-week risks of adverse events were generally low after administration of either the BNT162b2 or the mRNA-1273 vaccine. Compared with the mRNA-1273 group, the BNT162b2 group had an excess per 10 000 persons of 10.9 events (95% CI, 1.9-17.4 events) of ischemic stroke, 14.8 events (95% CI, 7.9-21.8 events) of myocardial infarction, 11.3 events (95% CI, 3.4-17.7 events) of other thromboembolic events, and 17.1 events (95% CI, 8.8-30.2 events) of kidney injury. Estimates were largely similar among subgroups defined by age (<40, 40-69, and ≥70 years) and race (Black, White), but there were higher magnitudes of risk differences of ischemic stroke among older persons and White persons, kidney injury among older persons, and other thromboembolic events among Black persons. Small-magnitude differences between the 2 vaccines were seen within 42 days of the first dose, and few differences were seen within 14 days of the first dose. Conclusions and Relevance: The findings of this cohort study suggest that there were few differences in risk of adverse events within 14 days of the first dose of either the BNT162b2 or the mRNA-1273 vaccine and small-magnitude differences within 42 days of the first dose. The 38-week risks of adverse events were low in both vaccine groups, although risks were lower for recipients of the mRNA-1273 vaccine than for recipients of the BNT162b2 vaccine. Although the primary analysis was designed to detect safety events unrelated to SARS-CoV-2 infection, the possibility that these differences may partially be explained by a lower effectiveness of the BNT162b2 vaccine in preventing the sequelae of SARS-CoV-2 infection compared with the mRNA-1273 vaccine could not be ruled out. These findings may help inform decision-making in future vaccination campaigns.

Estimates of Overall Survival in Patients With Cancer Receiving Different Treatment Regimens: Emulating Hypothetical Target Trials in the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked Database.

Importance: The Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database may provide insights into the comparative effectiveness of oncological treatments for elderly individuals who are underrepresented in clinical trials. Objective: To evaluate the suitability of SEER-Medicare data for assessing the effectiveness of adding a drug to an existing treatment regimen on the overall survival of elderly patients with cancer. Design, Setting, and Participants: This comparative effectiveness study analyzed SEER-Medicare data from 9549 individuals who received a new diagnosis of stage II colorectal cancer (2008-2012) and 940 patients who received a new diagnosis of advanced pancreatic adenocarcinoma (2007-2012), with follow-up to December 31, 2013 (SEER-Medicare data released in 2015). Two (hypothetical) target trials were designed and emulated based on 2 existing randomized clinical trials: (1) adjuvant fluorouracil after curative surgery for individuals with stage II colorectal cancer and (2) erlotinib added to gemcitabine for individuals with advanced pancreatic adenocarcinoma. Data were analyzed January 2018 to March 2019. Exposures: The following treatment strategies were compared: (1) fluorouracil initiation vs no initiation within 3 months of tumor resection and (2) erlotinib initiation vs no initiation within 12 weeks of gemcitabine initiation. Main Outcomes and Measures: All-cause mortality within 60 months of baseline for the fluorouracil trial and within 72 weeks for the erlotinib trial. Results: Compared with 3293 individuals in the existing fluorouracil trial, 9549 eligible individuals included in the present analyses were more likely to have colon cancer (8565 [90%] vs 2291 [71%]) and were older (median [interquartile range], 79 [73-84] vs 63 [56-68] years). The 5-year risk difference for initiation vs noninitiation of fluorouracil after surgery was -3.8% (95% CI, -14.8% to 12.6%), and the mortality hazard ratio (HR) was 0.95 (95% CI, 0.85-1.04). Compared with 569 individuals in the existing erlotinib trial, 940 eligible patients included in the present analysis were older (median [range], 74 [66-93] vs 64 [36-92] years) and more likely to be male (547 [58%] vs 298 [52%]). The 1-year risk difference for initiation vs noninitiation of erlotinib was 4.7% (95% CI, -9.4% to 18.0%), and the corresponding mortality HR was 1.04 (95% CI, 0.86-1.42). In naive analyses, the mortality HR estimate was 1.14 (95% CI, 0.95-1.36) for the fluorouracil emulation and 0.68 (95% CI, 0.54-0.87) for the erlotinib emulation. Conclusions and Relevance: The present estimates were similar to those from randomized clinical trials that studied adding the same cancer drugs to existing regimens. The published HR was 1.02 (95% CI, 0.70-1.48) in the fluorouracil trial for individuals aged 70 or older and 0.96 (95% CI, 0.74-1.24) in the erlotinib trial for individuals aged 65 years or older. The SEER-Medicare database may be adequate for studying the real-world effectiveness of adding a drug to treatment regimens used for elderly individuals with cancer.

Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States.

BACKGROUND AND OBJECTIVES: The common finding that low achieved hemoglobin in observational studies and high target hemoglobin in randomized trials each were associated with increased mortality and high epoetin dosage has suggested the possibility that high epoetin dosage might explain the increased mortality risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We considered data from 18,454 patients who were >or=65 yr, were in the US Renal Data System, started hemodialysis in 2003, and survived 3 mo on dialysis. We estimated the association between cumulative average epoetin dosage and survival through the subsequent 9 mo by using inverse probability weighting to adjust for time-dependent confounding by indication. RESULTS: Survival was similar throughout the entire follow-up period for the three hypothetical treatment regimens selected: Low dosage 15,000 U/wk, medium dosage 30,000 U/wk, and high dosage 45,000 U/wk. Compared with a cumulative average dosage of 20,000 to 30,000 U/wk, the estimated hazard ratio (HR; 95% confidence interval [CI]) was 0.90 (0.52 to 1.54) for <10,000, 0.84 (0.67 to 1.05) for 10,000 to <20,000 U/wk, 0.96 (0.76 to 1.21) for 20,000 to <40,000 U/wk, and 0.91 (0.67 to 1.22) for >40,000 U/wk. In contrast, conventional unweighted models, which do not adequately adjust for time-dependent confounding by indication, indicated an association between high cumulative average epoetin dosage and increased mortality. CONCLUSIONS: Our findings suggest that, on average, epoetin dosages >30,000 U/wk do not confer additional harm or benefit in elderly hemodialysis patients.

Activated injectable vitamin D and hemodialysis survival: a historical cohort study.

Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non-vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.

Diet and Parkinson's disease: a potential role of dairy products in men.

Diet may play a causative role in Parkinson's disease (PD), but potential associations between diet and PD risk rarely have been assessed in prospective studies. We investigated associations between food intakes and PD risk in two large prospective cohorts in which 210 incident PD cases in men and 184 in women were documented. A positive association was found between dairy intake and PD risk in men (relative risk [RR] comparing extreme categories, 1.8; p trend = 0.004), but not in women (RR, 1.1; p trend = 0.9). No other food groups were associated with PD risk in either men or women. Further analyses among men showed significant positive associations with PD risk for intakes of several dairy foods as well as dairy calcium (RR, 1.5; p trend = 0.02), dairy vitamin D (RR, 1.6; p trend = 0.004), dairy protein (RR, 1.6; p trend = 0.01), and lactose (RR, 1.8; p trend = 0.002), but not dairy fat (RR, 1.1; p trend = 0.4). Intakes of calcium, vitamin D, and protein from other dietary or supplemental sources were not related to PD risk in men. Our results suggest that higher intake of dairy products may increase the risk of PD in men; however, this finding needs further evaluation, and the underlying active components need to be identified.

A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease.

We conducted a systematic review to summarize the epidemiological evidence on the association between cigarette smoking, coffee drinking, and the risk of Parkinson's disease. Case-control and cohort studies that reported the relative risk of physician-confirmed Parkinson's disease by cigarette smoking or coffee drinking status were included. Study-specific log relative risks were weighted by the inverse of their variances to obtain a pooled relative risk and its 95% confidence interval (CI). Results for smoking were based on 44 case-control and 4 cohort studies, and for coffee 8 case-control and 5 cohort studies. Compared with never smokers, the relative risk of Parkinson's disease was 0.59 (95% CI, 0.54-0.63) for ever smokers, 0.80 (95% CI, 0.69-0.93) for past smokers, and 0.39 (95% CI, 0.32-0.47) for current smokers. The relative risk per 10 additional pack-years was 0.84 (95% CI, 0.81-0.88) in case-control studies and 0.78 (95% CI, 0.73-0.84) in cohort studies. Compared with non-coffee drinkers, relative risk of Parkinson's disease was 0.69 (95% CI, 0.59-0.80) for coffee drinkers. The relative risk per three additional cups of coffee per day was 0.75 (95% CI, 0.64-0.86) in case-control studies and 0.68 (95% CI, 0.46-1.00) in cohort studies. This meta-analysis shows that there is strong epidemiological evidence that smokers and coffee drinkers have a lower risk of Parkinson's disease. Further research is required on the biological mechanisms underlying this potentially protective effect.

Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology.

Common strategies to decide whether a variable is a confounder that should be adjusted for in the analysis rely mostly on statistical criteria. The authors present findings from the Slone Epidemiology Unit Birth Defects Study, 1992-1997, a case-control study on folic acid supplementation and risk of neural tube defects. When statistical strategies for confounding evaluation are used, the adjusted odds ratio is 0.80 (95% confidence interval: 0.62, 1.21). However, the consideration of a priori causal knowledge suggests that the crude odds ratio of 0.65 (95% confidence interval: 0.46, 0.94) should be used because the adjusted odds ratio is invalid. Causal diagrams are used to encode qualitative a priori subject matter knowledge.