In 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials. Secondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults (NCT04368728 and NCT04470427), focusing analysis on Brighton Collaboration adverse events of special interest. Pfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI −0.4 to 20.6 and −3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI –23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI −3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39). The excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.

Objectives To evaluate the association between bisphosphonate use and the risk of atypical femoral fractures among women aged 65 or older. Design Nested case–control study. Setting General practice research database in Spain. Exposures Use of oral bisphosphonates before the occurrence of atypical fractures among cases or the corresponding index date among controls. Bisphosphonate use was categorised as ever versus never users. Ever users were divided according to the total time since first prescription. Main outcome measures Cases were defined as women aged 65 years or older with a first diagnosis of subtrochanteric or diaphyseal fracture, recorded in the BIFAP database between 1 January 2005 and 31 December 2008, and with at least 1 year of follow-up before the index date. For each case, five age-matched and calendar-year-matched controls without a history of hip or atypical fracture were randomly selected from the database. Statistical analysis OR of atypical femoral fracture by bisphosphonate use was determined using conditional logistic regression. Models were adjusted for comorbidities and use of other medications. Results The analysis included 44 cases and 220 matched controls (mean age, 82 years). Ever use of bisphosphonates was more frequent in cases than controls (29.6% vs 10.5%). In multivariate analyses, OR (95% CI) of atypical femoral fracture was 4.30 (1.55 to 11.9) in ever versus never users of bisphosphonates. The risk increased with long-term use, with an OR of 9.46 (2.17 to 41.3) comparing those using bisphosphonates over 3 years versus no users (p for trend=0.01). Conclusions Bisphosphonate use was associated with an increased risk of subtrochanteric or diaphyseal fractures in elderly women in a low fracture risk population, with a higher risk among long-term bisphosphonate users.

Objectives To evaluate the association between the long-term use of bisphosphonates and the risk of hip fracture compared to never use among women aged 65 years or older. Design Case–control study nested in a cohort. Setting General practice research database operated by the Spanish Medicines Agency. Participants Cases of hip fracture were defined as women aged 65 years or older with a validated first diagnosis of hip fracture between 2005 and 2008. Five controls free of hip fracture were matched on age and calendar-year with each case. Interventions Information on bisphosphonate use, hip fractures, comedication and comorbidities was collected. Primary outcomes Hip fracture risk comparing bisphosphonate users versus never users. Secondary outcomes Hip fracture risk comparing bisphosphonate users versus never users by individual drugs. Results The study included 2009 incident hip fractures and 10 045 matched controls. Hip-fracture risk did not differ between bisphosphonate users and never users, adjusted OR=1.09 (95% CI 0.94 to 1.27). No association was observed between hip fracture risk and cumulative duration of bisphosphonate treatment. However, when treatment duration is analysed as time since first prescription, hip fracture risks of the different subgroups compared to never users obtained were as follows: <1 year, OR 0.85 (95% CI 0.60 to 1.21); 1 to <3 years, OR 1.02 (95% CI 0.82 to 1.26); ≥3 years, OR 1.32 (95% CI 1.05 to 1.65) (p for trend=0.03). Conclusions Ever use of oral bisphosphonates was not associated with a decreased risk of hip fracture in women aged 65 or older as compared to never use. No association was observed between hip fracture risk and cumulative duration of bisphosphonate treatment. However, when treatment duration is analysed as time since first prescription, a statistically significant increased risk for hip fracture was observed in patients exposed to bisphosphonates over 3 years. Trial Registration Spanish Ministry of Health. TRA-071

Objective The FOURIER trial showed a benefit of the PCSK9 inhibitor evolocumab over placebo with respect to cardiovascular outcomes in patients with cardiovascular disease. However, we observed some inconsistencies between the information in the Clinical Study Report (CSR) and that in the 2017 primary trial results publication. We aimed to restore the mortality data in the FOURIER trial based on the information contained in the death narratives in the CSR. Methods Mortality data in the primary results publication were compared with that in the CSR. In cases of discrepancy between the sources, an independent committee blindly readjudicated and restored the cause of death according to the information in the CSR narratives. Results For 360/870 deaths (41.4%), the cause of death adjudicated by the FOURIER clinical events committee differed from that declared by the local clinical investigator. When comparing the CSR information with the 2017 primary results publication, we found 11 more deaths from myocardial infarction in the evolocumab group (36 vs 25) and 3 less deaths in the placebo group (27 vs 30, respectively). In the CSR, the number of deaths due to cardiac failure in the evolocumab group was almost double those in the placebo group (31 vs 16). While cardiac and vascular deaths were not assessed as separate outcomes in the original trial analysis, after readjudication, we noted that cardiac deaths were numerically, but non-significantly, higher in the evolocumab group (113) than in the placebo group (88; relative risk (RR) 1.28, 95% CI 0.97 to 1.69, p=0.078), whereas non-cardiac vascular deaths were similar between groups (37 in each; RR 1.00, 95% CI 0.63 to 1.58, p=0.999). The reported HR for cardiovascular mortality in the original trial analysis was 1.05 (95% CI 0.88 to 1.25); after readjudication, we found a greater (although still non-significant) relative increase in cardiovascular mortality in the evolocumab treatment group (RR 1.20, 95% CI 0.95 to 1.51, p=0.13). Conclusion After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm. At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our readjudication. A complete restoration of the FOURIER trial data is required. In the meantime, clinicians should be sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease. Trial registration numbers NCT01764633.