Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data.

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.

Information for physicians and pharmacists about drugs that might cause dry mouth: a study of monographs and published literature.

BACKGROUND: Over three-quarters of the older population take medications that can potentially cause dry mouth. Physicians or pharmacists rarely inform patients about this adverse effect and its potentially severe damage to the teeth, mouth and general health. OBJECTIVES: The objectives of this study were to (1) identify warnings in the literature about dry mouth associated with the most frequently prescribed pharmaceutical products in Canada; and (2) consider how this information might be obtained by physicians, pharmacists and patients. METHODS: Monographs on the 72 most frequently prescribed medications during 2010 were retrieved from the Compendium of Pharmaceuticals and Specialties (CPS, a standard drug information reference for physicians and pharmacists), the National Library of Medicine's 'DailyMed' database, directly from the manufacturers, and from a systematic search of biomedical journals. RESULTS: The CPS provided monographs for 43% of the medications, and requests to manufacturers produced the remaining monographs. Mentions of dry mouth were identified in 61% of the products (43% amongst CPS monographs; an additional 43% amongst manufacturers' monographs; 7% in the DailyMed database and 7% from biomedical journals); five medications had contradictory reports in different monographs. CONCLUSION: Nearly two-thirds (61%) of the most commonly prescribed medications can cause dry mouth, yet warnings about this adverse effect and its potentially serious consequences are not readily available to physicians, pharmacists, dentists or patients.

Severe atovaquone-resistant Plasmodium falciparum malaria in a Canadian traveller returned from the Indian subcontinent.

BACKGROUND: We report the first case of atovaquone/proguanil treatment failure in severe Plasmodium falciparum malaria acquired by a non-immune traveller to the Indian subcontinent. Recrudescent infection was complicated by neurological involvement 14 days after directly observed therapy with atovaquone/proguanil. Sequence analysis of the plasmodial cytochrome b gene confirmed a contribution of atovaquone resistance to treatment failure. The recrudescent isolate had a single mutation at position 268 (Tyr268Cys). Video recordings illustrate dramatic but ephemeral manifestations of malaria with neurological involvement.

Coordinated response to SARS, Vancouver, Canada.

Two Canadian urban areas received travelers with severe acute respiratory syndrome (SARS) before the World Health Organization issued its alert. By July 2003, Vancouver had identified 5 cases (4 imported); Toronto reported 247 cases (3 imported) and 43 deaths. Baseline preparedness for pandemic threats may account for the absence of sustained transmission and fewer cases of SARS in Vancouver.

Excessive hypertension and pulmonary edema after electroconvulsive therapy.

A 53-year-old right-handed man was scheduled to receive 6 treatments of electroconvulsive therapy (ECT) for intractable depression. He was being treated for long-standing hypertension with nadolol and had no history of cardiopulmonary disease. Six months previously, he received 6 nondominant, unilateral ECT treatments. During each of these treatments, his blood pressure increased transiently to as high as 250/150, but he experienced no adverse consequence. He commenced the current course of ECT with well-controlled blood pressure (145/90). During his first bilateral treatment, his blood pressure rose to 280/160, and pulmonary edema ensued. Clinically evident pulmonary edema after ECT is an uncommon event that rarely has been described in the literature.