Contribution of Potentially Inappropriate Medications to Polypharmacy-Associated Risk of Mortality in Middle-Aged Patients: A National Cohort Study.

BACKGROUND: The role of potentially inappropriate medications (PIMs) in mortality has been studied among those 65 years or older. While middle-aged individuals are believed to be less susceptible to the harms of polypharmacy, PIMs have not been as carefully studied in this group. OBJECTIVE: To estimate PIM-associated risk of mortality and evaluate the extent PIMs explain associations between polypharmacy and mortality in middle-aged patients, overall and by sex and race/ethnicity. DESIGN: Observational cohort study. SETTING: Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. PARTICIPANTS: Patients aged 41 to 64 who received a chronic medication (continuous use of ≥ 90 days) between October 1, 2008, and September 30, 2017. MEASUREMENT: Patients were followed for 5 years until death or end of study period (September 30, 2019). Time-updated polypharmacy and hyperpolypharmacy were defined as 5-9 and ≥ 10 chronic medications, respectively. PIMs were identified using the Beers criteria (2015) and were time-updated. Cox models were adjusted for demographic, behavioral, and clinical characteristics. RESULTS: Of 733,728 patients, 676,935 (92.3%) were men, 479,377 (65.3%) were White, and 156,092 (21.3%) were Black. By the end of follow-up, 104,361 (14.2%) patients had polypharmacy, 15,485 (2.1%) had hyperpolypharmacy, and 129,992 (17.7%) were dispensed ≥ 1 PIM. PIMs were independently associated with mortality (HR 1.11, 95% CI 1.04-1.18). PIMs also modestly attenuated risk of mortality associated with polypharmacy (HR 1.07, 95% CI 1.03-1.11 before versus HR 1.05, 95% CI 1.01-1.09 after) and hyperpolypharmacy (HR 1.18, 95% CI 1.09-1.28 before versus HR 1.12, 95% CI 1.03-1.22 after). Patterns varied when stratified by sex and race/ethnicity. LIMITATIONS: The predominantly male VA patient population may not represent the general population. CONCLUSION: PIMs were independently associated with increased mortality, and partially explained polypharmacy-associated mortality in middle-aged people. Other mechanisms of injury from polypharmacy should also be studied.

Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

BACKGROUND: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Impact of Covid-19 Vaccination on Spontaneous Pharmacovigilance Reporting in France.

INTRODUCTION: In 2021, the massive Covid-19 vaccination campaign in France was accompanied by an intensified pharmacovigilance monitoring of their potential adverse drug reactions. The importance of this reporting might have led to an important selective reporting and overloading of Pharmacovigilance Centres, delaying the recording of some reports in the national pharmacovigilance database. In this context, we aimed to evaluate the impact of the Covid-19 vaccination campaign in France and related reports on spontaneous reporting of adverse drug reactions that were not related to the Covid-19 vaccine. METHODS: We performed time-series analyses considering the monthly number of adverse drug reactions reported between January 1, 2018 and April 30, 2022 using the French Pharmacovigilance database. The impact of the Covid-19 vaccination campaign on the monthly reporting not Covid-19 vaccine related was estimated using interrupted time-series. January 2021, marking the start of the campaign, was the intervention date in the models. Analyses were run globally first considering all adverse drug reaction reports, and second according to notifier type and to case seriousness. RESULTS: We included 170,294 reports registered in the French Pharmacovigilance database between January 1, 2018 and April 30, 2022 that were not Covid-19 vaccine-related. Among these, 77,067 (45.3%) were serious and 146,683 (86.1%) had been reported by health care professionals. The campaign start was associated with a nearly 35.0% decrease in average monthly reporting that was not Covid-19 vaccine-related, with a significant level decrease in the monthly number of reports of -658.0 (p < 10-3) immediately after the vaccination campaign start and a subsequent slope decrease of -50.0 (p < 10-3). This decrease was mainly due to a significant level and slope decrease (level: -739.2 p < 10-3; slope: -39 [p < 10-2]) for health care professional reports. A similar level decrease was found for the monthly number of both serious and non-serious reports (-402.3, p < 10-3; and -311.9, p = 10-2, respectively). According to the ATC 1 level, the decrease in the monthly number of reports showed similar patterns for all drugs. However, a potential increase in the number of serious reports suspecting antineoplastic and immunomodulating drugs (ATC L) or drugs targeting blood was observed (ATC B). CONCLUSION: Our study showed a significant impact of the Covid-19 campaign vaccination in the reporting of adverse drug reactions that were not Covid-19 vaccine-related, of roughly 35%. This leads to a loss of information regarding the monitoring of drug safety that could have impacted the system capacity to detect safety signals for drugs other than Covid-19 vaccines.

Trajectories of Benzodiazepine Use among Older Adults from a Concordance-with-Guidelines Perspective: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVE: Benzodiazepines (including zolpidem and zopiclone) are often associated with higher-than-recommended intake and durations of use, especially in older adults. The objective of this study was to characterize trajectories of benzodiazepine use according to recommended patterns in older adults, and to assess predictors of the risk of developing each of these trajectories. METHODS: Using the French Health Insurance database, we constituted a cohort of adults aged ≥ 65 years who initiated benzodiazepines in 2007 and were followed for up to 8 years. Concordance with benzodiazepine use guidelines was assessed on a quarterly basis according to a "concordance-with-guideline score" with values 1-5. Group-based trajectory modeling was then applied as implemented in the Proc Traj procedure in SAS to define guideline-concordant trajectories based on seven baseline patient-centered characteristics: sex, complementary health insurance coverage, treated alcohol and tobacco use disorder, polypharmacy, hospital stay, and registered chronic diseases. RESULTS: Among 5080 new users (64.1% women, median age 74 years), six trajectories of benzodiazepine use were identified. Three, representing 70% of users, were concordant with guidelines, whereas three implied non-concordant benzodiazepine use for part or all of the benzodiazepine use follow-up. Polymedicated patients were more prone to develop chronic non-guideline-concordant initially guideline-concordant use, whereas those with a history of long-term disease and hospitalization were more likely to develop chronic non-guideline-concordant use. The number of prescribers during the first quarter, number of daily defined doses, use of loperamide, and use of psychostimulants were associated with a higher risk of developing an initial and persistent non-guideline-concordant use. Treatment initiation by a psychiatrist, initial use of World Health Organization (WHO) step-2 opioids and non-benzodiazepine anxiolytics or sedatives were associated with a higher risk of late non-guideline-concordant use. CONCLUSIONS: Concordance with guidelines varied over time during benzodiazepine use in older adults. A third of these adults will hypothetically follow one of the identified non-guideline-concordant trajectories, consisting of initial and/or late non-guideline concordance. This was associated with modifiable and nonmodifiable factors that clinicians should be aware of for tailoring the monitoring of patients.

[Performing pharmacoepidemiological studies using the French health insurance data warehouse (SNDS): How to translate guidelines into practice]. / Réalisation d'études pharmacoépidémiologiques à partir du système national des données de santé (SNDS) : application des recommandations dans la pratique.

The French health insurance data warehouse named SNDS is one of the largest medico-administrative in the world allowing for powerful pharmacoepidemiological studies, based on real-life data collected prospectively. In addition to the absolute necessity of a strong pharmacological rationale, recommendations have been thought to improve the quality of pharmacoepidemiological studies. These guidelines emphasize the importance of an accurate definition of the study population, outcome and exposure, especially for studies performed on medico-administrative databases. Compliance with certain guidelines, particularly those concerning the identification of a specific population or an outcome and the definition of risk periods or exposure periods, may be difficult when performing studies on the SNDS because of its structure and the nature of the data recorded. The objective of this article is to provide advice for the conduct of pharmacoepidemiological studies according to the recommendationswhen using the SNDS, given its specificities. The performing of reliable studies from this rich but complex data warehouse requires the expertise of researchers with deep knowledge both in the SNDS and in pharmacological reasoning.

GLP-1 Receptor Agonists and the Risk of Thyroid Cancer.

OBJECTIVE: To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. RESEARCH DESIGN AND METHODS: A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. RESULTS: A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1-3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05). CONCLUSIONS: In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1-3 years of treatment.

Chronic polypharmacy at all age: A population-based drug utilization study.

Polypharmacy is a growing concern often described only in older people by cumulating all drugs taken. We aimed to describe chronic polypharmacy in France, regardless of age. A cross-sectional descriptive study was performed using the 1/97th representative sample of the French health insurance nationwide database (EGB). All subjects alive on January 1, 2015, and covered by the French healthcare insurance were included, and their information collected until December 31, 2015, or date of death. Drug exposures were estimated from drug dispensing dates and treatment durations. Chronic uses of drug were defined as drugs used daily for more than 6 months. Chronic polypharmacy corresponded to the exposure to five chronic uses of drug or more. In 2015, information of 584 862 subjects was collected (mean age: 42.2 years). Prevalence of chronic polypharmacy was 5.6% and incidence 1.1%. Prevalence of chronic polypharmacy increased noticeably from 0.2% for subjects aged 18 to 40 years to a maximum of 29.2% for subjects aged 80 to 90 years and then decreased to 23.6% for subjects aged 90 years and more. Lipid-modifying agents were the most frequent drugs involved in chronic polypharmacy (10% of exposure). According to age, the most important differences between the younger and older people were found for cardiovascular drugs (43.5% vs. 45.7% of exposure, respectively) and nervous system drugs (13.7% vs. 11.5% of exposure, respectively). This population-based study showed increasing of chronic polypharmacy and evolution of chronic drug patterns with age.

Systematising Pharmacovigilance Engagement of Patients, Healthcare Professionals and Regulators: A Practical Decision Guide Derived from the International Risk Governance Framework for Engagement Events and Discourse.

INTRODUCTION: Input from patients and healthcare professionals to regulatory assessments is essential for benefit-risk management of medicines. How to best obtain input in different risk scenarios is uncertain. OBJECTIVES: The objective of this study was to investigate whether the International Risk Governance Council (IRGC) Framework is applicable to pharmacovigilance and can guide selecting engagement mechanisms for optimising stakeholder input. METHODS: For proof-of-concept, classify 'iconic' cases of pharmacovigilance engagement at the European Medicines Agency (EMA) by IRGC risk scenario types and compare the engagement that happened with the engagement discourse recommended by the IRGC Framework for different risk scenarios. If the concept is proven, derive proposals for strengthening engagement. RESULTS: Six iconic cases were classified by risk scenario type at the respective time points when deciding on engagement: venous thromboembolism with combined hormonal contraceptives (complex risk); lipodystrophy with highly active antiretroviral therapy medicines, carcinogenicity with contaminated nelfinavir products (uncertain risks); teratogenicity with thalidomide, progressive multifocal leukoencephalopathy with natalizumab, teratogenicity and developmental disorders with valproate (ambiguous risks). The comparison of the engagement events with IRGC recommendations showed correspondence between the scope/outcomes of the events and the features of the recommended discourse. CONCLUSIONS: The IRGC Framework appears applicable to pharmacovigilance. Proposals derived from the IRGC recommendations may be valuable for guiding regulators when selecting mechanisms for engagement with patients and healthcare professionals in given risk scenarios. The proposed decision guide aims at ensuring systematic and consistent engagement across regulatory assessments and providing for the most purposeful discourse, to effectively obtain real-world input for regulatory risk assessment, evaluation of risk minimisation measures and decision making.

The Burden of Potentially Inappropriate Medications in Chronic Polypharmacy.

We aimed to describe the burden represented by potentially inappropriate medications (PIMs) in chronic polypharmacy in France. We conducted a nationwide cross-sectional study using data from the French National Insurance databases. The study period was from 1 January 2016 to 31 December 2016. Chronic drug use was defined as uninterrupted daily use lasting ≥6 months. Chronic polypharmacy was defined as the chronic use of ≥5 medications, and chronic hyperpolypharmacy as the chronic use of ≥10 medications. For individuals aged ≥65 (older adults), PIMs were defined according to the Beers and Laroche lists, and for individuals aged 45-64 years (middle-aged) PIMs were defined according to the PROMPT (Prescribing Optimally in Middle-aged People's Treatments) list. Among individuals with chronic polypharmacy, 4009 (46.2%) middle-aged and 18,036 (64.8%) older adults had at least one chronic PIM. Among individuals with chronic hyperpolypharmacy, these figures were, respectively, 570 (75.0%) and 2544 (88.7%). The most frequent chronic PIM were proton pump inhibitors (43.4% of older adults with chronic polypharmacy), short-acting benzodiazepines (older adults: 13.7%; middle-aged: 16.1%), hypnotics (6.1%; 7.4%), and long-acting sulfonylureas (3.9%; 12.3%). The burden of chronic PIM appeared to be very high in our study, concerning almost half of middle-aged adults and two-thirds of older adults with chronic polypharmacy. Deprescribing interventions in polypharmacy should primarily target proton pump inhibitors and hypnotics.

Impact of Secured Prescription Implementation for Zolpidem on Hypnotics Use in France: A Time-Series Analysis on National Data.

We evaluated the impact of the implementation of a requirement that zolpidem prescriptions be obtained via secured forms (April 2017) on zolpidem and other hypnotics use in France. We conducted a time-series analysis on data from the French national health care system, from January 1, 2015 to January 3, 2018, for all reimbursed hypnotics. An important and immediate decrease in zolpidem use (-161,873 defined daily doses [DDD]/month; -215,425 to -108,323) was evidenced, with a concomitant raise in zopiclone use (+64,871; +26,925 to +102,817). These findings suggest that the change in zolpidem prescribing policies was effective, but has resulted in a shift from zolpidem to zopiclone. Further interventions are needed to decrease hypnotics' overuse in France.

Use of benzodiazepines non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic disorders.

OBJECTIVE: To quantify benzodiazepine use non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic diseases and assess the risk of non-recommended use associated with these diseases. METHOD: A cohort study was conducted in the French health insurance databases, including 254,488 new benzodiazepine users between 2007 and 2014. Psychiatric, cardiovascular, cancer, diabetes and inflammatory diseases were identified. Patients were followed for 2 years. Non-recommended use was defined as excessive treatment duration, use of long half-life drugs in older patients and concomitant use of several benzodiazepines. Cox models identified the factors associated with non-recommended use. RESULTS: Non-recommended use was frequent, ranging from 44.9% to 68.1%. It was independently associated with each chronic disease, with a slight increase in patients with chronic inflammatory disease (HR = 1.07; 95%CI 1.03-1.13) or diabetes (HR = 1.09; 1.06-1.12), a higher risk in those with chronic cardiovascular disease (HR = 1.34; 1.31-1.37) or cancer (HR = 1.30; 1.25-1.35) and the highest risk in those with psychiatric disease (HR = 2.04; 2.00-2.09). CONCLUSION: Patients with chronic disease have a high risk of benzodiazepine use leading to a higher exposure than recommended. Prescribers should be aware of the need to comply with the recommendations, especially in these patients who are the most frail and vulnerable to adverse events.

Contribution of Causality Assessment for an Automated Detection of Safety Signals: An Example Using the French Pharmacovigilance Database.

INTRODUCTION: Qualitative approaches based on drug causality assessment estimate the causal link between a drug and the occurrence of an adverse event from individual case safety reports. Quantitative approaches based on disproportionality analyses were developed subsequently to allow automated statistical signal detection from pharmacovigilance databases. This study assessed the potential value of causality assessment for automated safety signal detection. METHODS: All drug-serious adverse event pairs with a positive rechallenge and a semiology suggestive of drug causality were identified in the French pharmacovigilance database (BNPV) from 2011 to 2017. The results were compared with those obtained from automated disproportionality analyses of the BNPV/World Health Organization (WHO) VigiBase®, complemented by the list of signals validated by the WHO-UMC (Uppsala Monitoring Centre). Summary of Product Characteristics (SmPCs), Martindale®, Meyler's® and MedLINE® were used as other sources of information for the purpose of comparison. RESULTS: Of the 155 pairs of interest, 115 (74.2%) were also identified by another source of information. Since the individual case reporting in the BNPV, 23 (14.8%) of the adverse events (AEs) have been added to the SmPC, seven of which were not identified by disproportionality. Finally, 40 pairs were not identified by any other source of information, 13 of which were considered as potential new safety signals after analysis of case reports by pharmacovigilance experts. The signals identified by causality assessment involved antineoplastic and immunomodulatory drugs especially, in comparison with signals identified by WHO-UMC or by disproportionality within the BNPV. CONCLUSION: The approach therefore appears useful as an additional tool for safety signal detection, especially for antineoplastic and immunomodulating agents.

Use of benzodiazepines and z-drugs not compliant with guidelines and associated factors: a population-based study.

Benzodiazepines and z-drugs are primarily indicated for the treatment of sleep disorders and anxiety symptoms. Their frequent long-term use contrasts with the international guidelines that limit treatment duration to a maximum of 4 weeks. The objective of this study was to assess the frequency of their use that was not in accordance with guidelines in the French general population between 2007 and 2012 and associated characteristics. A cohort of 67,550 benzodiazepine new users was set up in an exhaustive database for health-care reimbursements and representative of the French population. Benzodiazepine use not in accordance with guidelines was defined as the concomitant dispensation of several benzodiazepines, the dispensation of treatment over a period longer than recommended, or a new dispensing within the 2 months following the end of a previous treatment of maximum recommended duration, considering that French recommendations distinguish between hypnotic (4 weeks) and anxiolytic benzodiazepines (12 weeks). Benzodiazepine use not in accordance with guidelines was high, in about 30% of new hypnotic users and 20% of new anxiolytic users. Its frequency was stable over the study period. Associated characteristics were similar for new hypnotic or anxiolytic users, i.e.. older age, treatment initiation by a psychiatrist, presence of a chronic disease, hospitalization, or another psychotropic treatment. These findings provide a solid basis for establishing a public health policy to reduce benzodiazepine use not compliant with guidelines. They should be further explored in patients most at risk in the present study, e.g., patients treated by a psychiatrist.

Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study.

BACKGROUND: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs. AIM: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs. METHODS: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs. RESULTS: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P<0.0001 for all). The corresponding RORs for HF were 2.5 (2-3), 1.5 (1.3-1.7) and 2 (1.7-2.3), respectively (P<0.0001 for all). These results were concordant with the French and European pharmacovigilance databases. Mean times to AT and HF onset were shorter with abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) versus other ADTs (13.3±3.2 and 9.2±1.1 months, respectively) (both P<0.05). Cases on abiraterone versus other ADTs were more frequently associated with at least two ADR terms, including AT, HF, hypokalaemia, hypertension and oedema (13.6% vs 6%; P<0.0001). For abiraterone, age, but not dose, was associated with reporting of AT and HF versus any other ADR. CONCLUSIONS: Compared with other ADTs, abiraterone was associated with higher reporting of AT and HF, associated with hypokalaemia, hypertension and oedema. These findings are consistent with the hypermineralocorticism induced by abiraterone, but not by other ADTs.

Use of Lipid-Lowering Drugs and the Risk of Cataract: A Population-Based Nested Case-Control Study.

Eye lens membrane cells require high cholesterol concentrations that might be counteracted by lipid-lowering drugs. Using a nationwide database, we conducted a nested case-control study to evaluate the risk of cataract development associated with the use of lipid-lowering drugs. Patients aged 45 years and over with first cataract surgery in 2014 (cases) and up to four controls matched on age, gender, diabetes, hypothyroidism, glucocorticoid use, cardiovascular risk, and area of residence were included in the study. Among the 2,811 cases and 11,106 matched controls included, analyses showed a significantly increased risk of cataract surgery for a cumulative exposure to fibrates exceeding 5 years (adjusted odds ratio (aOR) 1.58; 95% confidence interval (CI): 1.17-2.15), unlike cumulative exposure to statins, whatever the dose or duration of treatment (aORs from 1.00-1.08, none being significant). This study highlighted an increased risk of cataract surgery with prolonged use of fibrates but not of statins.

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs. METHODS: In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540. FINDINGS: We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC025 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC025 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC025 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ2 test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001). INTERPRETATION: Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy). FUNDING: The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.