Comparison of atrial fibrillation prevalence and in-hospital cardiovascular outcomes between patients undergoing allogeneic versus autologous hematopoietic stem cell transplantation: insights from the national inpatient sample.

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for several malignant and non-malignant hematologic conditions. However, patients undergoing HSCT are at increased risk of developing serious cardiovascular events. Whether cardiovascular risks differ by the type of transplantation strategy used, allogeneic versus autologous HSCT, is unknown. Leveraging the National Inpatient Sample (2016-2019), we assessed the incidence of early cardiovascular events by HSCT mode (allogeneic vs autologous). The primary outcome was the incidence of atrial fibrillation (AF). The secondary outcome was the occurrence of any major adverse cardiac events (MACE), defined as acute heart failure, myocardial infarction (MI), symptomatic atrial or ventricular arrhythmia or heart block, and cardiovascular death. Outcomes were compared between those undergoing allogeneic versus autologous HSCT. Multivariable regression, adjusting for cardiovascular and cancer-related factors, was used to define the association between pre-HSCT factors and MACE. We further assessed the effect of acute cardiovascular events on in-patient mortality by calculating adjusted odds ratio (aOR) with corresponding 95% confidence intervals (CI) and p-values. Overall, 64,705 weighted hospitalizations for HSCT were identified, of which 22,655 (35.0%) were allogeneic HSCT and 42,050 (65.0%) were autologous HSCT. The prevalence of AF was 9.1%, and 12.1% for any arrhythmia. In multivariable regression, allogeneic HSCT was associated with higher adjusted odds of peri-HSCT acute heart failure (aOR 2.64; 1.86-3.76; p < 0.0001), QT prolongation (aOR 1.40; 1.04-1.88; p = 0.025), MI (aOR 2.87; 1.16-7.11; p = 0.023), any major cardiovascular complication (aOR 1.16; 1.03-1.32; p = 0.016), and inpatient mortality (aOR 4.87; 3.60-6.58; p < 0.0001). Following cerebrovascular events, AF was the strongest predictor of mortality. Allogeneic HSCT was associated with higher odds of in-hospital cardiovascular complications among patients undergoing HSCT.

Effect of implantable loop recorder-based continuous rhythm monitoring on incident atrial fibrillation and stroke: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: In patients with a history of stroke or those at high risk for developing stroke, a continuous rhythm monitoring strategy using an implantable loop recorder (ILR) is often performed to screen for atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to perform a systematic review (MEDLINE and EMBASE) including randomized controlled trials comparing ILR-based continuous rhythm monitoring vs usual care in patients with a history of stroke or patients at high risk for developing stroke. METHODS: A meta-analysis was performed, and aggregate risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI) were calculated. RESULTS: Four randomized controlled trials with 7237 patients (ILR 2114, non-ILR 5123) were included. ILR vs non-ILR was associated with increased detection of incident AF (RR 3.88; 95% CI 2.23-6.75; P <.00001; number needed to treat [NNT] = 7.7; I2 = 61%), increased appropriate initiation of anticoagulation (RR 2.29; 95% CI 2.07-2.55; P <.00001; NNT = 6.7; I2 = 0), and a 25% lower risk of developing stroke (RR 0.75; 95% CI 0.59-0.95]; P = .02; NNT = 100; I2 = 0%). In patients with history of stroke there was no difference in the risk of developing incident stroke (RR 0.83; 95% CI 0.61-1.14]; P = .25; I2 = 0%). CONCLUSION: Our meta-analysis showed that screening for AF with ILR is associated with increased detection of AF and increased initiation of appropriate anticoagulation therapy in patients with a history of stroke or those with risk factors for stroke. The benefit of stroke risk reduction with ILR remains unclear, and future studies focused on the inclusion of patients without a history of stroke are needed to elucidate this uncertainty.

Outcomes of patients with cardiac amyloidosis undergoing percutaneous left atrial appendage occlusion.

BACKGROUND: There is limited data on the safety and efficacy of left atrial appendage occlusion (LAAO) devices in patients with cardiac amyloidosis. We examined the outcomes of patients with cardiac amyloidosis undergoing LAAO device implantation in a nationally representative cohort of patients. METHODS: The National Readmissions Database (NRD) was analyzed from 2016 to 2019 to identify patients ≥ 18 years old with atrial fibrillation (AF) undergoing LAAO. Patients were divided into those with cardiac amyloidosis and those without cardiac amyloidosis. A multivariable logistic regression model was utilized to assess the independent association of cardiac amyloidosis with in-hospital, 30-day/90-day/180-day outcomes after adjusting for confounders. RESULTS: Our cohort included 54,900 LAAO implantation procedures, of which 220 (0.4%) had cardiac amyloidosis. Patients with cardiac amyloidosis had a lower proportion of women and a lower prevalence of comorbidities including anemia, obesity, diabetes, and peripheral vascular disorders but a higher prevalence of stroke, as compared to those without cardiac amyloidosis. On multivariable analysis, cardiac amyloidosis was associated with significantly higher odds of peri-procedural major adverse events (adjusted odds ratio [aOR]: 2.69; 95% confidence interval [CI]: 1.41-5.14; p<0.01) and neurological complications (aOR: 5.48; 95% CI: 2.47-12.8; p<0.01). There was no difference in the odds of other peri-procedural complications, in-hospital mortality, hospital resource utilization, and 30/90/180-day all-cause/bleeding/stroke-related readmissions between both groups. CONCLUSION: Patients with cardiac amyloidosis undergoing LAAO device implantation have an increased risk of peri-procedural complications without any difference in bleeding/stroke-related readmissions. These hypothesis-generating findings need validation in future prospective studies.

Contemporary trends of leadless pacemaker implantation in the United States.

INTRODUCTION: Leadless pacemakers (LPM) have established themselves as the important therapeutic modality in management of selected patients with symptomatic bradycardia. To determine real-world utilization and in-hospital outcomes of LPM implantation since its approval by the Food and Drug Administration in 2016. METHODS: For this retrospective cohort study, data were extracted from the National Inpatient Sample database from the years 2016-2020. The outcomes analyzed in our study included implantation trends of LPM over study years, mortality, major complications (defined as pericardial effusion requiring intervention, any vascular complication, or acute kidney injury), length of stay, and cost of hospitalization. Implantation trends of LPM were assessed using linear regression. Using years 2016-2017 as a reference, adjusted outcomes of mortality, major complications, prolonged length of stay (defined as >6 days), and increased hospitalization cost (defined as median cost >34 098$) were analyzed for subsequent years using a multivariable logistic regression model. RESULTS: There was a gradual increased trend of LPM implantation over our study years (3230 devices in years 2016-2017 to 11 815 devices in year 2020, p for trend <.01). The adjusted mortality improved significantly after LPM implantation in subsequent years compared to the reference years 2016-2017 (aOR for the year 2018: 0.61, 95% CI: 0.51-0.73; aOR for the year 2019: 0.49, 95% CI: 0.41-0.59; and aOR for the year 2020: 0.52, 95% CI: 0.44-0.62). No differences in adjusted rates of major complications were demonstrated over the subsequent years. The adjusted cost of hospitalization was higher for the years 2019 (aOR: 1.33, 95% CI: 1.22-1.46) and 2020 (aOR: 1.69, 95% CI: 1.55-1.84). CONCLUSION: The contemporary US practice has shown significantly increased implantation rates of LPM since its approval with reduced rates of inpatient mortality.

Trends and disparities in cardiac implantable electronic device infection-related mortality in the United States.

INTRODUCTION: We performed a cross-sectional study using the Centers for Disease Control and Prevention's (CDC's) Wide-Ranging Online Data for Epidemiologic Research (WONDER) database to analyze the trends in cardiac implantable electronic device (CIED) infection-related mortality from 1999 to 2020. METHODS: We analyzed the death certificate data from the CDC WONDER database from 1999 to 2020 for CIED infections in the US population aged ≥25 years using International Classification of Diseases, Tenth Revision (ICD-10) codes, listed as the underlying or contributing cause of death. Age-adjusted mortality rates (AAMR) and 95% confidence intervals (CIs) were computed per 1 million population by standardizing crude mortality rates to the 2000 US census population. To assess annual mortality trends, we employed the Joinpoint regression model, calculating the annual percent change (APC) in AAMR and corresponding 95% CIs. RESULTS: Overall, there was an observed declining trend in AAMRs related to CIED infection-related mortality. Males accounted for 55% of the total deaths, with persistently higher AAMRs compared to females over the study duration. Both males and females had an overall decreasing trend in AAMRs throughout the study duration. On race/ethnicity stratified analysis, non-Hispanic (NH) Blacks exhibited the highest overall AAMR, followed by NH American Indians or Alaska Natives, NH Whites, Hispanic or Latinos, and NH Asian or Pacific Islanders. On a stratified analysis based on region, the South region had the highest overall AAMR, followed by the Midwest, West, and Northeast regions. CONCLUSION: Our study demonstrates a significant decline in CIED infection-related mortality in patients over the last two decades. Notable gender, racial/ethnic, and regional differences exist in the rates of mortality related to CIED infections.

Sex differences in atrial fibrillation ablation outcomes in patients with heart failure.

BACKGROUND: There is a lack of data on the impact of sex on the outcomes of patients with heart failure (HF) undergoing atrial fibrillation (AF) ablation. We aimed to analyze the association of sex with outcomes of atrial fibrillation ablation in patients with heart failure. METHODS: The National Readmissions Database (NRD) was analyzed from 2016 to 2019 to identify patients ≥ 18 years old with heart failure (HF) undergoing AF ablation. The outcomes of interest included peri-procedural complications, in-hospital mortality, resource utilization, and unplanned 1-year readmissions. The final cohort was divided into patients with HFrEF and HFpEF and outcomes were compared between males and females in both cohorts. RESULTS: A total of 23,277 patients with HF underwent AF ablation between 2016 and 2019, of which 14,480 had HFrEF and 8,797 had HFpEF. Among patients with HFrEF, 61.6% were males and 38.4% were females whereas, among patients with HFpEF, 35.4% were males and 64.6% were females. On a multivariable-adjusted analysis, in patients with HFrEF, there was no difference in the odds of in-hospital mortality, peri-procedural complications, or 1-year HF-related/AF-related/all-cause readmissions between males and females. In patients with HFpEF, females had a higher risk 1-year HF-related readmissions (adjusted hazards ratio: 1.46; 95% CI: 1.13-1.87; p = 0.01), without any difference in the 1-year AF-related/all-cause readmissions, in-hospital mortality, or peri-procedural complications. CONCLUSION: Our results show that females with HFrEF undergoing AF ablation have similar outcomes whereas females with HFpEF have higher 1-year HF readmissions with no difference in the other outcomes, compared to males.

Pericardial effusion requiring intervention in patients undergoing leadless pacemaker implantation: A real-world analysis from the National Inpatient Sample database.

Background: Pericardial effusion requiring percutaneous or surgical-based intervention remains an important complication of a leadless pacemaker implantation. Objective: The study sought to determine real-world prevalence, risk factors, and associated outcomes of pericardial effusion requiring intervention in leadless pacemaker implantations. Methods: The National Inpatient Sample and International Classification of Diseases-Tenth Revision codes were used to identify patients who underwent leadless pacemaker implantations during the years 2016 to 2020. The outcomes assessed in our study included prevalence of pericardial effusion requiring intervention, other procedural complications, and in-hospital outcomes. Predictors of pericardial effusion were also analyzed. Results: Pericardial effusion requiring intervention occurred in a total of 325 (1.1%) leadless pacemaker implantations. Patient-level characteristics that predicted development of a serious pericardial effusion included >75 years of age (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08-1.75), female sex (OR 2.03, 95% CI 1.62-2.55), coagulopathy (OR 1.50, 95% CI 1.12-1.99), chronic pulmonary disease (OR 1.36, 95% CI 1.07-1.74), chronic kidney disease (OR 1.53, 95% CI 1.22-1.94), and connective tissue disorders (OR 2.98, 95% CI 2.02-4.39). Pericardial effusion requiring intervention was independently associated with mortality (OR 5.66, 95% CI 4.24-7.56), prolonged length of stay (OR 1.36, 95% CI 1.07-1.73), and increased cost of hospitalization (OR 2.49, 95% CI 1.92-3.21) after leadless pacemaker implantation. Conclusion: In a large, contemporary, real-world cohort of leadless pacemaker implantations in the United States, the prevalence of pericardial effusion requiring intervention was 1.1%. Certain important patient-level characteristics predicted development of a significant pericardial effusion, and such effusions were associated with adverse outcomes after leadless pacemaker implantations.

Prevalence and Predictors of Readmissions in Patients With Hypertrophic Cardiomyopathy and Atrial Fibrillation/Flutter.

Atrial fibrillation/flutter (AF) is the most common dysrhythmia in patients with hypertrophic cardiomyopathy (HCM). Unexplained left ventricular hypertrophy and left ventricular outflow tract obstruction are integral components of HCM pathology which can cause increased left atrial pressure and atrial myopathy contributing to the substrate for AF. We aimed to determine the impact of AF on hospital readmissions in patients with HCM. We conducted a retrospective analysis using the 2015 to 2019 Nationwide Readmission Database to analyze the effect of AF on 30-day readmission and causes of 30-day readmission in patients with HCM. We also determined the hospital, patient, and procedure-specific independent predictors of readmission in patients with HCM and AF. Of 191,235 index HCM hospitalizations, 81,390 (42.6%) had a secondary diagnosis of AF. A total of 16.9% of patients with HCM and AF were readmitted within 30 days as compared with 14% of HCM patients without AF. The presence of AF was independently associated with a higher risk of all-cause 30-day readmission (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.17 to 1.25, p <0.001). The foremost etiology of 30-day readmission in HCM patients with AF was hypertensive heart and chronic kidney disease with heart failure, whereas the foremost etiology of 30-day readmission in HCM patients without AF was sepsis. Interventions aimed toward AF management (electrical cardioversion: adjusted HR 0.91, 95% CI 0.82 to 1.01. p = 0.074, AF ablation: HR 0.92, 95% CI 0.74 to 1.13, p = 0.409, Watchman procedure: HR 1.50, 95% CI 0.16 to 14.6, p = 0.725) during index admission did not significantly impact the 30-day readmission in HCM patients with AF. Myectomy during index hospitalization (adjusted HR 0.54, 95% CI 0.34 to 0.86, p = 0.010) was most strongly associated with a lower risk of 30-day readmission in HCM patients with AF. In conclusion, in patients hospitalized for HCM, presence of AF was associated with excess risk of 30-day all-cause readmission. Interventions aimed toward HCM management, that is, myectomy rather than interventions aimed toward AF management predicted lower readmission rate in this patient population.

Association between atrial fibrillation and heart failure patient reported outcomes across the ejection fraction spectrum.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure (HF) and is associated with worse clinical outcomes. We evaluated the relationship between AF and longitudinal changes in health-related quality of life (HRQoL) measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) in both HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). METHODS: This is a post-hoc analysis of the TOPCAT and HF-ACTION trials. The effect of AF on KCCQ overall summary scores (OSS), in both trials, was examined using a mixed effects regression model. Patients were divided into 3 groups according to AF status at baseline: patients with a history of AF but no AF detected on ECG at enrollment (Hx AF group), patients with history of AF and AF detected on ECG at enrollment (ECG AF group) and patients with post-randomization new-onset AF (New AF group). RESULTS: In TOPCAT, among 1,710 patients with KCCQ data available, AF was associated with a significantly lower KCCQ-OSS (-3.98; 95% CI -7.21: -0.74) at 48 months, with a significant AF status by time interaction (P = .03). In HF-ACTION, among 1,814 patients with available KCCQ data, AF was associated with a significantly lower KCCQ-OSS (-3.67; 95% CI -6.21: -1.41) at 24 months but there was no significant AF status by time interaction. In both trials, the type of AF was not associated with significant changes in KCCQ-OSS score. CONCLUSION: Ιn patients with both HFpEF and HFrEF, AF was independently associated with worse HRQoL measured by KCCQ.

Association of chronic kidney disease and end-stage renal disease with procedural complications and inpatient outcomes of leadless pacemaker implantations across the United States.

BACKGROUND: Leadless pacemakers have emerged as a promising alternative to transvenous pacemakers in patients with kidney disease. However, studies investigating leadless pacemaker outcomes and complications based on kidney dysfunction are limited. OBJECTIVE: The objective of this study was to evaluate the association of chronic kidney disease (CKD) and end-stage renal disease (ESRD) with inpatient complications and outcomes of leadless pacemaker implantations. METHODS: National Inpatient Sample and International Classification of Diseases, Tenth Revision codes were used to identify patients with CKD and ESRD who underwent leadless pacemaker implantations in the United States from 2016 to 2020. Study end points assessed included inpatient complications, outcomes, and resource utilization of leadless pacemaker implantations. RESULTS: A total of 29,005 leadless pacemaker placements were identified. Patients with CKD (n = 5245 [18.1%]) and ESRD (n = 3790 [13.1%]) were younger than patients without CKD and had higher prevalence of important comorbidities. In crude analysis, ESRD was associated with higher prevalence of major complications, peripheral vascular complications, and inpatient mortality. After multivariable adjustment, CKD and ESRD were associated with inpatient mortality (CKD: adjusted odds ratio [aOR], 1.62 [95% CI, 1.40-1.86]; ESRD: aOR, 1.38 [95% CI, 1.18-1.63]) and prolonged length of stay (CKD: aOR, 1.55 [95% CI, 1.46-1.66]; ESRD: aOR, 1.81 [95% CI 1.67-1.96]). ESRD was also associated with higher hospitalization costs (aOR, 1.63; 95% CI, 1.50-1.77) and major complications (aOR, 1.33; 95% CI, 1.13-1.57) after leadless pacemaker implantation. CONCLUSION: Approximately one-third of patients undergoing leadless pacemaker implantation had CKD or ESRD. CKD and ESRD were associated with greater length and cost of stay and inpatient mortality.

Environmental Exposome and Atrial Fibrillation: Emerging Evidence and Future Directions.

There has been increased awareness of the linkage between environmental exposures and cardiovascular health and disease. Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting millions of people worldwide and contributing to substantial morbidity and mortality. Although numerous studies have explored the role of genetic and lifestyle factors in the development and progression of atrial fibrillation, the potential impact of environmental determinants on this prevalent condition has received comparatively less attention. This review aims to provide a comprehensive overview of the current evidence on environmental determinants of atrial fibrillation, encompassing factors such as air pollution, temperature, humidity, and other meteorologic conditions, noise pollution, greenspace, and the social environment. We discuss the existing evidence from epidemiological and mechanistic studies, critically evaluating the strengths and limitations of these investigations and the potential underlying biological mechanisms through which environmental exposures may affect atrial fibrillation risk. Furthermore, we address the potential implications of these findings for public health and clinical practice and identify knowledge gaps and future research directions in this emerging field.

Risk factors, clinical implications, and management of peridevice leak following left atrial appendage closure: A systematic review.

BACKGROUND: Left atrial appendage closure (LAAC) is a treatment modality for stroke prevention in patients with atrial fibrillation (AF). One of the potential complications of LAAC is a peri-device leak (PDL), which could potentially increase the risk of thromboembolism formation. METHODS: This systematic review was done according to PRISMA guidelines. Using four databases, all primary studies through April 2022 that met selection criteria were included. Outcomes of interest were studies reporting on PDL characteristics, risk factors and management. RESULTS: A total of 116 studies met selection criteria (97 original studies and 19 case reports/series). In the original studies (n = 30,133 patients), the weighted mean age was 72.0 ± 7.4 years (57% females) with a HAS-BLED and CHA2DS2-VASc weighted means of 2.8 ± 1.1 and 3.8 ± 1.3, respectively. The most common definition of PDL was based on size; 5 mm: major, 3-5 mm: moderate, < 1 mm minor, or trivial. Follow up time for PDL detection was 7.15 ± 9.0 months. 33% had PDL, irrespective of PDL severity/size, and only 0.9% had PDL of greater than 5 mm. The main risk factors for PDL development included lower degree of over-sizing, lower left ventricular ejection fraction, device/LAA shape mismatch, previous radiofrequency ablation, and male sex. The most common methods to screen for PDL included transesophageal echocardiogram and cardiac CT. PDL Management approaches include Amplatzer Patent Foramen Ovale occluder, Hookless ACP, Amplatzer vascular plug II, embolic coils, and detachable vascular coils; removal or replacement of the device; and left atriotomy. CONCLUSION: Following LAAC, the emergence of a PDL is a significant complication to be aware of. Current evidence suggests possible risk factors that are worth assessing in-depth. Additional research is required to assess suitable candidates, timing, and strategies to managing patients with PDL.

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial.

BACKGROUND: Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS). OBJECTIVES: In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation. METHODS: tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points. RESULTS: Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed. CONCLUSIONS: Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Treatment-related adverse events, including fatal toxicities, in patients with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. METHODS: For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatment-related deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3-4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741. FINDINGS: 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1·76, 95% CI 0·95-3·25; p=0·073), consistent across immune checkpoint blockade subtype (I2=0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15·0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3-4 treatment-related adverse events (OR 2·73, 95% CI 1·98-3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45-5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88-3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04-15·63; p=0·044) and grade 3-4 adverse events (5·31, 3·08-9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38-3·29; p=0·84) or grade 3-4 adverse events (1·17, 0·90-1·51; p=0·23). INTERPRETATION: The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3-4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings. FUNDING: None.