Es, Nick van

Abstract Background Patients with cancer treated with immune checkpoint inhibitors are at increased risk of myocardial infarction and ischemic stroke. The mechanism is incompletely understood but may involve accelerated atherosclerosis due to plaque inflammation. Pre-clinical studies may provide insight in these mechanisms. Aim To assess the effects of modulating co-inhibitory immune checkpoint proteins on atherosclerosis progression in animal models. Methods A systematic review was performed in MEDLINE, Embase, Web of Science, and Scopus up to September 2023. Animal studies were included if the effect of modulation of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and/or lymphocyte-activation gene 3 (LAG-3) on atherosclerotic plaque size was evaluated. Secondary outcomes were plaque composition and systemic inflammation. The ratios of means (RoM) across the studies were pooled in a random effects meta-analysis. Results 1,655 studies were identified of which twelve were included. All studies used an atherosclerotic mouse model (Apoe-/-, Ldlr-/-, or ApoE3*Leiden) and either evaluated pharmacological or genetic modulation of co-inhibitory immune checkpoint proteins. Upon inhibition, atherosclerotic plaque size in the aorta was 49% higher in exposed mice compared to control mice (RoM, 1.49; 95% CI, 1.12-1.82; I2=86%). Plaque composition was predominantly characterized by a greater abundance of CD4+ T cells, CD8+ T cells, and macrophages. Studies stimulating co-inhibitory immune checkpoint proteins corroborated these findings and demonstrated that atherosclerotic plaque size was reduced by 28% in treated mice compared to controls (RoM, 0.72; 95% CI, 0.65-0.80; I2=85%). This reduction was paralleled by a decrease in the number of macrophages and T cells in plaques. Conclusion Immune checkpoint inhibition leads to plaque inflammation and a significant increase in murine atherosclerotic plaque size. These changes may reflect the cause of the increased risk of myocardial infarction and ischemic stroke in patients treated with immune checkpoint inhibitors.

Abstract Background: Guidelines suggest the use of the Khorana score to select patients with solid cancer receiving chemotherapy for thromboprophylaxis to prevent venous thromboembolism (VTE), but its performance in different types of cancers remains uncertain. Methods: The present analysis includes individual patient data from seven randomized controlled trials that had compared prophylactic (ultra)-low-molecular-weight heparin (LMWH) with placebo or observation in patients with solid cancer. The analysis addresses the performance of the continuous and dichotomized Khorana score in predicting the 6-month risk of VTE in the trial control groups, overall and in types of cancer studies, as well as the efficacy and safety of LMWH among patients with a high-risk Khorana score. Random effects meta-analysis provided the basis for summary estimates. Findings: In the 3,403 patients from the control groups included in the analyses, the mean age was 61 years, 59% were male, and 58% had lung cancer. During 6-months of follow-up, 188 patients (5.5%) developed VTE. Overall, the 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate risk patients (OR 1.6; 95%-CI 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95%-CI, 0.72-1.7) than in those with other types of cancer (OR 4.4; 95%-CI, 2.7-7.3; P interaction=0.002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared to placebo or observation (OR 0.36; 95%-CI, 0.22-0.58). In the group of patients with types of cancer other than lung cancer and a high-risk Khorana score (N=619), the 6-month VTE incidence was 3.3% (95% CI, 1.4 to 7.7) among LMWH recipients and 13% (95% CI, 6.8 to 24) among those not receiving LMWH (OR 0.23, 95% CI, 0.11 to 0.46; P <0.001). There was no difference in major bleeding (OR 1.2, 95% CI, 0.56 to 2.5). Interpretation: The Khorana score performs poorly in differentiating between those at high and low risk of VTE in patients with lung cancer, but is associated with a 4-fold increased risk of VTE in those with other types of cancer. Thromboprophylaxis is effective and safe in patients with a high-risk Khorana score. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Cancer Research UK: Research Funding; Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant > 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: Daiichi Sankyo: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; BMS-Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Schünemann: Canadian Institutes of Health Research: Research Funding.

Abstract Background: Parenteral anticoagulants may improve outcomes in patients with cancer by reducing the risk of venous thromboembolism (VTE) and through a direct anti-tumour effect. Study-level meta-analysis indicates a reduction in VTE and provide moderate certainty that a small survival benefit exists; it is unclear if patients with specific cancers benefit more or less. Utilizing data from randomized controlled trials (RCT), this individual participant data meta-analysis examines the impact of heparin on survival, VTE and major bleeding in oncological patients randomized to low-molecular weight heparin (LMWH) or no LMWH. Methods: We performed a comprehensive systematic search for all RCTS (last search date March 2017) and contacted authors and sponsors to obtain individual participant data of patients with solid cancers and no other indication for prophylactic or therapeutic anticoagulation. We utilized the GRADE approach to evaluate the certainty of evidence and produce an evidence profile. All analyses followed the intention-to-treat principle. We calculated the impact on mortality through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We adjusted the analysis for age, cancer type and metastasis status. To investigate whether intervention effects vary by predefined subgroups, including type of cancer, we tested interaction terms in the statistical model. Results: A total of 18 RCTs (n=10,041 participants) were eligible for inclusion and we obtained data from 82.4% of the participants (13 RCTs, n=8,278; n=4,139 for LMWH and n=4,139 for no LMWH). The meta-analysis revealed an adjusted relative risk of mortality within one year of 0.99 (95% CI: 0.95, 1.03) and a hazard ratio of 0.97 (95% CI: 0.82, 1.14) after one year. The relative risk for VTE was 0.58 (95% CI: 0.48, 0.71), 0.57 (95% CI: 0.44, 0.74) for symptomatic deep vein thrombosis and 0.58 (95%CI: 0.44, 0.77) for symptomatic pulmonary embolism, separately. For every 1,000 patients treated, approximately 16 fewer would experience symptomatic DVT and 16 fewer would experience any PE. The adjusted relative risk for major bleeding throughout trial duration was 1.24 (95% CI: 0.91, 1.69; P=0.17). Subgroup analysis, by cancer type, of VTE occurrence throughout trial duration identified lung cancer OR=0.52 (95% CI: 0.39, 0.68; P<0.001) and pancreatic cancer OR=0.55 (95% CI: 0.35, 0.88; P=0.01) patients as experiencing the greatest benefit from LMWH treatment. The certainty of the evidence for the outcomes was moderate to high. Conclusion: LMWH reduces risk of VTE without increasing risk of bleeding but does not improve survival across all patients. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Schünemann: Canadian Institutes of Health Research: Research Funding. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial; Cancer Research UK: Research Funding. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant > 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: BMS-Pfizer: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project.

Abstract Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

Introduction Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits. Methods and analysis First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials. Ethics and dissemination Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings. Trial registration number PROSPERO CRD42013003526.