James, Stefan Karl

Abstract Background Inflammatory bowel disease (IBD) is associated with increased risk of major adverse cardiovascular events (MACE), likely driven by systemic inflammation. Treating inflammation may reduce this risk. We aimed to investigate MACE across different therapies in patients with IBD. Methods We used Swedish nationwide registers (2007–2023) to describe MACE rates (ischemic heart disease, stroke, heart failure, and cardiovascular mortality) in patients with IBD receiving different therapies. For contextualization, we compared MACE rates during therapy exposure periods in patients with IBD with matched (by age, sex, and residence) general population comparators without IBD. Comparisons included exposure periods naïve to immunomodulators/advanced therapies and periods of different treatments (immunomodulators, TNF-α inhibitors (TNFi), vedolizumab, ustekinumab, and Janus kinase inhibitors). Each patient could contribute with multiple periods, with a new period starting upon switch of therapy. Incidence rates (IRs) and adjusted hazard ratios (aHRs) were estimated by using Cox regression (Model 1: conditioned on matching variables; Model 2: additional adjustment for Charlson Comorbidity Index). Among patients with IBD, we performed 1:1 propensity score (PS)-matched analysis, with exposure periods of TNFi or vedolizumab as the reference, to compare MACE rates between advanced therapies. In these comparisons, we adjusted for demographics, disease characteristics, healthcare utilization, prior treatment, and cardiovascular risk factors. Results We included 106,894 patients with IBD with 99,661 exposure periods naïve to immunomodulators/advanced therapy, 60,573 exposure periods of immunomodulators, and 71,551 of advanced therapies. Distribution of age, sex and disease duration differed substantially across therapy exposures (data not shown). Compared with the general population, MACE rates in patients with IBD were similar across therapies (IRs=3.0-13.0/1,000 person-years; aHRs=1.02-1.49) (Table 1), and significantly increased only for exposure periods naïve to immunomodulators/advanced therapy, immunomodulators, or ustekinumab. In PS-matched comparisons, no significant differences were found between periods of TNFi, vedolizumab and other advanced therapies (Table 2). Conclusion Therapy exposure periods in patients with IBD showed only slightly increased MACE rates compared to corresponding periods in the general population, and significantly so only for periods naïve to immunomodulators/advanced therapy and exposure to immunomodulators or ustekinumab. In PS-matched analyses of patients with IBD, no significant differences in MACE rates were observed when comparing exposure periods of different advanced therapies. Conflict of interest: Eriksson, Carl: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Forss, Anders: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Singh, Siddharth: Dr. Singh has research grants from Pfizer. Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova ( 2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson &amp Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp &amp Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson &amp Johnson, Merck Sharp &amp Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp &amp Dohme and Takeda. Sun, Jiangwei: No conflicts Söderling, Jonas: Dr. Söderling has worked on projects at Karolinska Institutet and SWIBREG partly financed by grants from Ferring and Janssen. Everhov, Åsa H: Dr Everhov has worked on projects at Karolinska Institutet and SWIBREG, partly financed by grants from Ferring and Janssen. Bröms, Gabriella: Dr. Bröms has served as a speaker for Takeda and Janssen and worked on projects at Karolinska Institutet, partly financed by Janssen, UCB and Pfizer. James, Stefan: Dr. James reports institutional research grants from Novo Nordisk, Astra Zeneca, Amgen, Jansen, Alnylam and proctor fees from Medtronic. Ludvigsson, Jonas: Dr. Ludvigsson has coordinated an unrelated study for the Swedish IBD Quality Register (SWIBREG). That study received funding from Jansen Corporation. Ludvigsson has also received financial support from MSD/Merck for unrelated research on inflammatory bowel disease, and for developing a paper reviewing national healthcare registers in China. Ludvigsson has an ongoing research collaboration with Takeda about celiac disease and is discussing additional collaboration on chronic liver disease with this company. Olen, Ola: Karolinska Institutet has received research grants from Pfizer, Janssen, AbbVie, Takeda, Ferring, Bristol Myers Squibb, and Alfasigma for projects led by Olén. Ola Olén has also received fees for lectures from Pfizer, Janssen, Bristol Myers Squibb, and Takeda.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Abstract Aims The aim of this article was to compare rates of all-cause death at 10 years following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in patients with or without diabetes. Methods and results The SYNTAXES study evaluated up to 10-year survival of 1800 patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to receive either PCI or CABG in the SYNTAX trial. Ten-year all-cause death according to diabetic status and revascularization strategy was examined. In diabetics (n = 452), the risk of mortality was numerically higher with PCI compared with CABG at 5 years [19.6% vs. 13.3%, hazard ratio (HR): 1.53, 95% confidence interval (CI): 0.96, 2.43, P = 0.075], with the opposite seen between 5 and 10 years (PCI vs. CABG: 20.8% vs. 24.4%, HR: 0.82, 95% CI: 0.52, 1.27, P = 0.366). Irrespective of diabetic status, there was no significant difference in all-cause death at 10 years between patients receiving PCI or CABG, the absolute treatment difference was 1.9% in diabetics (PCI vs. CABG: 36.4% vs. 34.5%, difference: 1.9%, 95% CI: −7.6%, 11.1%, P = 0.551). Among insulin-treated patients (n = 182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%, difference: 8.2%, 95% CI: −6.5%, 22.5%, P = 0.227). Conclusions The treatment effects of PCI vs. CABG on all-cause death at 10 years in patients with 3VD and/or LMCAD were similar irrespective of the presence of diabetes. There may, however, be a survival benefit with CABG in patients with insulin-treated diabetes. The association between revascularization strategy and very long-term ischaemic and safety outcomes for patients with diabetes needs further investigation in dedicated trials. Trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972 and SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

AbstractBackgroundGuidelines suggest that “upstream” P2Y12 receptor antagonists should be considered in patients with non–ST‐segment elevation acute coronary syndromes (NSTE‐ACS).HypothesisEarly use of ticagrelor in patients managed with an invasive strategy would be more effective than clopidogrel because of its more rapid onset of action and greater potency.MethodsIn the PLATO trial, 6792 NSTE‐ACS patients were randomized to ticagrelor or clopidogrel (started prior to angiography) and underwent angiography within 72 hours of randomization. We compared efficacy and safety outcomes of ticagrelor vs clopidogrel as a function of “early” (<3h) vs “late” (≥3h) time to angiography. Adjusted Cox proportional hazards models evaluated interaction between randomized treatment and time from randomization to angiography on subsequent outcomes.ResultsOverall, a benefit of ticagrelor vs clopidogrel for cardiovascular death/myocardial infarction/stroke was seen at day 7 (hazard ratio [HR]: 0.67, P = 0.002), day 30 (HR: 0.81, P = 0.042), and 1 year (HR: 0.80, P = 0.0045). There were no significant interactions in the <3h vs ≥3h groups at any timepoint. For major bleeding, overall there was no significant increase (HR: 1.04, 95% confidence interval: 0.85‐1.27); but there was a significant interaction with no difference between ticagrelor and clopidogrel in the early group (HR: 0.79), but higher bleeding risk with ticagrelor in the late angiography group, at 7 days (HR: 1.51, Pint = 0.002). Patterns were similar at 30 days and 1 year.ConclusionsThe benefit of ticagrelor over clopidogrel was consistent in those undergoing early and late angiography, supporting upstream use of ticagrelor.

Objective The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Methods This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects. Results During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013). Conclusions In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial. Trial registration number NCT00391872; Results.