Bernhard Witzenbichler

Background: Diabetes mellitus and high platelet reactivity (HPR) on clopidogrel are both associated with increased risk of ischemic events after percutaneous coronary intervention, but whether the HPR‐associated risk of adverse ischemic events differs by diabetes mellitus status is unknown. Methods and Results: ADAPT‐DES (Assessment of Dual Antiplatelet Therapy With Drug‐Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug‐eluting stents. HPR was defined as P2Y12 reaction units >208 by the VerifyNow point‐of‐care assay. Cox multivariable analysis was used to assess whether HPR‐associated risk of major adverse cardiac events (MACE; cardiac death, myocardial infarction, or stent thrombosis) varied for patients with insulin‐treated diabetes mellitus (ITDM), non–ITDM, and no diabetes mellitus. Diabetes mellitus and HPR were included in an interaction analysis. Of 8582 patients enrolled, 2429 (28.3%) had diabetes mellitus, of whom 998 (41.1%) had ITDM. Mean P2Y12 reaction units were higher in patients with diabetes mellitus versus without diabetes mellitus, and HPR was more frequent in patients with diabetes mellitus. HPR was associated with consistently increased 2‐year rates of MACE in patients with and without diabetes mellitus ( P _interaction =0.36). A significant interaction was present between HPR and non–insulin‐treated diabetes mellitus versus ITDM for 2‐year MACE (adjusted hazard ratio [HR] for non–ITDM, 2.28 [95% CI, 1.39–3.73] versus adjusted HR for ITDM, 1.02 [95% CI, 0.70–1.50]; P _interaction =0.01). Conclusions: HPR was more common in patients with diabetes mellitus and was associated with an increased risk of MACE in both patients with and without diabetes mellitus. In patients with diabetes mellitus, a more pronounced effect of HPR on MACE was present in lower‐risk non–ITDM patients than in higher‐risk patients with ITDM. Registration: URL: https://clinicaltrials.gov/ct2/show/NCT00638794 ; Unique identifier: NCT00638794. ADAPT‐DES (Assessment of Dual Antiplatelet Therapy With Drug‐Eluting Stents).

Background: The efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome and prior myocardial infarction (MI) remain unstudied. We aimed to assess the treatment effect of ticagrelor versus prasugrel according to prior MI status in patients with ACS. Methods and Results: Patients with acute coronary syndrome planned for an invasive strategy and randomized to ticagrelor or prasugrel in the ISAR‐REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial were included. The primary end point was the composite of 1‐year all‐cause death, MI, or stroke; the secondary safety end point was the composite of 1‐year Bleeding Academic Research Consortium type 3 to 5 bleeding. The study included 4015 patients (prior MI=631 patients; no prior MI=3384 patients). As compared with patients without prior MI, the primary end point occurred more frequently in patients with prior MI (12.6% versus 7.2%; hazard ratio [HR], 1.78 [95% CI, 1.38–2.29]); the secondary safety end point appears to differ little between patients with and without prior MI (5.8% versus 5.7%, respectively; HR, 1.02 [95% CI, 0.71–1.45]). With regard to the primary end point, ticagrelor versus prasugrel was associated with an HR of 1.62 (95% CI, 1.03–2.55) in patients with prior MI and an HR of 1.28 (95% CI, 0.99–1.65) in patients without prior MI ( P _int =0.37). With regard to the secondary safety end point, ticagrelor versus prasugrel was associated with an HR of 1.28 (95% CI, 0.56–2.91) in patients with prior MI and an HR of 1.13 (95% CI, 0.82–1.55) in patients without prior MI ( P _int =0.79). Conclusions: Patients with acute coronary syndrome and prior MI are at higher risk for recurrent ischemic but not bleeding events. Prasugrel is superior to ticagrelor in reducing the risk of ischemic events without a tradeoff in bleeding regardless of prior MI status. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Background: The relative efficacy and safety of more potent P2Y ₁₂ inhibitors in patients with acute coronary syndrome and high bleeding risk (HBR) undergoing percutaneous coronary intervention remains unclear. We aimed to study the treatment effect of ticagrelor and prasugrel in percutaneous coronary intervention patients presenting with acute coronary syndrome and HBR. Methods: This post hoc analysis of the ISAR-REACT 5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) included patients with acute coronary syndrome undergoing percutaneous coronary intervention, randomized to ticagrelor or prasugrel, in whom HBR was defined as per Academic Research Consortium criteria. The primary (efficacy) end point was the composite of all-cause death, myocardial infarction, or stroke. The secondary (safety) end point was Bleeding Academic Research Consortium type 3 to 5 bleeding. Outcomes were assessed 12 months after randomization. Results: Out of the 3239 patients included in this analysis, 486 fulfilled the criteria for Academic Research Consortium-HBR definition (HBR group; ticagrelor, n=230 and prasugrel, n=256), while 2753 did not (non-HBR group; ticagrelor, n=1375 and prasugrel, n=1378). Compared with the non-HBR group, the HBR group had a higher risk for the primary (hazard ratio [HR]=3.57 [95% CI, 2.79–4.57]; P P P for interaction=0.12) or secondary ( P for interaction=0.80) end points. Conclusions: In patients with acute coronary syndrome undergoing percutaneous coronary intervention, HBR status increased both ischemic and bleeding risk without significant impact on the relative efficacy and safety of either ticagrelor or prasugrel. These results warrant confirmation in larger cohorts. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Aims: We aimed to evaluate the treatment effects of ticagrelor monotherapy in the very high risk cohort of patients with concomitant diabetes mellitus (DM) and chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). Methods and results: In the TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, after 3-month dual antiplatelet therapy with ticagrelor and aspirin post-PCI, event-free patients were randomized to either aspirin or placebo in addition to ticagrelor for 12 months. Those with available information on DM and CKD status were included in this subanalysis and were stratified by the presence or absence of either condition: 3391 (54.1%) had neither DM nor CKD (DM−/CKD−), 1822 (29.0%) had DM only (DM+/CKD−), 561 (8.9%) had CKD only (DM−/CKD+), and 8.0% had both DM and CKD (DM+/CKD+). The incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding did not differ according to DM/CKD status (P-trend = 0.13), but there was a significant increase in BARC 3 or 5 bleeding (P-trend < 0.001) as well as the key secondary endpoint of death, myocardial infarction, or stroke (P-trend < 0.001). Ticagrelor plus placebo reduced bleeding events compared with ticagrelor plus aspirin across all four groups, including DM+/CKD+ patients with respect to BARC 2–5 [4.5% vs. 8.7%; hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.24–1.01] as well as BARC 3–5 (0.8% vs. 5.3%; HR 0.15, 95% CI 0.03–0.53) bleeding, with no evidence of heterogeneity. The risk of death, myocardial infarction, or stroke was similar between treatment arms across all groups. Conclusion: Irrespective of the presence of DM, CKD, and their combination, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events compared with ticagrelor plus aspirin.

To assess whether the efficacy and safety of ticagrelor vs. prasugrel in patients with acute coronary syndromes (ACSs) are influenced by pre-admission treatment with aspirin and/or clopidogrel. Patients (n = 4018) were categorized into two groups: pre-admission aspirin and/or clopidogrel group (n = 1455) and no pre-admission aspirin or clopidogrel group (n = 2563). The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke; the secondary safety endpoint was Bleeding Academic Research Consortium (BARC) type 3–5 bleeding, both at 1 year. Patients in the pre-admission aspirin and/or clopidogrel group had a higher risk of ischaemic events, but a similar risk of bleeding to patients in the no pre-admission aspirin or clopidogrel group (cumulative incidences 10.5% vs. 6.7%, and 5.7% vs. 5.7%, respectively). The primary endpoint occurred in 81/717 patients assigned to ticagrelor and 69/738 patients assigned to prasugrel in the pre-admission aspirin and/or clopidogrel group [11.5% vs. 9.5%; hazard ratio (HR) = 1.23; 95% confidence interval (CI) 0.89–1.69], and in 103/1295 patients assigned to ticagrelor and 68/1268 patients assigned to prasugrel in the no pre-admission aspirin or clopidogrel group [8.0% vs. 5.4%; HR = 1.50 (1.10–2.03); P_int = 0.38]. BARC type 3–5 bleeding events did not differ between ticagrelor and prasugrel in patients in the pre-admission aspirin and/or clopidogrel (6.2% vs. 4.5%) or no pre-admission aspirin or clopidogrel (5.3% vs. 5.1%) group (P_int = 0.54). In patients with ACS, pre-admission therapy with aspirin and/or clopidogrel has no influence on the relative efficacy and safety of ticagrelor and prasugrel.

BACKGROUND: Whether there are differences in the risk profile and treatment effect in patients recruited in a low recruitment center (LRC) versus patients recruited in a high recruitment center (HRC) in a randomized multicenter trial remains unknown. METHODS AND RESULTS: This study included 4018 patients with acute coronary syndrome recruited in the ISAR‐REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial. The primary end point was a composite of all‐cause death, myocardial infarction, or stroke. Overall, 3011 patients (75%) were recruited in the HRCs (7 centers recruiting 258 to 628 patients; median, 413 patients) and 1007 patients (25%) were recruited in the LRCs (16 centers recruiting 5 to 201 patients; median, 52 patients). Patients recruited in the LRCs had more favorable cardiovascular risk profiles than patients recruited in the HRCs. The primary end point occurred in 72 patients in the LRCs and 249 patients in the HRCs (cumulative incidence, 7.3% and 8.4%; P =0.267). All‐cause mortality was lower among patients recruited in the LRCs (n=29) than among patients recruited in the HRCs (n=134; cumulative incidence 2.9% versus 4.5%; P =0.031). There was no significant interaction between the treatment effect of ticagrelor versus prasugrel and patient recruitment category (LRC versus HRC) regarding the primary efficacy end point (LRC: hazard ratio [HR], 1.42 [95% CI, 0.89–2.28]; HRC: HR, 1.33 [95% CI, 1.04−1.72]; P for interaction=0.800). CONCLUSIONS: Patients with acute coronary syndrome recruited in a LRC appear to have more favorable cardiovascular risk profiles and lower 1‐year mortality rates compared with patients recruited in a HRC. The recruitment volume did not interact with the treatment effect of ticagrelor versus prasugrel. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Patients at high bleeding risk (HBR) represent a prevalent subgroup among those undergoing percutaneous coronary intervention (PCI). Early aspirin discontinuation after a short course of dual antiplatelet therapy (DAPT) has emerged as a bleeding avoidance strategy. The aim of this study was to assess the effects of ticagrelor monotherapy after 3-month DAPT in a contemporary HBR population. This prespecified analysis of the TWILIGHT trial evaluated the treatment effects of early aspirin withdrawal followed by ticagrelor monotherapy in HBR patients undergoing PCI with drug-eluting stents. After 3 months of ticagrelor plus aspirin, event-free patients were randomized to 12 months of aspirin or placebo in addition to ticagrelor. A total of 1064 (17.2%) met the Academic Research Consortium definition for HBR. Ticagrelor monotherapy reduced the incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding compared with ticagrelor plus aspirin in HBR (6.3% vs. 11.4%; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.35–0.82) and non-HBR patients (3.5% vs. 5.9%; HR 0.59, 95% CI 0.46–0.77) with similar relative (P_interaction = 0.67) but a trend towards greater absolute risk reduction in the former [−5.1% vs. −2.3%; difference in absolute risk differences (ARDs) −2.8%, 95% CI −6.4% to 0.8%, P = 0.130]. A similar pattern was observed for more severe BARC 3 or 5 bleeding with a larger absolute risk reduction in HBR patients (−3.5% vs. −0.5%; difference in ARDs −3.0%, 95% CI −5.2% to −0.8%, P = 0.008). There was no significant difference in the key secondary endpoint of death, myocardial infarction, or stroke between treatment arms, irrespective of HBR status. Among HBR patients undergoing PCI who completed 3-month DAPT without experiencing major adverse events, aspirin discontinuation followed by ticagrelor monotherapy significantly reduced bleeding without increasing ischaemic events, compared with ticagrelor plus aspirin. The absolute risk reduction in major bleeding was larger in HBR than non-HBR patients. Effects of ticagrelor plus placebo vs. ticagrelor plus aspirin on bleeding and ischaemic events among high bleeding risk and non-high bleeding risk patients who tolerated 3 months of dual antiplatelet therapy after percutaneous coronary intervention with a drug-eluting stent. BARC, Bleeding Academic Research Consortium; CI, confidence interval; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention; tica, ticagrelor.

The aim of this study was to assess the impact of chronic kidney disease (CKD) on the safety and efficacy of ticagrelor monotherapy among patients undergoing percutaneous coronary intervention (PCI). In this prespecified subanalysis of the TWILIGHT trial, we evaluated the treatment effects of ticagrelor with or without aspirin according to renal function. The trial enrolled patients undergoing drug-eluting stent implantation who fulfilled at least one clinical and one angiographic high-risk criterion. Chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) 2, was a clinical study entry criterion. Following a 3-month period of ticagrelor plus aspirin, event-free patients were randomly assigned to aspirin or placebo on top of ticagrelor for an additional 12 months. Of the 6835 patients randomized and with available eGFR at baseline, 1111 (16.3%) had CKD. Ticagrelor plus placebo reduced the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding as compared with ticagrelor plus aspirin in both patients with [4.6% vs. 9.0%; hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31–0.80] and without (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47–0.75; P_interaction = 0.508) CKD, but the absolute risk reduction was greater in the former group. Rates of death, myocardial infarction, or stroke were not significantly different between the two randomized groups irrespective of the presence (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88–2.22) or absence of (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68–1.20; P_interaction = 0.111) CKD. Among CKD patients undergoing PCI, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events as compared with ticagrelor plus aspirin.

Background: The comparative efficacy and safety of ticagrelor and prasugrel in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention (PCI) has not been defined. Methods: This post hoc analysis included all patients with acute coronary syndrome treated with PCI and randomized to either ticagrelor or prasugrel in the ISAR-REACT 5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment). Complex PCI was defined as at least one of the following: multivessel PCI, ≥3 stents implanted, ≥3 lesions treated, and total stented length >60 mm. The primary efficacy end point was the composite of all-cause death, myocardial infarction, or stroke; the safety end point was Bleeding Academic Research Consortium types 3 to 5 bleeding. Outcomes were assessed out to 12 months after randomization. Results: Among the 3377 patients treated with PCI in the ISAR-REACT 5 trial, 1429 underwent complex PCI (ticagrelor, N=696 and prasugrel, N=733) and 1948 underwent noncomplex PCI (ticagrelor, N=980 and prasugrel, N=968). There was no interaction between PCI complexity, assignment to either ticagrelor or prasugrel, and the primary efficacy or safety end points ( P for interaction: ≥0.13). In the complex PCI group, the primary efficacy end point (11.0% versus 9.2%, hazard ratio: 1.19 [0.85–1.66], P =0.303) and the safety end point (5.2% versus 6.1%, hazard ratio: 0.83 [0.53–1.31], P =0.419) were not statistically different in patients receiving either ticagrelor or prasugrel. In the noncomplex PCI group, the primary efficacy end point occurred more frequently in patients assigned to ticagrelor as compared to prasugrel (8.9% versus 5.5%, hazard ratio: 1.66 [1.18–2.34], P =0.004) without significant difference in terms of the safety end point (5.4% versus 4.1%, hazard ratio: 1.41 [0.92–2.17], P =0.110). Conclusions: In patients with acute coronary syndrome, PCI complexity does not influence the comparative efficacy and safety of ticagrelor and prasugrel. The observed comparable performance of ticagrelor and prasugrel in patients with acute coronary syndrome undergoing complex PCI requires further confirmation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.