Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial

AIMS The GLOBAL LEADERS trial is a superiority study in patients undergoing percutaneous coronary intervention, with a uniform use of Biolimus A9-eluting stents (BES) and bivalirudin. GLOBAL LEADERS was designed to assess whether a 24-month antithrombotic regimen with ticagrelor and one month of acetylsalicylic acid (ASA), compared to conventional dual antiplatelet therapy (DAPT), improves outcomes. METHODS AND RESULTS Patients (n >16,000) are randomised (1:1 ratio) to ticagrelor 90 mg twice daily for 24 months plus ASA ≤100 mg for one month versus DAPT with either ticagrelor (acute coronary syndrome) or clopidogrel (stable coronary artery disease) for 12 months plus ASA ≤100 mg for 24 months. The primary outcome is a composite of all-cause mortality or non-fatal, new Q-wave myocardial infarction at 24 months. The key safety endpoint is investigator-reported class 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definitions. Sensitivity analysis will be carried out to explore potential differences in outcome across geographic regions and according to specific angiographic and clinical risk estimates. CONCLUSIONS The GLOBAL LEADERS trial aims to assess the role of ticagrelor as a single antiplatelet agent after a short course of DAPT for the long-term prevention of cardiac adverse events, across a wide spectrum of patients, following BES implantation.

Thrombus formation in the left ventricle after large myocardial infarction – assessment with cardiac magnetic resonance imaging

INTRODUCTION Left ventricular thrombus (LVT) formation may worsen the post-infarct outcome as a result of thromboembolic events. It also complicates the use of modern antiplatelet regimens, which are not compatible with long-term oral anticoagulation. The knowledge of the incidence of LVT may therefore be of importance to guide antiplatelet and antithrombotic therapy after acute myocardial infarction (AMI). METHODS In 177 patients with large, mainly anterior AMI, standard cardiac magnetic resonance imaging (CMR) including cine and late gadolinium enhancement (LGE) imaging was performed shortly after AMI as per protocol. CMR images were analysed at an independent core laboratory blinded to the clinical data. Transthoracic echocardiography (TTE) was not mandatory for the trial, but was performed in 64% of the cases following standard of care. In a logistic model, 3 out of 61 parameters were used in a multivariable model to predict LVT. RESULTS LVT was detected by use of CMR in 6.2% (95% confidence interval [CI] 3.1%-10.8%). LGE sequences were best to detect LVT, which may be missed in cine sequences. We identified body mass index (odds ratio 1.18; p = 0.01), baseline platelet count (odds ratio 1.01, p = 0.01) and infarct size as assessed by use of CMR (odds ratio 1.03, p = 0.02) as best predictors for LVT. The agreement between TTE and CMR for the detection of LVT is substantial (kappa = 0.70). DISCUSSION In the current analysis, the incidence of LVT shortly after AMI is relatively low, even in a patient population at high risk. An optimal modality for LVT detection is LGE-CMR but TTE has an acceptable accuracy when LGE-CMR is not available.

Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial

IMPORTANCE Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond 1 year provides ischemic event protection after DES, ischemic event risk is perceived to be less after BMS, and the appropriate duration of DAPT after BMS is unknown. OBJECTIVE To compare (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs 12 months of thienopyridine in patients treated with BMS taking aspirin and (2) treatment duration effect within the combined cohorts of randomized patients treated with DES or BMS as prespecified secondary analyses. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, randomized, double-blinded, placebo-controlled trial comparing extended (30-months) thienopyridine vs placebo in patients taking aspirin who completed 12 months of DAPT without bleeding or ischemic events after receiving stents. The study was initiated in August 2009 with the last follow-up visit in May 2014. INTERVENTIONS Continued thienopyridine or placebo at months 12 through 30 after stent placement, in 11,648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES. MAIN OUTCOMES AND MEASURES Stent thrombosis, MACCE, and moderate or severe bleeding. RESULTS Among 1687 patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5% vs 1.11% (n = 4 vs 9; hazard ratio [HR], 0.49; 95% CI, 0.15-1.64; P = .24), rates of MACCE were 4.04% vs 4.69% (n = 33 vs 38; HR, 0.92; 95% CI, 0.57-1.47; P = .72), and rates of moderate/severe bleeding were 2.03% vs 0.90% (n = 16 vs 7; P = .07), respectively. Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41% vs 1.32% (n = 23 vs 74; HR, 0.31; 95% CI, 0.19-0.50; P < .001), rates of MACCE were 4.29% vs 5.74% (n = 244 vs 323; HR, 0.73; 95% CI, 0.62-0.87; P < .001), and rates of moderate/severe bleeding were 2.45% vs 1.47% (n = 135 vs 80; P < .001). CONCLUSIONS AND RELEVANCE Among patients undergoing coronary stent placement with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Plasma NGAL and glomerular filtration rate in cardiac transplant recipients treated with standard or reduced calcineurin inhibitor levels.

AIM Predictors of renal recovery following conversion from calcineurin inhibitor- to proliferation signal inhibitor-based therapy are lacking. We hypothesized that plasma NGAL (P-NGAL) could predict improvement in glomerular filtration rate (GFR) after conversion to everolimus. PATIENTS & METHODS P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. RESULTS P-NGAL correlated with measured GFR (mGFR) at baseline (R(2) = 0.21; p < 0.001). Randomization to everolimus improved mGFR after 1 year (median [25-75 % percentiles]: ΔmGFR 5.5 [-0.5-11.5] vs -1 [-7-4] ml/min/1.73 m(2); p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R(2) = 0.18; p < 0.001), but this association disappeared after controlling for baseline mGFR. CONCLUSION P-NGAL and GFR correlate with renal dysfunction in long-term heart transplantation recipients. P-NGAL did not predict improvement of renal function after conversion to everolimus-based immunosuppression.

Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial.

BACKGROUND Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. METHODS In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. RESULTS No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. CONCLUSIONS Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death.

The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric impulse. Emerging evidence over the past 20 years strongly suggests that the normal electric function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post-translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electric function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.

Antifactor Xa Activity for the Management of Anticoagulation during Cardiac Surgery

Background In patients with autoimmune diseases associated with antiphospholipid antibodies, precise management of anticoagulation during extracorporeal circulation (ECC) is complicated. It was the aim of the present study to determine whether antifactor Xa (aXa) activity is useful in guiding heparin therapy during ECC. Methods In 15 patients undergoing cardiac surgery, anticoagulation with unfractionated heparin (UFH) and its reversal with protamine were guided using activated clotting time (ACT) (>400 second during ECC; ≤100 second for UFH reversal). For each ACT, the corresponding aXa activity levels were measured. Results A total of 144 blood samples were obtained. ACT and aXa activity were significantly correlated (r = 0.771, p< 0.0001, Spearman rank-order correlation). Using receiver operating characteristic curve (ROC) analyses, the cutoffvalues for aXa activity were 1.14 IU/mL (area under the ROC curve [AUC]: 0.89; inaccuracy rate: 9.4%) to predict ACT > 400 seconds and 0.55 IU/mL (AUC: 0.85; inaccuracy rate: 13.3%) for ACT ≤ 100 seconds. Conclusion AXa activity is strongly correlated with ACT, and therefore may be feasible for managing anticoagulation with UFH during ECC.