Prognostic impact of secondary prevention after coronary artery bypass grafting-insights from the TiCAB trial.

OBJECTIVES: There are disparities in the adherence to guideline-recommended therapies after coronary artery bypass graft (CABG). We therefore sought to evaluate the effect of guideline-adherent medical secondary prevention on 1-year outcome after CABG. METHODS: Data were taken from the randomized 'Ticagrelor in CABG' trial. From April 2013 until April 2017, patients who underwent CABG were included. For the present analysis, we compared patients who were treated with optimal medical secondary prevention with those where 1 or more of the recommended medications were missing. RESULTS: Follow-up data at 12 months were available in 1807 patients. About half (54%) of them were treated with optimal secondary prevention. All-cause mortality [0.5% vs 3.5%, hazard ratio (HR) 0.14 (0.05-0.37), P < 0.01], cardiovascular mortality [0.1% vs 1.7%, HR 0.06 (0.01-0.46), P = 0.007] and major adverse events [6.5% vs 11.5%, HR 0.54 (0.39-0.74), P < 0.01] were significantly lower in the group with optimal secondary prevention. The multivariable model for the primary end point based on binary concordance to guideline recommended therapy identified 3 independent factors: adherence to guideline recommended therapy [HR 0.55 (0.39-0.78), P < 0.001]; normal renal function [HR 0.99 (0.98-0.99), P = 0.040]; and off-pump surgery [HR 2.06 (1.02-4.18), P = 0.045]. CONCLUSIONS: Only every second patient receives optimal secondary prevention after CABG. Guideline adherent secondary prevention therapy is associated with lower mid-term mortality and less adverse cardiovascular events after 12 months.

Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial.

AIMS: The antiplatelet treatment strategy providing optimal balance between thrombotic and bleeding risks in patients undergoing coronary artery bypass grafting (CABG) is unclear. We prospectively compared the efficacy of ticagrelor and aspirin after CABG. METHODS AND RESULTS: We randomly assigned in double-blind fashion patients scheduled for CABG to either ticagrelor 90 mg twice daily or 100 mg aspirin (1:1) once daily. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), repeat revascularization, and stroke 12 months after CABG. The main safety endpoint was based on the Bleeding Academic Research Consortium classification, defined as BARC ≥4 for periprocedural and hospital stay-related bleedings and BARC ≥3 for post-discharge bleedings. The study was prematurely halted after recruitment of 1859 out of 3850 planned patients. Twelve months after CABG, the primary endpoint occurred in 86 out of 931 patients (9.7%) in the ticagrelor group and in 73 out of 928 patients (8.2%) in the aspirin group [hazard ratio 1.19; 95% confidence interval (CI) 0.87-1.62; P = 0.28]. All-cause mortality (ticagrelor 2.5% vs. aspirin 2.6%, hazard ratio 0.96, CI 0.53-1.72; P = 0.89), cardiovascular death (ticagrelor 1.2% vs. aspirin 1.4%, hazard ratio 0.85, CI 0.38-1.89; P = 0.68), MI (ticagrelor 2.1% vs. aspirin 3.4%, hazard ratio 0.63, CI 0.36-1.12, P = 0.12), and stroke (ticagrelor 3.1% vs. 2.6%, hazard ratio 1.21, CI 0.70-2.08; P = 0.49), showed no significant difference between the ticagrelor and aspirin group. The main safety endpoint was also not significantly different (ticagrelor 3.7% vs. aspirin 3.2%, hazard ratio 1.17, CI 0.71-1.92; P = 0.53). CONCLUSION: In this prematurely terminated and thus underpowered randomized trial of ticagrelor vs. aspirin in patients after CABG no significant differences in major cardiovascular events or major bleeding could be demonstrated. CLINICALTRIALS.GOV IDENTIFIER: NCT01755520.

A randomized, parallel group, double-blind study of ticagrelor compared with aspirin for prevention of vascular events in patients undergoing coronary artery bypass graft operation: Rationale and design of the Ticagrelor in CABG (TiCAB) trial: An Investigator-Initiated trial.

BACKGROUND: For patients with coronary artery disease undergoing coronary bypass surgery, acetylsalicylic acid (ASA) currently represents the gold standard of antiplatelet treatment. However, adverse cardiovascular event rates in the first year after coronary artery bypass grafting (CABG) still exceed 10%. Graft failure, which is predominantly mediated by platelet aggregation, has been identified as a major contributing factor in this context. Therefore, intensified platelet inhibition is likely to be beneficial. Ticagrelor, an oral, reversibly binding and direct-acting P2Y12 receptor antagonist, provides a rapid, competent, and consistent platelet inhibition and has shown beneficial results compared with clopidogrel in the subset of patients undergoing bypass surgery in a large previous trial. HYPOTHESIS: Ticagrelor is superior to ASA for the prevention of major cardiovascular events within 1 year after CABG. STUDY DESIGN: The TiCAB trial (NCT01755520) is a multicenter, phase III, double-blind, double-dummy, randomized trial comparing ticagrelor with ASA for the prevention of major cardiovascular events within 12 months after CABG. Patients undergoing CABG will be randomized in a 1:1 fashion to either ticagrelor 90 mg twice daily or ASA 100 mg once daily. The study medication will be started within 24 hours after surgery and maintained for 12 months. The primary end point is the composite of cardiovascular death, myocardial infarction, stroke, and repeat revascularization at 12 months after CABG. The sample size is based on an expected event rate of 13% of the primary end point within the first 12 months after randomization in the control group, a 2-sided α level of .0492 (to preserve the overall significance level of .05 after planned interim analysis), a power of 0.80%, 2-sided testing, and an expected relative risk of 0.775 in the active group compared with the control group and a dropout rate of 2%. According to power calculations based on a superiority design for ticagrelor, it is estimated that 3,850 patients should be enrolled. SUMMARY: There is clinical equipoise on the issue of optimal platelet inhibition after CABG. The TiCAB trial will provide a pivotal comparison of the efficacy and safety of ticagrelor compared with ASA after CABG.

Networks for improving care in patients with acute coronary syndrome: A framework.

In recent years, it has become evident that the level of guideline adherence in patients presenting with acute coronary syndrome (ACS) is highly correlated with patient outcomes. Unfortunately, guideline adherence is low in some geographic areas and especially in those patients at high-risk. Regional networks including ambulance systems and hospitals with catheterization laboratories are able to increase guideline adherence and patient outcomes by streamlining the critical pre- and intra-hospital processes as well as improving timely access to invasive procedures and recommended medication. Successful organization of an ACS network requires engagement of multiple stakeholders to create effective solutions for the specific local setting. There is no 'one-size-fits all' strategy to set-up and successfully run an ACS network. We present a framework for how to set up and organize an effective ACS network, delivering guideline-based care to improve patient outcomes.

Relative efficacy of bivalirudin versus heparin monotherapy in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a network meta-analysis.

In the absence of head-to-head clinical data, the objective of this study was to indirectly compare the efficacy and safety of a bivalirudin-based anticoagulation strategy with that of heparin monotherapy in patients with ST-elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention. A systematic literature review was performed to identify randomized controlled trials to build a network of bivalirudin and heparin monotherapy strategies in STEMI patients using heparin, with glycoprotein IIb/IIIa inhibitor as a common reference strategy. At 30 days, the bivalirudin-based strategy was expected to result in lower mortality rates than heparin monotherapy (odds ratio [OR], 0.55; credible limit [CrL], 0.32-0.95). This relationship was sustained at 1 year. At 30 days, the risk for stroke (OR, 0.88; CrL, 0.37-2.13), myocardial infarction (OR, 0.79; CrL, 0.40-1.55), and thrombolysis in myocardial infarction major and minor bleedings (OR, 0.66; CrL, 0.45-0.98) tended to be numerically reduced with bivalirudin in comparison with heparin monotherapy. For patients with STEMI intended for primary percutaneous coronary intervention, bivalirudin is associated with lower mortality rates in comparison with heparin monotherapy. This study suggests that bivalirudin is more effective and safer than heparin monotherapy and should therefore be preferred over heparin monotherapy.

Effect of platelet inhibition with cangrelor during PCI on ischemic events.

BACKGROUND: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

Preclinical evaluation of a novel drug-eluting balloon in an animal model of in-stent stenosis.

Despite advances in contemporary stent technology, in-stent restenosis (ISR) remains the major limitation following revascularization procedures. We developed a porcine model of ISR to specifically investigate the preclinical outcomes of a novel drug-eluting balloon (DEB) in this particular setting. Fifteen pigs received bare metal stents in each of the major coronary arteries for 28 days to induce neointimal growth. Following repeat angiography, animals were allocated to fourdifferent treatment groups. The control group consisted of a bare angioplasty catheter, while the Pantera Lux™ (3.0 µg/mm(2) paclitaxel) (30 s inflation) was compared to two consecutive deployments of the Pantera Lux™ (60 s inflation each) and the commercial SeQuent(®) Please balloon (60 s inflation). Twenty-eight days following balloon deployment, the animals underwent repeat angiography and were subsequently sacrificed for histopathologic assessment. There was a trend in reduction of percent diameter stenosis in the DEB group versus control (13.9% vs. 20.4%), while longer inflation duration or consecutive DEB deployment had no additional growth-limiting effect. Neointimal thickness was reduced from 0.38 ± 0.13 to 0.30 ± 0.09 mm in the control versus DEB group. All DEB groups showed delayed vascular healing characterized by dose-dependent increases in fibrin deposition and neointimal cell vacuity. Investigation of DEB in a porcine model of ISR is feasible and more accurately represents human disease conditions. The magnitude of neointima suppression is lower than that observed in non-diseased animal models and is accompanied by delayed vascular healing.

B-type natriuretic peptide and risk of contrast-induced acute kidney injury in acute ST-segment-elevation myocardial infarction: a substudy from the HORIZONS-AMI trial.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention is associated with adverse short- and long-term outcomes. However, identification of patients at risk for CI-AKI is challenging. Using a large contemporary randomized trial database of patients with ST-segment-elevation myocardial infarction, we therefore sought to examine whether admission B-type natriuretic peptide (BNP) levels predict the development of CI-AKI. METHODS AND RESULTS: A total of 979 ST-segment-elevation myocardial infarction patients enrolled in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial had BNP levels measured in the emergency room prior to primary percutaneous coronary intervention as part of the study protocol. CI-AKI was defined as a relative increase in serum creatinine of ≥25%, or an absolute increase of ≥0.5 mg/dL, occurring within 48 hours after contrast administration. Logistic regression analysis was used to estimate the association of admission BNP with development of CI-AKI. CI-AKI occurred in 131 patients (13.3%). Baseline BNP was a significant univariable correlate of CI-AKI (odds ratio 1.31, 95% confidence interval, 1.14-1.51; P=0.0001). After multivariable adjustment for clinical, laboratory, and angiographic variables, BNP remained a significant independent predictor of CI-AKI (1.29 [1.10, 1.51]; P<0.001). Significant net reclassification improvement was achieved by addition of BNP to the current clinical risk prediction model (net reclassification improvement=0.177; P<0.001) and to the Mehran Risk Score (net reclassification improvement=0.100; P=0.015). CONCLUSIONS: Measurement of serum BNP at hospital admission may help identify patients who are at risk for developing CI-AKI after primary percutaneous coronary intervention in ST-segment-elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Elevation of matrix metalloproteinases in different areas of ascending aortic aneurysms in patients with bicuspid and tricuspid aortic valves.

Our aim is to investigate the elevation of matrix proteins in tissues obtained from distal, above the sinotubular junction (proximal), concave, and convex sites of aneurysms in the ascending aorta using a simultaneous multiplex protein detection system. Tissues were collected from 41 patients with ascending aortic aneurysms. A total of 31 patients had a bicuspid aortic valve (BAV), whereas 10 had a tricuspid aortic valve (TAV). Concave and convex aortic site samples were collected from all patients, whereas proximal and distal convexity samples were obtained from 19 patients with BAV and 7 patients with TAV. Simultaneous detection of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was performed at each of the four aortic sites. MMP-2 levels were higher in the concave aortic sites than in the convex aortic sites. In contrast, MMP-8 levels were higher in the convex sites than in the concave sites, as were MMP-9 levels. In both BAV and TAV patients, TIMP-3 levels were higher in the concave sites than in the convex sites. However, TIMP-2 and TIMP-4 levels were significantly elevated in the sinotubular proximal aorta of BAV patients. Simultaneous detection of MMPs and TIMPs revealed different levels at different aortic sites in the same patient.

Release patterns of copeptin and troponin in Tako-Tsubo cardiomyopathy.

Copeptin, in addition to troponin, has recently been suggested for non-invasive differentiation between Tako-Tsubo cardiomyopathy (TTC) and acute myocardial infarction (AMI). In order to test this hypothesis, we investigated release patterns of pituitary copeptin and cardiac troponin in 49 patients with TTC and 49 age-, gender-, and ECG-matched control patients with AMI. Elevated copeptin levels (i.e. >12 pmol/l) at cardiac catheterization were found in 23/49 (47%) TTC patients and 25/49 (51%) AMI patients. Of these, median copeptin levels were almost identical in both cohorts (34.1 vs. 35.4 pmol/l). Subgroup analysis according to ECG changes revealed that AMI patients with ST-segment elevation had 3.6-fold higher copeptin levels than AMI patients without ST-segment elevation (p<0.05). Furthermore, in patients with TTC and atypical (midventricular) ballooning on left ventricular angiography, copeptin levels were 5.7-fold higher than in TTC patients with a typical (apical) type of ballooning (p<0.01). Elevated troponin T levels (i.e. >0.01 µg/l) at catheterization were detectable in 47/49 (96%) TTC patients and 45/49 (92%) AMI patients; however, peak levels did not differ significantly between both cohorts (median 0.35 vs. 0.27 µg/l). Subgroup analysis according to ECG changes revealed 2-fold higher peak troponin T levels in TTC patients presenting with ST-segment elevation than non-ST-segment elevation (p<0.05). In conclusion, copeptin does not seem to significantly increase non-invasive differentiation between TTC and AMI. At present, coronary angiography, specifically in patients with ST-segment elevation at presentation remains absolutely mandatory.

Vascular effects of paclitaxel following drug-eluting balloon angioplasty in a porcine coronary model: the importance of excipients.

AIMS: The vascular effects of drug- eluting balloon (DEB) deployment in the absence of coronary stents have not been characterised. This study evaluated potential vascular effects of paclitaxel-coated angioplasty balloons using different excipients in the absence of additional stents. METHODS AND RESULTS: A total 45 porcine arteries were treated with paclitaxel-coated DEBs using four different excipients (all 3.0 µg/mm2): A) iopromide (n=9), B) ATEC excipient (n=8), C) BTHC excipient (n=10), D) lecithine excipient (n=10). Uncoated bare angioplasty balloons served as controls (n=8). Histology, histomorphometry, and quantitative angiography analysis were performed 28 days following intervention. Tissue concentrations of paclitaxel were measured in selected animals using BTHC excipient (n=39 arteries) and reached maximum concentrations of 165 ng/mg 30 min after delivery in coronary target tissue. There were no differences in efficacy endpoints using histomorphology or quantitative angiography between groups. In contrast, however, treatment with DEBs using BTHC excipient or iopromide was associated with increased fibrin deposition and inflammation indicating delayed vascular healing. DEBs using lecithin excipient or uncoated angioplasty balloons did not induce any comparable vascular effects. CONCLUSIONS: Effective excipients are necessary to accomplish successful balloon facilitated paclitaxel delivery, which is associated with delayed vascular healing as a sign of successful drug transfer. The potential of DEBs to diminish restenosis following angioplasty may be insufficient in the absence of additional stents.

[Acute myocardial infarction: diagnosis and treatment]. / Der akute Myokardinfarkt. Eine Ubersicht über Diagnostik und Therapie.

Acute ST-elevation myocardial infarction (STEMI) represents a cardiac emergency with a high early mortality. Over the last decades, prognosis of patients with STEMI has dramatically improved. This has primarily been a result of advances in coronary interventional techniques as well as medical therapy. Direct percutaneous recanalization of the infarct-related artery represents the gold standard in treating STEMI, specifically when performed within two hours after first medical contact. These timelines imply logistical challenges for ambulance and hospital services. Furthermore, the broad variety of antithrombotic (acetylsalicylic acid, P2Y12 and GPIIb/IIIa receptor antagonists) and antithrombin medication (heparins, direct thrombin inhibitors) requires a sound understanding of the current evidence, guidelines and the individual patient characteristics to offer optimal medical therapy to the individual patient.

Drug eluting balloons for the treatment of coronary artery disease: What can we expect?

Drug-eluting balloons (DEBs) represent an enhancement of the therapeutic repertoire for the interventional cardiologist. The therapeutic concept of DEBs is promising, notably on the basis of initial studies in patients with diffuse in-stent restenosis (ISR). At present, however, a number of questions regarding long-term efficacy and safety remain, specifically in indications other than diffuse ISR. The results of the evaluation of different substances, balloon systems and clinical indications will determine the long-term success of DEBs.

[Wasp sting, adrenaline injection and acute thoracic pain: an un usual case of stress-induced (tako-tsubo) cardiomyopathy]. / Wespenstich, Adrenalingabe und akuter Thoraxschmerz: ein ungewöhnlicher Fall von stressinduzierter (Tako-Tsubo) Kardiomyopathie.

Tako-tsubo cardiomyopathy is characterized by a transient and reversible left ventricular dysfunction and shows clinical similarities with the acute coronary syndrome. Here, the authors report and discuss a case of a patient with tako-tsubo cardiomyopathy triggered by adrenaline injection after a wasp sting.