Zenon Huczek

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): A randomised, open-label, multicentre trial

BACKGROUND Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Transcatheter aortic valve implantation in patients with bicuspid aortic valve: A patient level multi-center analysis

OBJECTIVE We sought to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BiAV). BACKGROUND BiAV remains a relative contraindication to TAVI resulting in exclusion from TAVI trials and thus limiting data on the clinical performance of transcatheter valves in these patients. METHODOLOGY We conducted an international patient level multicenter analysis on outcomes in patients with BiAV undergoing TAVI. The primary outcome of the study was the combined early safety endpoint--a composite of 30 day mortality, stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction, major vascular complication and valve related dysfunction. Secondary endpoints included the individual components of the primary endpoint as well as post-TAVI paravalvular leak (PVL), rehospitalization, new pacemaker insertion and device success rates at 30 days and 1 year. RESULTS A total of 108 patients with BiAV were identified in 21 centers in Canada, Spain, Italy, Poland and Singapore who underwent TAVI between January 2005 and March 2014. The composite primary outcome occurred in one quarter of patients (26.9%)--mainly driven by re-intervention for valve malposition (9.3%). The 30-day and 1 year mortality rates were 8.3% and 16.9% respectively with AR ≥ 3+ occurring in 9.6% of patients. Device success was achieved in 85.2% of cases with pacemaker insertion in 19.4%. While PVL was not associated with an increased risk of 30 day or 1 year mortality--Type I BiAV anatomy with left and right cusp fusion had significantly better outcomes than other valve variants. CONCLUSION In selected patients with BiAV and severe aortic stenosis, TAVI appears both safe and feasible with acceptable clinical outcomes. Clinical studies of TAVI in this patient population are warranted.

Baseline platelet size is increased in patients with acute coronary syndromes developing early stent thrombosis and predicts future residual platelet reactivity. A case-control study

INTRODUCTION Pre-procedural predictors of early stent thrombosis (ST) and future response to platelet inhibitors are in demand. We sought to evaluate the impact of baseline platelet indices on the occurrence of early ST and future residual platelet reactivity. MATERIALS AND METHODS Hundred and eight patients with acute coronary syndromes (ACS) in whom stents were implanted were included: 36 consecutive ST cases and 72 matched controls. Platelet indices assessed with flow cytometry before stent implantation were retrieved from the departments data base. Residual platelet reactivity specific to aspirin (aspirin reaction units-ARU) and clopidogrel (P2Y12 reaction units-PRU) was assessed prospectively with VerifyNow under dual antiplatelet treatment. RESULTS Platelet size reported as mean platelet volume (MPV) or proportion of large platelets (LPLT) was significantly higher in ST cases compared with controls (10.4, 95% confidence intervals [CI], 10.1-10.8 vs. 9.7, CI, 9.5-9.9, P=0.0004 and 35.8, CI, 34.2-37.3 vs. 33.3, CI, 32.2-34.3, P=0.007, respectively). Dual aspirin and clopidogrel poor-responsiveness was diagnosed significantly more often in ST cases than in controls (19.6% vs. 1.4%, P=0.004), whereas no difference was observed for single aspirin or clopidogrel poor-responsiveness. A strong correlation was found between MPV and both, ARU (r=0.66, P<0.0001) and PRU (r=0.55, P<0.0001). Similarly, higher LPLT was associated with higher ARU (r=0.47, P<0.0001) and PRU (r=0.38, P=0.0001). CONCLUSIONS Baseline platelet size is increased in patients with ACS developing early ST and correlates with future residual platelet reactivity under aspirin and clopidogrel therapy. Dual but not isolated aspirin or clopidogrel poor-responsiveness appears to be associated with early ST.

Transcatheter implantation of an aortic valve prosthesis in a female patient with severe bicuspid aortic stenosis

A successful implantation of transcatheter aortic valve was performed in a highrisk 85-year-old female with severe symptomatic stenosis of a bicuspid aortic valve (BAV) [ Panel A ] and tight lesions in left anterior descending (LAD) and circumflex artery (LCx). Until recently, BAV remained a contraindication to transcatheter aortic valve replacement …

A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial.

Outcomes of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) have been significantly improved with the use of potent P2Y12 receptor inhibitors like prasugrel. While most of the ischaemic risk reduction for prasugrel versus clopidogrel was demonstrated in the early treatment period, the risk of bleeding became particularly prominent during the chronic course of therapy. It may therefore be a valid approach to substitute prasugrel for clopidogrel in the early phase of chronic antiplatelet treatment after PCI. In the Testing Responsiveness To Platelet Inhibition On Chronic Antiplatelet Treatment For Acute Coronary Syndromes (TROPICAL-ACS) trial, we aim to compare standard prasugrel therapy with a de-escalating antiplatelet treatment approach guided by platelet function testing (PFT). The study is an investigator-initiated European multicentre, randomised clinical trial in biomarker-positive ACS patients after successful PCI. Two thousand six hundred patients will be randomised prior to hospital discharge in a 1:1 fashion to either receive standard prasugrel therapy (control group) or de-escalating therapy (one-week prasugrel followed by one-week clopidogrel and PFT-guided maintenance therapy from day 14 after hospital discharge, monitoring group). Patients of the monitoring group with high on-clopidogrel platelet reactivity (HPR) based on Multiplate analyzer testing (HPR: ≥ 46U per consensus definition) will be switched back to prasugrel, whereas those without HPR (<46 U) will continue clopidogrel treatment. The overall study treatment duration will be one year in both groups. The primary endpoint of the study is net clinical benefit (combined incidence of cardiovascular death, myocardial infarction, stroke and bleeding ≥ grade 2 according to BARC criteria) one-year after randomisation. TROPICAL-ACS is the first large-scale, randomised controlled trial assessing the clinical value of a PFT-guided de-escalation of antiplatelet treatment in biomarker positive ACS patients undergoing PCI.

Incidence, Predictors and Impact of Severe Periprocedural Bleeding According to VARC-2 Criteria on 1-Year Clinical Outcomes in Patients After Transcatheter Aortic Valve Implantation

There are differences in reporting bleeding complications after transcatheter aortic valve implantation (TAVI), which is a consequence of the lack of consensus for their definition. Furthermore, the amount of data on the impact of peri-procedural bleeding on the mid-term prognosis is still limited. The aim of this study was to investigate the incidence, predictors, and impact of life-threatening and major bleedings as defined by the Valve Academic Research Consortium 2 (VARC-2) in patients after TAVI over the mid-term prognosis.Consecutive patients who underwent TAVI from March 2010 to December 2013 were included. All data were classified according to the VARC-2 criteria. We assessed the incidence and the predictors of serious bleeding events (SBE), defined as life-threatening/disabling (LT/D) or major bleeding, and analyzed their impact on 30-day and 1-year clinical outcome.A total of 129 patients were included (79.1 ± 8.3 years; mean EuroSCORE = 17.8 ± 12.7). The SBE occurred in 25 patients (19.4%), of which 9 (7.0%) had LT/D and 16 (12.4%) had major bleeding. Trans-subclavian (TS) access (OR 4.38, 95% CI 2.13-14.29, P = 0.01) and diabetes (OR 2.93, 95% CI 1.08-7.93, P = 0.03) were identified as independent predictors of SBE. Patients with SBE had higher 30-day mortality (20.0% versus 4.0% P = 0.02) and 1-year mortality (40.0% versus 11.1%, P < 0.002). SBE independently predicted 1-year, all-cause mortality (HR 5.88, 95% CI 1.7319,94, P = 0.005).SBE are frequent after TAVI and are associated with decreased short and mid-term survival. Diabetes and TS access are independent risk factors for SBE.

Outcome prediction following transcatheter aortic valve implantation: Multiple risk scores comparison.

BACKGROUND The aim of the study was to compare 7 available risk models in the prediction of 30-day mortality following transcatheter aortic valve implantation (TAVI). Heart team decision supported by different risk score calculations is advisable to estimate the individual procedural risk before TAVI. METHODS One hundred and fifty-six consecutive patients (n = 156, 48% female, mean age 80.03 ± 8.18 years) who underwent TAVI between March 2010 and October 2014 were in-cluded in the study. Thirty-day follow-up was performed and available in each patient. Base-line risk was calculated according to EuroSCORE I, EuroSCORE II, STS, ACEF, Amblers, OBSERVANT and SURTAVI scores. RESULTS In receiver operating characteristics analysis, neither of the investigated scales was able to distinguish between patients with or without an endpoint with areas under the curve (AUC) not exceeding 0.6, as follows: EuroSCORE I, AUC 0.55; 95% confidence intervals (CI) 0.47-0.63, p = 0.59; EuroSCORE II, AUC 0.59; 95% CI 0.51-0.67, p = 0.23; STS, AUC 0.55; 95% CI 0.47-0.63, p = 0.52; ACEF, AUC 0.54; 95% CI 0.46-0.62, p = 0.69; Amblers, AUC 0.54; 95% CI 0.46-0.62, p = 0.70; OBSERVANT, AUC 0.597; 95% CI 0.52-0.67, p = 0.21; SURTAVI, AUC 0.535; 95% CI 0.45-0.62, p = 0.65. SURTAVI model was calibrated best in high-risk patients showing coherence between expected and observed mortality (10.8% vs. 9.4%, p = 0.982). ACEF demonstrated best classification accuracy (17.5% vs. 6.9%, p = 0.053, observed mortality in high vs. non-high-risk cohort, respectively). CONCLUSIONS None of the investigated risk scales proved to be optimal in predicting 30-day mortality in unselected, real-life population with aortic stenosis referred to TAVI. This data supports primary role of heart team in decision process of selecting patients for TAVI.

Access for percutaneous coronary intervention in ST segment elevation myocardial infarction: radial vs. femoral ??? a prospective, randomised clinical trial (OCEAN RACE)

BACKGROUND Percutaneous treatment of patients with ST segment elevation myocardial infarction (STEMI) has become the standard and default mode of management as recommended by the European Society of Cardiology guidelines for managing acute myocardial infarction in patients presenting with STEMI. The choice of vascular access is made by the operator and has a potential impact on the safety and efficacy of the procedure and outcomes. AIM To understand the influence of a radial approach on bleeding complications and angiographic success, we performed a prospective, controlled randomised trial. METHODS Patients were allocated to radial (TR) or femoral (TF) vascular access. The primary endpoints were major bleeding by the REPLACE-2 scale and minor bleeding by the EASY scale (TR arm) or the FEMORAL scale (TF arm). Other outcomes included procedural data, in-hospital and long-term survival. RESULTS There were 103 patients analysed in total, 52 in the TR arm and 51 in the TF arm. The demographic and clinical baseline characteristics were well matched between the two study groups. The frequency of the primary endpoint was the same in both arms (TR: 25.0% vs. TF: 33.3%, p = 0.238). In per protocol analysis, there was a significant benefit of the TR approach among independent operators (17.4% vs. 36.8%, p = 0.038). Major bleeding by the REPLACE-2 scale occurred in 4.2% of patients (TR: 5.8% vs. TF: 3.9%, p = 0.509). There were no differences in terms of the rate of major cardiac adverse events, which happened in 10.7% of the study population (TR: 9.6% vs. TF: 11.8%, p = 0.48). In the TF arm, there was a trend towards a higher risk of local bleedings (TR: 22.4% vs. TF: 37.7%, p = 0.081) and a significantly higher frequency of local haematoma (class III, EASY/FEMORAL) (TR: 0% vs. TF: 9.8%, p = 0.027). CONCLUSIONS There were no significant differences between the TR and TF approaches in terms of clinical efficacy and patient safety. However, patients treated by independent operators might benefit from TR access. The overall complication risk of percutaneous coronary intervention treatment of STEMI patients remains low.

Cost-effectiveness of radial vs. femoral approach in primary percutaneous coronary intervention in STEMI – Randomized, control trial

INTRODUCTION AND OBJECTIVES Primary percutaneous coronary intervention infarction became the preferred method of treatment for myocardial ST segment elevation. Improved safety was reported in transradial access (radial) compared to transfemoral access (femoral). The aim of this study was to compare the cost between the two access points in ST segment elevation myocardial infarction. METHODS This is a subanalysis of the OCEAN RACE trial in which 103 myocardial infarction patients were randomized to either the radial (n=52) or femoral (n=51) groups. The clinical safety and efficacy were recorded during the hospital stay. The procedural metrics were meticulously logged, and costs were evaluated using the micro-cost method. The indirect costs were estimated using the human capital approach. RESULTS Clinical success was numerically higher in the radial group (90.4 vs. 80.4%, p=0.123). There were no differences in major adverse cardiac events (9.6% vs. 11.8%, p=0.48) and death (2.0% vs. 6.0%, p=0.31). The average in-hospital cost per patient was 2,740 ± 1,092 EUR. The cost of therapeutic success was lower in the radial group at 3,060 EUR vs. 3,374 EUR. The indirect costs related to absence at work were 138 EUR per patient, which were lower in the radial group compared to the femoral group. CONCLUSIONS The total in-hospital costs were similar between the study groups. The indirect costs were lower in the radial group. Introduction of radial access as the default approach in all centers may significantly reduce the overall financial burden from a social perspective.

BleeMACS: rationale and design of the study.

Background Bleeding events after an acute coronary syndrome have a negative impact on prognosis. Available risk scores are limited by suboptimal accuracy, prediction of only in-hospital events and absence of patients treated with new antiplatelet agents in the current era of widespread use of percutaneous coronary intervention. Design The BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) project is a multicenter investigator-initiated international retrospective registry that enrolled more than 15 000 patients discharged with a definitive diagnosis of acute coronary syndrome and treated with percutaneous revascularization. The primary end point is the incidence of major bleeding events requiring hospitalization and/or red cell transfusion concentrates within 1 year. An integer risk score for bleeding within the first year after hospital discharge will be developed from a multivariate competing-risks regression. Conclusion The BleeMACS registry collaborative will allow development and validation of a risk score for prediction of major bleeding during follow-up for patients receiving contemporary therapies for acute coronary syndrome.