TransCatheter aortic valve implantation and fractional flow reserve-guided percutaneous coronary intervention versus conventional surgical aortic valve replacement and coronary bypass grafting for treatment of patients with aortic valve stenosis and multivessel or advanced coronary disease: The transcatheter valve and vessels trial (TCW trial): Design and rationale.

BACKGROUND: Patients with severe aortic stenosis (AS) frequently present with concomitant obstructive coronary artery disease (CAD). In those, current guidelines recommend combined coronary artery bypass grafting (CABG) and surgical aortic valve replacement (SAVR) as the preferred treatment option, although this surgical approach is associated with a high rate of clinical events. Combined transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) with or without FFR have evolved as a valid alternative for cardiac surgery in patients with AS and multivessel or advanced CAD. To date, no dedicated trial has prospectively evaluated the outcomes of a percutaneous versus surgical treatment for patients with both severe AS and CAD. AIMS: To investigate whether fractional-flow reserve (FFR)-guided PCI and TAVI is noninferior to combined CABG and SAVR for the treatment of severe AS and multivessel or advanced CAD. METHODS: The Transcatheter Valve and Vessels (TCW) trial (clinicaltrial.gov: NCT03424941) is a prospective, randomized, controlled, open label, international trial. Patients ≥ 70 years with severe AS and multivessel (≥ 2 vessels) or advanced CAD, deemed feasible by the heart team for both; a full percutaneous or surgical treatment, will be randomised in a 1:1 fashion to either FFR-guided PCI followed by TAVI (intervention arm) vs. CABG and SAVR (control arm). The primary endpoint is a patient-oriented composite of all-cause mortality, myocardial infarction, disabling stroke, unscheduled clinically-driven target vessel revascularization, valve reintervention, and life threatening or disabling bleeding at 1 year. The TCW trial is powered for noninferiority, and if met, superiority will be tested. Assuming a primary endpoint rate of 30% in the CABG-SAVR arm, with a significance level α of 5%, a noninferiority limit delta of 15% and a loss to follow-up of 2%, a total of 328 patients are needed to obtain a power of 90%. The primary endpoint analysis is performed on an intention-to-treat basis. SUMMARY: The TCW Trial is the first prospective randomized trial that will study if a less invasive percutaneous treatment for severe AS and concomitant advanced CAD (i.e., FFR-guided PCI-TAVI) is noninferior to the guidelines recommended approach (CABG-SAVR).

Prehospital treatment with zalunfiban (RUC-4) in patients with ST- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial.

BACKGROUND: Early and complete restoration of target vessel patency in ST-elevation myocardial infarction (STEMI) is associated with improved outcomes. Oral P2Y12 inhibitors have failed to demonstrate either improved patency or reduced mortality when administered in the prehospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the prehospital setting. Zalunfiban, a novel subcutaneously administered glycoprotein IIb/IIIa inhibitor designed for prehospital administration, has shown to achieve rapid, high-grade platelet inhibition that exceeds that of P2Y12 inhibitors. Whether prehospital administration of zalunfiban can improve clinical outcome is unknown. HYPOTHESIS: The present study is designed to assess the hypothesis that a single, prehospital injection of zalunfiban given in the ambulance, in addition to standard-of-care in patients with STEMI with intent to undergo primary percutaneous coronary intervention (PCI) will improve clinical outcome compared to standard-of-care with placebo. STUDY DESIGN: The ongoing CELEBRATE trial (NCT04825743) is a phase 3, randomized, double-blinded, placebo-controlled, international trial. Patients with STEMI intended to undergo primary PCI will receive treatment with a single subcutaneous injection containing either zalunfiban dose 1 (0.110 mg/kg), zalunfiban dose 2 (0.130 mg/kg) or placebo, and the study drug will be administered in the ambulance before transportation to the hospital. A target of 2499 patients will be randomly assigned to one of the treatment groups in a 1:1:1 ratio, ie, to have approximately 833 evaluable patients per group. The primary efficacy outcome is a ranked 7-point scale on clinical outcomes. The primary safety outcome is severe or life-threatening bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria. SUMMARY: The CELEBRATE trial will assess whether a single prehospital subcutaneous injection of zalunfiban in addition to standard-of-care in patients with STEMI with intent to undergo primary PCI will result in improved clinical outcome.

Short-term dual antiplatelet therapy in diabetic patients admitted for acute coronary syndrome treated with a new-generation drug-eluting stent.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) admitted with acute coronary syndrome (ACS) and treated with a drug-eluting stent (DES) remains unclear. This is a prespecified sub-study from the Randomised Evaluation of short-term DUal antiplatelet therapy in patients with acute Coronary syndromE treated with a new generation DES (REDUCE) trial that was designed to determine the efficacy and safety of short-term versus standard 12 months DAPT in diabetic patients with ACS undergoing percutaneous coronary intervention (PCI) using the COMBO stent. METHODS: In this study we included ACS diabetic patients enroled in the REDUCE trial treated with the COMBO stent and randomly assigned to either 3 or 12 months of DAPT. The primary study endpoint was the composite of all-cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke, target vessel revascularisation (TVR), and bleeding complications at 12 and 24 months follow-up. RESULTS: A total of 307 diabetic patients were included, of which 162 (52.8%) in the 3 months DAPT group and 145 (47.2%) in the 12 months DAPT group. Patient characteristics, PCI success, and number of stents used were similar in the 3 and 12 months DAPT groups. Occurrence of the primary study endpoint at 12 and 24 months follow-up was comparable between the two groups (3.1 vs. 3.5%, p = 0.865, and 15.8 vs. 14.9%, p = 0.824, respectively). Moreover, the prevalence of the specific clinical outcome parameters (all-cause mortality), MI, ST, stroke, TVR, and bleeding was similar in both study groups. CONCLUSIONS: This sub-analysis shows similar clinical outcomes following 3 months DAPT as compared to 12 months DAPT in diabetic patients undergoing PCI for ACS using the COMBO stent. These results suggest that, even in this particular subset of patients, short duration of DAPT might be considered safe. Future larger studies are warranted to provide more precise estimations in terms of safety and efficacy of short term DAPT in these high-risk patients.

Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Pre-hospital platelet inhibition in patients with ST-segment elevation myocardial infarction (STEMI) may improve outcomes. RUC-4 is a novel, second-generation glycoprotein IIb/IIIa inhibitor designed for first-point-of-medical-contact treatment for STEMI by subcutaneous injection. AIMS: The open-label, phase 2A, CEL-02 trial aimed to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI (pPCI). METHODS: A total of 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before pPCI in escalating doses (0.075 mg/kg [n=8], 0.090 mg/kg [n=9], or 0.110 mg/kg [n=10]). RESULTS: The primary PD endpoint of high-grade (≥77%) inhibition of the VerifyNow iso-TRAP assay at 15 minutes was met in 3/8, 7/8, and 7/8 patients in the three cohorts with a dose-response relationship (mean inhibition [min - max] of 77.5% [65.7%-90.6%], 87.5% [73.8%-93.1%], and 91.7% [76.4%-99.3%], respectively; ptrend=0.002). Fifty percent (50%) inhibition remained after 89.1 (38.0-129.7), 104.2 (17.6-190.8), and 112.4 (19.7-205.0) minutes. Injection site reactions or bruising were observed in 1 (4%) and 11 (41%) patients, respectively. Mild access-site haematomas occurred in 6 (22%), and severe access-site haematomas occurred in 2 patients (7%). No thrombocytopaenia was observed within 72 hours post dose. CONCLUSIONS: In patients with STEMI, a single subcutaneous dose of RUC-4 at 0.075, 0.090, and 0.110 mg/kg showed dose-response high-grade inhibition of platelet function within 15 minutes.

Impact of age on the comparison between short-term vs 12-month dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: 2-Year follow-up results of the REDUCE trial.

BACKGROUND AND AIMS: The impact of advanced age on the optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary revascularization (PCI) is still greatly debated. Therefore, the aim of the present sub-analysis of the REDUCE trial was to assess the impact of age on the comparison between a short 3 months vs standard 12 months DAPT in ACS patients treated with the COMBO Dual Stent Therapy. METHODS: The REDUCE trial is a prospective, multicenter, investigator-initiated study that randomized ACS patients undergoing PCI with the COMBO drug eluting stent to either 3 or 12 months of DAPT. The study population was divided according to age (

Beta-blocker effect on ST-segment: a prespecified analysis of the EARLY-BAMI randomised trial.

OBJECTIVE: The effect of early intravenous (IV) beta-blockers (BBs) administration in patients undergoing primary percutaneous coronary intervention (pPCI) on ST-segment deviation is unknown. We undertook a prespecified secondary analysis of the Early Beta-blocker Administration before primary PCI in patients with ST-elevation Myocardial Infarction (EARLY-BAMI) trial to investigate the effect of early IV BB on ST-segment deviation. METHODS: The EARLY-BAMI trial randomised patients with ST-elevation myocardial infarction (STEMI) to IV metoprolol (2×5 mg bolus) or matched placebo before pPCI. The prespecified outcome, evaluated by an independent core laboratory blinded to study treatment, was the residual ST-segment deviation 1 hour after pPCI (ie, the percentage of patients with >3 mm cumulative ST deviation at 1 hour after pPCI). RESULTS: An ECG for the evaluation of residual ST-segment deviation 1 hour after pPCI was available in 442 out of 683 randomised patients. The BB group had a lower heart rate after pPCI compared with placebo (71.2±13.2 vs 74.3±13.6, p=0.016); however, no differences were noted in the percentages of patients with >3 mm cumulative ST deviation at 1 hour after pPCI (58.6% vs 54.1%, p=0.38, in BB vs placebo, respectively) neither a significant difference was found for the percentages of patients in each of the four prespecified groups (normalised ST-segment; 1-3 mm; 4-6 mm;>6 mm residual ST-deviation). CONCLUSIONS: In patients with STEMI, who were being transported for primary PCI, early IV BB administration did not significantly affect ST-segment deviation after pPCI compared with placebo. The neutral result of early IV BB administration on an early marker of pharmacological effect is consistent with the absence of subsequent improvement of clinical outcomes.

Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).

AIMS: The optimal duration of DAPT in ACS patients treated with DES is still unclear. Therefore, the aim of the current study was to investigate a short versus a standard 12-month DAPT regimen in ACS patients undergoing new-generation DES implantation. METHODS AND RESULTS: REDUCE was a prospective, open-label, multicentre, investigator-initiated study that randomised 1,496 ACS patients after treatment with the COMBO stent to either three (n=751) or 12 months (n=745) of DAPT. The primary study endpoint was a composite of all-cause mortality, myocardial infarction, stent thrombosis, stroke, target vessel revascularisation and bleeding at 12 months. No difference was observed in the demographic and clinical characteristics between the two groups, except for gender (p=0.01). At one-year follow-up, non-inferiority of three- versus 12-month DAPT in the primary endpoint was met (8.2% vs 8.4%, pnon-inferiority<0.001). The similar outcome between the two groups was confirmed at two-year follow-up (11.6% vs 12.1%, p=0.76), with no significant difference in overall mortality (3.1% vs 2.2%, p=0.27), cardiac mortality (1.8% vs 1.1%, p=0.28), stent thrombosis (1.6% vs 0.8%, p=0.16) and major bleeding (3.3% vs 4.0%, p=0.46). CONCLUSIONS: The results show that, among ACS patients treated with the COMBO stent, three months is non-inferior to 12 months of DAPT. However, given the numerically higher rates of mortality and ST in the three-month DAPT group, one-year DAPT should still be recommended in ACS until more information becomes available. A three-month DAPT strategy should be considered only if clinically mandated.

Field triage in the ambulance versus referral via non-percutaneous coronary intervention centre in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A systematic review.

AIMS: The purpose of this study was to determine whether direct ambulance transport of ST-elevation myocardial infarction (STEMI) patients to a percutaneous coronary intervention (PCI) hospital (field triage) leads to a lower 30-day mortality compared to transport via a referral non-PCI hospital (referral via a spoke centre) in STEMI patients. METHODS AND RESULTS: We performed a systematic review of interventions. An experienced librarian searched in PubMed, EMBASE.com and The Cochrane Library (via Wiley) from January 1980-February 2013. Studies that examined field triage and/or referral via a spoke centre in STEMI patients treated with primary or facilitated PCI were included. Two authors independently conducted the study selection and data extraction. Multivariable frequency weighted logistic regression analysis was performed to assess the effect of the type of transfer on the outcome measures. We identified 14 randomised clinical trials (RCTs), including 20 transfer groups and 4474 participants. Thirty-day mortality was lower in patients who underwent field triage (3.0%; 95% confidence interval (CI) 2.2-4.2) compared to patients who were referred via a spoke centre (4.7%; 95% CI 4.0-5.5). In multivariable frequency weighted logistic regression analysis, field triage was independently associated with a lower incidence of 30-day mortality (odds ratio (OR): 0.58; 95% CI 0.37-0.89). CONCLUSION: Field triage compared to referral via a spoke centre leads to a lower 30-day mortality in STEMI patients. Therefore, direct ambulance transport to a PCI hospital should become the transfer type for STEMI patients.

Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention.

BACKGROUND: The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established. OBJECTIVES: This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population. METHODS: STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock. RESULTS: A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups. CONCLUSIONS: In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19).

The influence of system delay on 30-day and on long-term mortality in patients with anterior versus non-anterior ST-segment elevation myocardial infarction: a cohort study.

AIM: To evaluate the relationship between system delay and 30-day and long-term mortality in patients with anterior versus non-anterior ST-elevation myocardial infarction (STEMI). METHODS: We conducted a prospective observational cohort study. Patients with STEMI who were transported to the Isala Hospital, Zwolle, and underwent primary percutaneous coronary intervention (pPCI) from 2005 until 2010 were included. These patients were divided into quartiles of system delay (time from first medical contact until reperfusion therapy): Q1-Q4. RESULTS: In total, 3041 patients were included in our study. 41% (n=1253) of the patients had an anterior myocardial infarction (MI) and 59% of the patients (n=1788) had a non-anterior MI. Only in patients with an anterior MI, prolonged system delay was associated with a higher mortality (30-day Q1: 2.6%, Q2: 3.1%, Q3: 6.8%, Q4: 7.4%, p=0.001; long-term Q1: 12.8%, Q2: 13.7%, Q3: 24.1%, Q4: 22.6%, p<0.001). After multivariable adjustment, prolonged system delay was associated with a higher 30-day and long-term mortality in patients with an anterior MI (30 day Q2: HR 1.18, 95% CI (0.46 to 3.00), Q3: HR 2.45, 95% CI (1.07 to 5.63), Q4: HR 2.25, 95% CI (0.97 to 5.25)); long-term Q2: HR 1.09, 95% CI (0.71 to 1.68), Q3: HR 1.68, 95% CI (1.13 to 2.49), Q4: HR 1.55, 95% CI (1.03 to 2.33)), but not in patients with a non-anterior MI. CONCLUSIONS: Prolonged system delay significantly increased short-term as well as long-term mortality in patients with an anterior MI. This effect was not demonstrated in patients with a non-anterior MI. Therefore, it is of the greatest importance to minimise system delay in patients who present with an anterior MI.

Prehospital treatment of ST-segment elevated myocardial infarction patients.

Providing optimal care to patients with ST-segment elevated myocardial infarction is challenging. If a patient experiences chest pain and calls the emergency number, a cascade of actions is initiated that should lead to a diagnosis, start of treatment and reperfusion of the infarcted myocardium. This should all happen within 90 min after first medical contact, irrespective of the location of the patient or the time of day. The complex organization that is needed to achieve this goal in every ST-segment elevated myocardial infarction patient accounts for a fascinating interplay between prehospital and in-hospital care, in a situation when every minute counts. State-of-the-art care should be provided according to the latest insights and guidelines.

Predictors and outcome of grade 3 ischemia in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

PURPOSE: Grade 3 ischemia (G3I: distortion of the terminal portion of the QRS complex) is a predictor of serious complications after acute myocardial infarction. However, less is known about which patients are more prone to present with G3I. METHODS: Patients who were enrolled in the Ongoing Tirofiban In Myocardial infarction Evaluation trial 2 were included. These patients were divided in 2 groups based on the enrolment electrocardiogram: grade 2 ischemia (G2I) or G3I. RESULTS: Between June 2004 and November 2007, 1308 patients with interpretable electrocardiograms were enrolled. Grade 3 ischemia was found in 426 (32.6%) patients. Patients with G3I were older, more often male, more often had diabetes, had a Thrombolysis In Myocardial Infarction (TIMI) risk score of greater than 3, had 3 vessel disease, had an anterior infarction, more often presented in Killip class greater than 1, less often had a preprocedural TIMI 3 flow, and less often had a myocardial blush grade 3 post-PCI. One hour post-PCI, residual ST deviation was higher in patients with G3I compared with patients with G2I. Furthermore, G3I was associated with more major cardiac events (including death, myocardial infarction, urgent target vessel revascularization). After multivariate adjustment, G3I was an independent predictor of failure of ST-segment resolution 1 hour post-PCI (odds ratio, 1.4; 95% confidence interval, 1.1-1.9) and 30-day mortality (odds ratio, 3.2; 95% confidence interval, 1.2-8.7). CONCLUSION: Grade 3 ischemia was associated with high-risk patient criteria (older age, diabetes, TIMI risk score >3, Killip class >1, and anterior myocardial infarction) and represents a subgroup of high-risk patients who seems to be associated with poor myocardial reperfusion and worse outcome.

Prehospital triage in the ambulance reduces infarct size and improves clinical outcome.

BACKGROUND: We evaluated the effect of prehospital triage (PHT) in the ambulance on infarct size and clinical outcome and studied its relationship to the distance of patient's residence to the nearest percutaneous coronary intervention (PCI) center. METHODS: All consecutive ST-segment elevation myocardial infarction patients who were transported to the Isala klinieken from 1998 to 2008 were registered in a dedicated database. Of these, 2,288 (45%) were referred via a spoke center and 2.840 (55%) via PHT. RESULTS: PHT patients were more often treated within 3 hours after symptom onset (46.2% vs 26.8%, P < .001), more often had a post-procedural thrombolysis in myocardial infarction (TIMI) 3 flow (93.0% vs 89.7%, P < .001) had a smaller infarct size (peak creatine kinase 2,188 ± 2,187 vs 2,575 ± 2,259 IU/L, P < .001) and had a lower 1-year mortality (4.9% vs 7.0%, P = .002). After multivariate analysis, PHT was independently associated with ischemic time less than 3 hours (OR 2.45, 95% CI 2.13-2.83), a peak creatine kinase less than the median value (OR 1.19, 95% CI 1.04-1.36) and a lower 1-year mortality (OR 0.67, 95% CI 0.50-0.91). The observed differences between PHT patients and the spoke group were more pronounced in the subgroup of patients living >38 km from the PCI center. CONCLUSION: PHT in the ambulance is associated with a shorter time to treatment, a smaller infarct size and a more favorable clinical outcome, especially with longer distance from the patient's residence to the nearest PCI center. Therefore, PHT in the ambulance may reduce the negative effect of living at a longer distance from the PCI center.

A comparison between the Plateletworks-assay and light transmittance aggregometry for monitoring the inhibitory effects of clopidogrel.

A simple and rapid point-of-care platelet function assay that guides antiplatelet responses to aspirin and clopidogrel may be of great clinical value for the individual tailoring of therapy. The Plateletworks assay is based on single platelet counting and has been described as a promising point-of-care assay for the monitoring of the effects of the GP IIb/IIIa antagonists. However, data about its utility and reliability in monitoring the effects of thienopyridines is limited. In the present study we assessed reproducibility of the Plateletworks assay over time. In addition, a comparison between the Plateletworks assay and optical aggregometry was performed in a large cohort of patients on maintenance therapy with aspirin and clopidogrel. The Plateletworks assay demonstrated a good agreement with optical aggregometry in measuring the response to clopidogrel. The results of Plateletworks are, however, highly time dependent which implicates that measurements should be performed within 10 min.

An observational study on the effects of nadroparin-based and citrate-based continuous venovenous hemofiltration on calcium metabolism.

BACKGROUND: To study calcium homeostasis during citrate-based compared to nadroparin-based CVVH in critically-ill patients with acute renal failure. METHODS: 11 patients were observed during citrate anticoagulation, 9 with nadroparin and 10 controls. Citrate was chosen for patients with active or at risk for bleeding. RESULTS: The controls had, at 24 h, a median serum iCa of 1.1 mmol/l, the citrate group 0.87 mmol/l and the nadroparin group 1.1 mmol/l (citrate vs. control p = 0.001, citrate vs. nadroparin p = 0.002). At 48 h, iCa was not significantly different anymore. Ca balance was negative for the citrate group in contrast to the nadroparin group (p = 0.012). Median serum PTH was higher (30.0 pmol/l vs. 6.5 pmol/l, p = 0.003) in the citrate group. CONCLUSION: With a relative low target-serum-iCa (0.8-0.9 mmol/l) citrate CVVH-treated patients had a negative daily calcium balance and a temporarily lower iCa level resulting in an enhanced PTH response in comparison to nadroparin.