Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy.

BACKGROUND AND AIMS: The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as assessed by flow-mediated dilation (FMD) in patients with acute myocardial infarction (AMI) are unknown. Therefore, we aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT). METHODS: This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PACMAN-AMI trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks. RESULTS: 139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab (n = 68, 5.44 ± 2.24%) versus placebo (n = 71, 5.45 ± 2.19%) group (difference = -0.21%, 95% CI -0.77 to 0.35, p = 0.47). FMD improved throughout 52 weeks in both groups similarly (p < 0.001). There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS) (n = 139, slope = -1.00, p = 0.006), but not with lipid pool (NIRS) (n = 139, slope = -7.36, p = 0.32), or fibrous cap thickness (OCT) (n = 81, slope = -1.57, p = 0.62). CONCLUSIONS: Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness.

Pretreatment With P2Y12 Inhibitors in ST-Segment Elevation Myocardial Infarction: Insights From the Bern-PCI Registry.

BACKGROUND: Evidence to support immediate P2Y12 inhibitor loading in ST-segment elevation myocardial infarction (STEMI) is limited. OBJECTIVES: This study sought to compare outcomes of STEMI patients receiving immediate or delayed P2Y12 inhibitor treatment. METHODS: Using data from the prospective Bern-PCI registry between 2016 and 2020, we stratified STEMI patients undergoing percutaneous coronary intervention according to time periods with different institutional recommendations regarding P2Y12 inhibitor pretreatment. In cohort 1 (October 2016-September 2018), immediate P2Y12 inhibitor treatment was recommended. In cohort 2 (October 2018-September 2020), P2Y12 inhibitor treatment was recommended after coronary anatomy was confirmed. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events (MACCEs) defined as all-cause death, recurrent myocardial infarction, stroke, or definite stent thrombosis at 30 days. Sensitivity analysis included only patients in whom these recommendations were followed. RESULTS: Cohort 1 included 1,116 patients; pretreatment was actually given in 708 (63.4%). Cohort 2 included 847 patients; pretreatment was withheld in 798 (94.2%). The mean age was 65 ± 13 years, and 24% were female. Baseline characteristics were well-balanced between groups. The median difference for P2Y12 loading to angiography was 52 minutes between cohort 1 and 2 and 100 minutes between patients receiving vs not receiving pretreatment. Rates of MACCEs were similar between cohort 1 and cohort 2 (10.1% vs 8.1%; adjusted HR: 0.91; 95% CI: 0.65-1.28; P = 0.59) and between patients receiving vs not receiving pretreatment (7.1% vs 8.4%; adjusted HR: 1.17; 95% CI: 0.78-1.74; P = 0.45). CONCLUSIONS: In this cohort study of patients with STEMI undergoing primary percutaneous coronary intervention, P2Y12 inhibitor pretreatment was not associated with improved MACCEs.

Quantitative Flow Ratio to Predict Non-Target-Vessel Events Before Planned Staged Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome.

BACKGROUND: The optimal time point of staged percutaneous coronary intervention (PCI) among patients with acute coronary syndrome (ACS) remains a matter of debate. Quantitative flow ratio (QFR) is a novel noninvasive method to assess the hemodynamic significance of coronary stenoses. We aimed to investigate whether QFR could refine the timing of staged PCI of non-target vessels (non-TVs) on top of clinical judgment for patients with ACS. METHODS AND RESULTS: For this cohort study, patients with ACS from Bern University Hospital, Switzerland, scheduled to undergo out-of-hospital non-TV staged PCI were eligible. The primary end point was the composite of non-TV myocardial infarction and urgent unplanned non-TV PCI before planned staged PCI. The association between lowest QFR per patient measured in the non-TV (from index angiogram) and the primary end point was assessed using multivariable adjusted Cox proportional hazards regressions with QFR included as linear or penalized spline (nonlinear) term. QFR was measured in 1093 of 1432 patients with ACS scheduled to undergo non-TV staged PCI. Median time to staged PCI was 28 days. The primary end point occurred in 5% of the patients. In multivariable analysis (1018 patients), there was no independent association between non-TV QFR and the primary end point (hazard ratio, 0.87 [95% CI, 0.69-1.05] per 0.1 increase; P=0.125; nonlinear P=0.648). CONCLUSIONS: In selected patients with ACS scheduled to undergo staged PCI at a median of 4 weeks after index PCI, QFR did not emerge as an independent predictor of non-TV events before planned staged PCI. Thus, this study does not provide conceptual evidence that QFR is helpful to refine the timing of staged PCI on top of clinical judgment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02241291.

Impact of design characteristics among studies comparing coronary computed tomography angiography to noninvasive functional testing in chronic coronary syndromes.

BACKGROUND: Coronary computed tomography angiography (CCTA) is widely adopted to detect obstructive coronary artery disease (CAD) in patients with chronic coronary syndromes (CCS). However, it is unknown to which extent study-specific characteristics yield different conclusions. METHODS: We summarized non-randomized and randomized studies comparing CCTA and noninvasive functional testing for CCS with information on the outcome of myocardial infarction (MI). We evaluated the differential effect according to study characteristics using random-effect meta-analysis with Hartung-Knapp-Sidik-Jonkman adjustments. RESULTS: Fifteen studies (8 non-randomized, 7 randomized) were included. CCTA was associated with decrease in relative (odds ratio (OR) 0.54, 95%CI 0.47 to 0.62, P < .001) and absolute MI risk (risk difference (RD) -0.4%, 95%CI -0.6 to -0.1, P = .005). The results remained consistent among the non-randomized (RD -0.4%, 95%CI -0.7 to -0.1, P=.029), but not among the randomized trials where there was no difference in the observed risk (RD 0.2%, 95%CI -0.6 to 0.1, P = .158). CCTA was not associated with MI reduction in studies with clinical outcome definition (OR 0.77, 95%CI 0.41 to 1.44, P = .212), research driven follow-up (OR 0.54, 95%CI 0.24 to 1.21, P = .090), central event assessment (OR 0.63, 95%CI 0.21 to 1.86, P = .207), outcome adjudication (OR 0.74, 95%CI 0.24 to 2.23, P = .178), or at low-risk of bias (OR 0.74, 95%CI 0.24 to 2.23, P = .178). CONCLUSIONS: Among studies of any design, CCTA was associated with lower risk of MI in CCS compared to noninvasive functional testing. This benefit was diminished among studies with clinical outcome definition, central outcome assessment/adjudication or at low-risk of bias.

Biodegradable polymer sirolimus-eluting stents vs durable polymer everolimus-eluting stents in patients undergoing percutaneous coronary intervention: A meta-analysis of individual patient data from 5 randomized trials.

BACKGROUND: Newest generation drug-eluting stents combine biodegradable polymers with ultrathin stent platforms in order to minimize vessel injury and inflammatory response. Evidence from randomized controlled trials suggested that differences in stent design translate into differences in clinical outcome. The aim of the present study was to evaluate the safety and efficacy of ultrathin strut, biodegradable polymer sirolimus eluting stents (BP SES) compared with thin strut, durable polymer everolimus-eluting stents (DP EES) among patients undergoing percutaneous coronary intervention (PCI). METHODS: We pooled individual participant data from 5 randomized trials (NCT01356888, NCT01939249, NCT02389946, NCT01443104, NCT02579031) including a total of 5,780 patients, and performed a one-stage meta-analysis using a mixed effects Cox regression model. RESULTS: At a median duration of follow-up of 739 days (interquartile range 365-1,806 days), target-lesion failure occurred in 337 (10.3%) and 304 (12.2%) patients treated with BP SES and DP EES (HR 0.86, 95%CI 0.71-1.06, P = .16). There were no significant differences between BP SES and DP EES with regards to cardiac death (111 (3.4%) vs 102 (4.1%); HR 1.05, 95%CI 0.80-1.37, P = .73), target-vessel myocardial infarction (136 (4.1%) vs 126 (5.0%), HR 0.79, 95%CI 0.62-1.01, P = .061), and clinically-driven target-lesion revascularization (163 (5.0%) vs 147 (5.9%); HR 0.94, 95%CI 0.75-1.18, P = .61). The effect was consistent across major subgroups. In a landmark analysis, there was no significant interaction between treatment effect and timing of events. CONCLUSIONS: In this patient-level meta-analysis of 5 randomized controlled trials, BP SES were associated with a similar risk of target-lesion failure compared with DP EES among patients undergoing PCI. STUDY REGISTRATION: PROSPERO registry (CRD42018109098).

Cardiovascular clinical trials in the era of a pandemic.

COVID-19 has reached pandemic levels in March 2020 and impacted public health with unpredictable consequences.1, 2 The conduct of clinical research in areas unrelated to COVID-19 has been disrupted and will be further affected. Researchers, trial participants and study personnel have to overcome challenges to sustain proper and safe conduct of clinical trials (i.e. logistical challenges, lower enrollment than expected, difficulties in follow-up and outcome assessment/adjudication, incomplete data collection, research funding prolongation).

Effect of Galectin 3 on Aldosterone-Associated Risk of Cardiovascular Mortality in Patients Undergoing Coronary Angiography.

Recent experimental studies have suggested that galectin-3 has an interaction with aldosterone, and modifies its adverse effects. We therefore aimed to elucidate whether the relationship between plasma aldosterone concentrations (PACs) and long-term fatal cardiovascular (CV) events would depend on plasma galectin-3 levels. A total of 2,457 patients (median age: 63.5 [interquartile range (IQR) = 56.3 to 70.6] years, 30.1% women) from the LUdwigshafen RIsk and Cardiovascular Health study, with a median follow-up of 9.9 (IQR = 8.5 to 10.7) years, were included. We tested the interaction between aldosterone and galectin-3 for CV-mortality using a multivariate Cox proportional hazard model, reporting hazard ratios (HRs) with 95% confidence intervals (95%CIs). Adjustments for multiple CV risk factors as well as medication use were included. Mean PAC was 79.0 (IQR = 48.0 to 124.0) pg/ml and there were 558 (16.8%) CV deaths. There was a significant interaction between PAC and galectin-3 (p = 0.021). When stratifying patients by the median galectin-3, there was a significant association between aldosterone and CV-mortality for those above (HR per 1 standard deviation = 1.14; 95%CI [1.01 to 1.30], p = 0.023), but not below the cut-off value (HR per 1 standard deviation = 1.00; 95%CI [0.87 to 1.15], p = 0.185). In conclusion, the current study demonstrates for the first time a modifying effect of galectin-3 on the association between aldosterone and CV-mortality risk in humans. These findings indicate that galectin-3 is an intermediate between aldosterone and adverse outcomes.

Impact of left ventricular function on clinical outcomes among patients with coronary artery disease.

AIMS: To investigate the clinical relevance of contemporary cut-offs of left ventricular ejection fraction (LVEF) including an intermediate phenotype with mid-range reduced ejection fraction among patients with coronary artery disease undergoing percutaneous coronary intervention. METHODS AND RESULTS: Patient-level data were summarized from five randomized clinical trials in which 6198 patients underwent clinically indicated percutaneous coronary intervention in different clinical settings. We assessed all-cause mortality as primary endpoint at five-year follow-up. According to the proposed LVEF cut-offs, 3816 patients were included in the preserved LVEF group (LVEF ≥ 50%), 1793 in the mid-range reduced LVEF group (LVEF 40-49%) and 589 patients in the reduced LVEF group (LVEF < 40%). Patients in the reduced LVEF group were at increased risk for the primary outcome of all-cause mortality compared with both, preserved and mid-range LVEF throughout five years of follow-up (adjusted hazard ratio 2.39 (95% confidence interval 1.75-3.28, p < 0.001) and 1.68 (95% confidence interval 1.34-2.10, p < 0.001), respectively). The risk of cardiac death and the composite endpoint of cardiac death, myocardial infarction, or stroke were higher for patients in the reduced LVEF group compared with the preserved and mid-range reduced LVEF groups, but also for the mid-range LVEF compared with preserved LVEF group (adjusted p < 0.05 for all comparisons) throughout five years. Irrespective of clinical presentation at baseline (stable coronary artery disease or acute coronary syndrome), patients with reduced or mid-range LVEF were at increased risk of all-cause mortality and cardiac death up to five years compared with the other group (adjusted p < 0.05 for all comparisons). CONCLUSION: Patients with reduced LVEF <40% or mid-range LVEF 40-49% in the context of coronary artery disease undergoing clinically indicated percutaneous coronary intervention are at increased risk of all-cause mortality, cardiac death and the composite of cardiac death, stroke and myocardial infarction throughout five years of follow-up. The recently proposed LVEF cut-offs contribute to the differentiation and risk stratification of patients with ischaemic heart disease.

Percutaneous patent foramen ovale closure during live case demonstrations.

BACKGROUND: Live case demonstrations serve as an educational tool for interventional techniques in cardiology. The aim of this study was to assess the safety and technical success of percutaneous patent foramen ovale (PFO) closure during live case demonstrations. METHODS: All patients who had undergone percutaneous PFO closure with Amplatzer devices during live case demonstrations at our institution were consecutively included in this retrospective analysis. Procedure related events were compared with summary event rates derived from the eight randomized controlled trials (RCTs) investigating PFO closure, as well as with a propensity matched cohort of patients treated under usual conditions. RESULTS: From April 2004 to June 2015, 142 patients underwent percutaneous PFO closure during live demonstrations, mainly for secondary prevention of cryptogenic cerebrovascular events. The interventions were fluoroscopy guided and successful in all but three cases (2%). Minor adverse events occurred in nine patients (6%). Contrast TEE performed at about 6 months showed complete closure in 84%. No significant differences with regard to technical success and major complications rate were found compared to RCTs, except for an increased rate of minor bleeding observed during live case demonstrations (P for difference < 0.001), mainly attributable to concomitant arterial access for incidental coronary angiography performed in 70% of patients. Except for slightly longer procedure duration, no difference was found compared to a matched population treated under usual conditions. CONCLUSION: Percutaneous PFO closure can be performed during live case demonstrations with the same high technical success as during routine cases.

The Impact of Left Ventricular Diastolic Dysfunction on Clinical Outcomes After Transcatheter Aortic Valve Replacement.

OBJECTIVES: This study sought to determine the impact of left ventricular diastolic dysfunction (LVDD) on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Left ventricular (LV) hypertrophy in response to afterload increase promotes the development of LVDD and represents an early stage in the progression to valvular heart failure. METHODS: In a consecutive cohort of 777 aortic stenosis patients undergoing TAVR, LVDD was categorized according to the latest guidelines. The primary endpoint was 1-year all-cause mortality. RESULTS: There were 545 (70.1%) patients with LVDD. Ninety-eight (18.0%), 198 (36.3%), and 104 (19.1%) patients were classified as LVDD grades I, II, and III, respectively. In 145 (26.6%) patients, LVDD grade could not be determined because of only 1 or 2 discrepant variables. One-year all-cause mortality was higher in patients with LVDD grades I (16.3%; adjusted hazard ratio [HR]adj: 2.32; 95% confidence interval [CI]: 1.15 to 4.66), II (17.9%; HRadj: 2.58; 95% CI: 1.43 to 4.67), and III (27.6%; HRadj: 4.21; 95% CI: 2.25 to 7.86) than in those with normal diastolic function (6.9%). The difference in clinical outcome emerged within 30 days, was driven by cardiovascular death, and maintained in a sensitivity analysis of patients with normal systolic LV function. Furthermore, LVDD grades I (HRadj: 2.36; 95% CI: 1.17 to 4.74), II (HRadj: 2.58; 95% CI: 1.42 to 4.66), and III (HRadj: 4.41; 95% CI: 2.37 to 8.20) were independent predictors of 1-year mortality. CONCLUSIONS: Advancing stages of LVDD are associated with an incremental risk of all-cause mortality after TAVR, driven by cardiovascular death and taking effect as early as 30 days after the intervention.

Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomised controlled trials.

OBJECTIVE: To evaluate differences in downstream testing, coronary revascularisation, and clinical outcomes following non-invasive diagnostic modalities used to detect coronary artery disease. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Medline in process, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, SCOPUS, WHO International Clinical Trials Registry Platform, and Clinicaltrials.gov. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Diagnostic randomised controlled trials comparing non-invasive diagnostic modalities in patients presenting with symptoms suggestive of low risk acute coronary syndrome or stable coronary artery disease. DATA SYNTHESIS: A random effects network meta-analysis synthesised available evidence from trials evaluating the effect of non-invasive diagnostic modalities on downstream testing and patient oriented outcomes in patients with suspected coronary artery disease. Modalities included exercise electrocardiograms, stress echocardiography, single photon emission computed tomography-myocardial perfusion imaging, real time myocardial contrast echocardiography, coronary computed tomographic angiography, and cardiovascular magnetic resonance. Unpublished outcome data were obtained from 11 trials. RESULTS: 18 trials of patients with low risk acute coronary syndrome (n=11 329) and 12 trials of those with suspected stable coronary artery disease (n=22 062) were included. Among patients with low risk acute coronary syndrome, stress echocardiography, cardiovascular magnetic resonance, and exercise electrocardiograms resulted in fewer invasive referrals for coronary angiography than coronary computed tomographic angiography (odds ratio 0.28 (95% confidence interval 0.14 to 0.57), 0.32 (0.15 to 0.71), and 0.53 (0.28 to 1.00), respectively). There was no effect on the subsequent risk of myocardial infarction, but estimates were imprecise. Heterogeneity and inconsistency were low. In patients with suspected stable coronary artery disease, an initial diagnostic strategy of stress echocardiography or single photon emission computed tomography-myocardial perfusion imaging resulted in fewer downstream tests than coronary computed tomographic angiography (0.24 (0.08 to 0.74) and 0.57 (0.37 to 0.87), respectively). However, exercise electrocardiograms yielded the highest downstream testing rate. Estimates for death and myocardial infarction were imprecise without clear discrimination between strategies. CONCLUSIONS: For patients with low risk acute coronary syndrome, an initial diagnostic strategy of stress echocardiography or cardiovascular magnetic resonance is associated with fewer referrals for invasive coronary angiography and revascularisation procedures than non-invasive anatomical testing, without apparent impact on the future risk of myocardial infarction. For suspected stable coronary artery disease, there was no clear discrimination between diagnostic strategies regarding the subsequent need for invasive coronary angiography, and differences in the risk of myocardial infarction cannot be ruled out. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry no CRD42016049442.