Non-invasive diagnosis, antithrombotic treatment, and invasive management of ischaemic heart disease

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease contains the Fast Track Clinical Research article entitled ‘Duration of antiplatelet therapy after complex percutaneous coronary intervention in patients at high bleeding risk: a MASTER DAPT trial sub-analysis’ by Marco Valgimigli from the Università della Svizzera Italiana in Switzerland, and colleagues. The duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is widely debated.1 The MASTER DAPT trial assessed the effects of 1 or ≥3 month dual DAPT in high bleeding risk (HBR) patients who received biodegradable-polymer sirolimus-eluting stents. In this pre-specified analysis, the authors assessed the consistency of the treatment effects of 1 month vs. a more prolonged DAPT duration based on PCI complexity.2 In the MASTER DAPT trial, 3383 patients underwent non-complex (abbreviated DAPT, n = 1707; standard DAPT, n = 1676) and 1196 complex (abbreviated DAPT, n = 588; standard DAPT, n = 608) PCI. Co-primary outcomes at 335 days were net adverse clinical events [NACE; composite of all-cause death, myocardial infarction (MI), stroke, and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding events]; major adverse cardiac or cerebral events (MACCE; all-cause death, MI, and stroke); and Types 2, 3, or 5 BARC bleeding. NACE and MACCE did not differ with abbreviated vs. standard DAPT among patients with complex [hazard ratio (HR) 1.03 and HR 1.24, respectively] and non-complex PCI (HR 0.90 and HR 0.91; P for interaction = 0.60 and 0.26, respectively). BARC 2, 3, or 5 was significantly reduced with abbreviated DAPT in patients with and without complex PCI (HR 0.64 and HR 0.70; P for interaction = 0.72) (Figure 1). One-month DAPT after PCI with a biodegradable-polymer sirolimus-eluting stent in HBR patients was associated with similar NACE and MACCE and lower bleeding rates compared with standard DAPT, regardless of PCI complexity and/or ACS.2 The authors conclude that in HBR patients free from recurrent ischaemic events at 1 month, DAPT discontinuation is associated with similar NACE and MACCE and lower bleeding rates compared with standard DAPT, regardless of PCI or patient complexity. The contribution is accompanied by an Editorial by Luis Ortega-Paz and Dominick Angiolillo from the University of Florida in the USA.3 The authors conclude that ultimately, the most important take-home message is how can we implement these results into clinical practice. As the authors acknowledge, there is no formal definition for complex PCI. Moreover, it should be highlighted that instead of focusing on the complexity of the procedure, the complex high-risk and indicated PCI (CHIP) concept is broader and encompasses multiple factors, including patient, lesion, procedure, and haemodynamic characteristics. Therefore, compared with the population analysed in this MASTER-DAPT substudy, the CHIP population in clinical practice may be broader and at higher risk of bleeding, ischaemic, and procedure-related complications. Moreover, the HBR population is heterogeneous, ranging from patients with low to high iscahemic risk. Accordingly, implementing a trade-off model to help select patients who may benefit the most from an abbreviated DAPT regimen (i.e. maximum bleeding reduction without an increase in ischaemic risk) may be useful for clinicians in the decision-making process. Non-invasive imaging plays an important role in diagnostic assessment of patients with ischaemic heart disease.4–8 The diagnostic performance of non-invasive imaging in patients with prior coronary artery disease (CAD) has not been tested in prospective head-to-head comparative studies. In a Clinical Research article entitled ‘Functional stress imaging to predict abnormal coronary fractional flow reserve: the PACIFIC 2 study’, Roel Driessen from Amsterdam UMC in the Netherlands and colleagues compared the diagnostic performance of qualitative single-photon emission computed tomography (SPECT), quantitative positron emission tomography (PET), and qualitative magnetic resonance imaging (MRI) in patients with a prior MI or PCI.9 In this prospective clinical study, all patients with prior MI and/or PCI and new symptoms of ischaemic CAD underwent 99mTc-tetrofosmin SPECT, [15O]H2O PET, and MRI, followed by invasive coronary angiography with fractional flow reserve (FFR) in all coronary arteries. All modalities were interpreted by core laboratories. Haemodynamically significant CAD was defined by at least one coronary artery with an FFR ≤0.80. Among the 189 enrolled patients, 63% had significant CAD. Sensitivity was 67% for SPECT, 81% for PET, and 66% for MRI. Specificity was 61% for SPECT, 65% for PET, and 62% for MRI. Sensitivity of PET was higher than that of SPECT (P = 0.016) and MRI (P = 0.014), whereas specificity did not differ among the modalities. Overall, PET had a numerically higher diagnostic accuracy (75%) than SPECT (65%, P = 0.03) and MRI (64%, P = 0.052), and a significantly higher area under the receiver operating characteristic curve (AUC; 0.80) than SPECT (0.66, P = 0.001) and MRI (0.67, P = 0.001). SPECT and MRI showed similar diagnostic performance measures, and no significant differences were found between these modalities. Driessen et al. conclude that in this prospective head-to-head comparative study, SPECT, PET, and MRI do not show a clinically relevant different accuracy for diagnosing FFR-defined significant CAD in patients with prior PCI and/or MI. Overall diagnostic performances appears to be rather discouraging, and the additive value of non-invasive imaging in this high-risk population is questionable. The article is accompanied by an Editorial by Patrizio Lancellotti and Alain Nchimi from the University of Liège Hospital in Belgium and Yun Yun Go from the National Heart Research Institute Singapore.10 The Editorialists conclude that the authors of the PACIFIC 2 study should be commended for adding an important, well thought out, and eloquent piece of literature to the field of multimodality stress testing. Because of the conceptual and technical limitations of comparing stress testing with invasive FFR (or vice versa), their study results were somewhat ‘negative’ in the sense that non-invasive stress perfusion tests failed to accurately predict FFR-defined haemodynamically significant CAD in patients with prior MI/PCI. The bigger picture, nevertheless, suggests that none of the coronary physiological testing methods surpasses the others. We should thus work towards creating an inclusive environment that encourages integration, collaboration, and open communication between the imagers, interventionists, and the ordering physicians. Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) have been associated with myocardial ischaemia. In a Clinical Research article entitled ‘Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial’, Sashiananthan Ganesananthan from the Imperial College London in the UK, and colleagues examined the relationship between CPET parameters, myocardial ischaemia, and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to PCI.11 Patients with severe single-vessel CAD were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE), and symptom assessment. These assessments were repeated at the end of a 6 week blinded follow-up period. A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had a higher (more ischaemic) DSE score (P = 0.0068) and lower FFR (P = 0.011) compared with those without. In addition, at lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on Seattle angina physical-limitation score. Impaired peak VO2, VE/VCO2 slope, peak oxygen pulse, and oxygen uptake efficacy slope were significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. The authors conclude that although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD. This contribution is accompanied by an Editorial by Alessandro Spirito, Davide Cao, and Roxana Mehran from the Icahn School of Medicine at Mount Sinai in New York, USA.12 The authors highlight that the oxygen pulse, calculated by dividing oxygen uptake by heart rate, is a surrogate of stroke volume, and an impaired increment of this parameter during exercise (i.e. oxygen-pulse plateau) has been related to the inability of the myocardium to increase the stroke volume. They conclude that the ORBITA substudy by Ganesananthan and colleagues confirms that a certain degree of myocardial ischaemia is required to establish the indication of revascularization vs. conservative management in symptomatic patients with obstructive CAD and left ventricular ejection fraction (LVEF) ≥35%. CPET might be a valuable tool to detect myocardial ischaemia and predict angina relief after PCI in this setting, but further evidence is needed to understand its value compared with other functional testing and which CPET parameter(s) should be evaluated. The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial.13,14 In a meta-analysis entitled ‘Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials’, Thomas A. Kite from the University of Leicester and University Hospitals of Leicester NHS Trust in the UK, and colleagues performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared an early IS vs. delayed IS for NSTE-ACS.15 The meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included MI, recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality (RR 0.90), MI (RR 0.86), admission for HF (RR 0.66), repeat re-vascularization (RR 1.04), major bleeding (RR 0.86), or stroke (RR 0.95) were observed. Recurrent ischaemia (RR 0.57) and length of stay (median difference −22 h) were significantly reduced with an early IS (Figure 2). Left: time to invasive coronary angiography in the included randomized controlled trials. The bars represent median time and interquartile ranges in the early invasive strategy group (red) and the delayed invasive strategy group (blue). The studies of Tekin et al. and Liu et al. are not displayed as medians were not reported. Interquartile ranges were not reported in the OPTIMA and Zhang et al. trials. Right: summary relative risks for all-cause mortality, myocardial infarction, recurrent ischaemia, admission for heart failure, repeat revascularization, major bleeding, and stroke.15 The authors conclude that in all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, nor it increases major bleeding or stroke risk when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS. The contribution is accompanied by an Editorial by Paul Guedeney and Jean-Philippe Collet from the Sorbonne Université in Paris, France and Holger Thiele from the Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute in Germany.16 The authors conclude that in the light of this interesting study level meta-analysis, a dedicated RCT comparing an early with a delayed invasive strategy only in high-risk NSTE-ACS patients or at least an updated patient-level meta-analysis remain warranted to better identify which patients, if any, may benefit from early invasive management in the setting of NSTE-ACS and to fill the void left by the early termination of the RAPID N-STEMI trial. While a lot has been published on epidemiology, pathogeneisis and treatment of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2),17–26 the effect of the COVID-19 pandemic on care and outcomes across non-COVID-19 cardiovascular (CV) diseases is still largely unknown. In a meta-analysis entitled ‘The collateral damage of COVID-19 to cardiovascular services: a meta-analysis’, Ramesh Nadarajah from the University of Leeds in the UK and colleagues performed a systematic review and meta-analysis to quantify the effect of the COVID-19 pandemic on care and outcomes investigating for variation by CV disease, geographic region, country income, and the time course of the pandemic.27 From January 2019 to December 2021, Medline and Embase databases were searched for observational studies comparing a pandemic and pre-pandemic period in relation to CV disease hospitalizations, diagnostic and interventional procedures, outpatient consultations, and mortality. The study was registered with PROSPERO (CRD42021265930). A total of 158 studies, covering 49 countries and 6 continents, were used for quantitative synthesis. Most studies (80%) reported information for high-income countries (HICs). Across all CV diseases and geographies, there were fewer hospitalizations, diagnostic and interventional procedures, and outpatient consultations during the pandemic. By meta-regression, in low–middle income countries (LMICs) compared with HICs the decline in ST-segment elevation myocardial infarction (STEMI) hospitalizations (RR 0.79) and myocardial revascularizations (RR 0.73) were significantly more severe. In LMICs, but not in HICs, in-hospital mortality significantly increased for STEMI (RR 1.22) and HF (RR 1.08). The magnitude of decline in hospitalizations for CV diseases did not differ between the first and second wave. The authors conclude that there was substantial global collateral CV damage during the COVID-19 pandemic with disparity in severity by country income classification. The contribution is accompanied by an Editorial by Ankeet S. Bhatt and Muthiah Vaduganathan from Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.28 Bhatt and Vaduganathan conclude that the work by Nadarajah et al. highlights the far-reaching effects of the COVID-19 pandemic, extending well beyond those who have contracted the virus itself. As the clinical community grapples with continued surges while trying to forge a new normal, emerging data suggest that there will be a long-lasting legacy of CV disease in the wake of the COVID-19 pandemic, with many waves yet to hit the shore. The editors hope that readers of this issue of the European Heart Journal will find it of interest. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.