Prehospital risk assessment and direct transfer to a percutaneous coronary intervention centre in suspected acute coronary syndrome.

OBJECTIVE: Prehospital risk stratification and triage are currently not performed in patients suspected of non-ST-segment elevation acute coronary syndrome (NSTE-ACS). This may lead to prolonged time to revascularisation, increased duration of hospital admission and higher healthcare costs. The preHEART score (prehospital history, ECG, age, risk factors and point-of-care troponin score) can be used by emergency medical services (EMS) personnel for prehospital risk stratification and triage decisions in patients with NSTE-ACS. The aim of the current study was to evaluate the effect of prehospital risk stratification and direct transfer to a percutaneous coronary intervention (PCI) centre, based on the preHEART score, on time to final invasive diagnostics or culprit revascularisation. METHODS: Prospective, multicentre, two-cohort study in patients with suspected NSTE-ACS. The first cohort is observational (standard care), while the second (interventional) cohort includes patients who are stratified for direct transfer to either a PCI or a non-PCI centre based on their preHEART score. Risk stratification and triage are performed by EMS personnel. The primary endpoint of the study is time from first medical contact until final invasive diagnostics or revascularisation. Secondary endpoints are time from first medical contact until intracoronary angiography (ICA), duration of hospital admission, number of invasive diagnostics, number of inter-hospital transfers and major adverse cardiac events at 7 and 30 days. RESULTS: A total of 1069 patients were included. In the interventional cohort (n=577), time between final invasive diagnostics or revascularisation (42 (17-101) hours vs 20 (5-44) hours, p<0.001) and length of hospital admission (3 (2-5) days vs 2 (1-4) days, p=0.007) were shorter than in the observational cohort (n=492). In patients with NSTE-ACS in need for ICA or revascularisation, healthcare costs were reduced in the interventional cohort (€5599 (2978-9625) vs €4899 (2278-5947), p=0.02). CONCLUSION: Prehospital risk stratification and direct transfer to a PCI centre, based on the preHEART score, reduces time from first medical contact to final invasive diagnostics and revascularisation, reduces duration of hospital admission and decreases healthcare costs in patients with NSTE-ACS in need for ICA or revascularisation. TRIAL REGISTRATION: NCT05243485.

Predicting target lesion failure following percutaneous coronary intervention through machine learning risk assessment models.

Aims: Central to the practice of precision medicine in percutaneous coronary intervention (PCI) is a risk-stratification tool to predict outcomes following the procedure. This study is intended to assess machine learning (ML)-based risk models to predict clinically relevant outcomes in PCI and to support individualized clinical decision-making in this setting. Methods and results: Five different ML models [gradient boosting classifier (GBC), linear discrimination analysis, Naïve Bayes, logistic regression, and K-nearest neighbours algorithm) for the prediction of 1-year target lesion failure (TLF) were trained on an extensive data set of 35 389 patients undergoing PCI and enrolled in the global, all-comers e-ULTIMASTER registry. The data set was split into a training (80%) and a test set (20%). Twenty-three patient and procedural characteristics were used as predictive variables. The models were compared for discrimination according to the area under the receiver operating characteristic curve (AUC) and for calibration. The GBC model showed the best discriminative ability with an AUC of 0.72 (95% confidence interval 0.69-0.75) for 1-year TLF on the test set. The discriminative ability of the GBC model for the components of TLF was highest for cardiac death with an AUC of 0.82, followed by target vessel myocardial infarction with an AUC of 0.75 and clinically driven target lesion revascularization with an AUC of 0.68. The calibration was fair until the highest risk deciles showed an underestimation of the risk. Conclusion: Machine learning-derived predictive models provide a reasonably accurate prediction of 1-year TLF in patients undergoing PCI. A prospective evaluation of the predictive score is warranted. Registration: Clinicaltrial.gov identifier is NCT02188355.

Quantitative aortography for assessment of aortic regurgitation in the era of percutaneous aortic valve replacement.

Paravalvular leak (PVL) is a shortcoming that can erode the clinical benefits of transcatheter valve replacement (TAVR) and therefore a readily applicable method (aortography) to quantitate PVL objectively and accurately in the interventional suite is appealing to all operators. The ratio between the areas of the time-density curves in the aorta and left ventricular outflow tract (LVOT-AR) defines the regurgitation fraction (RF). This technique has been validated in a mock circulation; a single injection in diastole was further tested in porcine and ovine models. In the clinical setting, LVOT-AR was compared with trans-thoracic and trans-oesophageal echocardiography and cardiac magnetic resonance imaging. LVOT-AR > 17% discriminates mild from moderate aortic regurgitation on echocardiography and confers a poor prognosis in multiple registries, and justifies balloon post-dilatation. The LVOT-AR differentiates the individual performances of many old and novel devices and is being used in ongoing randomized trials and registries.

Prehospital risk assessment in patients suspected of non-ST-segment elevation acute coronary syndrome: a systematic review and meta-analysis.

OBJECTIVE: To review, inventory and compare available diagnostic tools and investigate which tool has the best performance for prehospital risk assessment in patients suspected of non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Systematic review and meta-analysis. Medline and Embase were searched up till 1 April 2021. Prospective studies with patients, suspected of NSTE-ACS, presenting in the primary care setting or by emergency medical services (EMS) were included. The most important exclusion criteria were studies including only patients with ST-elevation myocardial infarction and studies before 1995, the pretroponin era. The primary end point was the final hospital discharge diagnosis of NSTE-ACS or major adverse cardiac events (MACE) within 6 weeks. Risk of bias was evaluated by the Quality Assessment of Diagnostic Accuracy Studies Criteria. MAIN OUTCOME AND MEASURES: Sensitivity, specificity and likelihood ratio of findings for risk stratification in patients suspected of NSTE-ACS. RESULTS: In total, 15 prospective studies were included; these studies reflected in total 26 083 patients. No specific variables related to symptoms, physical examination or risk factors were useful in risk stratification for NSTE-ACS diagnosis. The most useful electrocardiographic finding was ST-segment depression (LR+3.85 (95% CI 2.58 to 5.76)). Point-of-care troponin was found to be a strong predictor for NSTE-ACS in primary care (LR+14.16 (95% CI 4.28 to 46.90) and EMS setting (LR+6.16 (95% CI 5.02 to 7.57)). Combined risk scores were the best for risk assessment in an NSTE-ACS. From the combined risk scores that can be used immediately in a prehospital setting, the PreHEART score, a validated combined risk score for prehospital use, derived from the HEART score (History, ECG, Age, Risk factors, Troponin), was most useful for risk stratification in patients with NSTE-ACS (LR+8.19 (95% CI 5.47 to 12.26)) and for identifying patients without ACS (LR-0.05 (95% CI 0.02 to 0.15)). DISCUSSION: Important study limitations were verification bias and heterogeneity between studies. In the prehospital setting, several diagnostic tools have been reported which could improve risk stratification, triage and early treatment in patients suspected for NSTE-ACS. On-site assessment of troponin and combined risk scores derived from the HEART score are strong predictors. These results support further studies to investigate the impact of these new tools on logistics and clinical outcome. FUNDING: This study is funded by ZonMw, the Dutch Organisation for Health Research and Development. TRIAL REGISTRATION NUMBER: This meta-analysis was published for registration in PROSPERO prior to starting (CRD York, CRD42021254122).

Microvascular Resistance Reserve for Assessment of Coronary Microvascular Function: JACC Technology Corner.

The need for a quantitative and operator-independent assessment of coronary microvascular function is increasingly recognized. We propose the theoretical framework of microvascular resistance reserve (MRR) as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and based on operator-independent measurements of absolute values of coronary flow and pressure. In its general form, MRR equals coronary flow reserve (CFR) divided by fractional flow reserve (FFR) corrected for driving pressures. In 30 arteries, pressure, temperature, and flow velocity measurements were obtained simultaneously at baseline (BL), during infusion of saline at 10 mL/min (rest) and 20 mL/min (hyperemia). A strong correlation was found between continuous thermodilution-derived MRR and Doppler MRR (r = 0.88; 95% confidence interval: 0.72-0.93; P < 0.001). MRR was independent from the epicardial resistance, the lower the FFR value, the greater the difference between MRR and CFR. Therefore, MRR is proposed as a specific, quantitative, and operator-independent metric to quantify coronary microvascular dysfunction.

Decision Trees for Predicting Mortality in Transcatheter Aortic Valve Implantation.

Current prognostic risk scores in cardiac surgery do not benefit yet from machine learning (ML). This research aims to create a machine learning model to predict one-year mortality of a patient after transcatheter aortic valve implantation (TAVI). We adopt a modern gradient boosting on decision trees classifier (GBDTs), specifically designed for categorical features. In combination with a recent technique for model interpretations, we developed a feature analysis and selection stage, enabling the identification of the most important features for the prediction. We base our prediction model on the most relevant features, after interpreting and discussing the feature analysis results with clinical experts. We validated our model on 270 consecutive TAVI cases, reaching a C-statistic of 0.83 with CI [0.82, 0.84]. The model has achieved a positive predictive value ranging from 57% to 64%, suggesting that the patient selection made by the heart team of professionals can be further improved by taking into consideration the clinical data we identified as important and by exploiting ML approaches in the development of clinical risk scores. Our approach has shown promising predictive potential also with respect to widespread prognostic risk scores, such as logistic European system for cardiac operative risk evaluation (EuroSCORE II) and the society of thoracic surgeons (STS) risk score, which are broadly adopted by cardiologists worldwide.

Thermodilution-Based Invasive Assessment of Absolute Coronary Blood Flow and Microvascular Resistance: Quantification of Microvascular (Dys)Function?

During the last two decades, there has been a sharp increase in both interest and knowledge about the coronary microcirculation. Since these small vessels are not visible by the human eye, physiologic measurements should be used to characterize their function. The invasive methods presently used (coronary flow reserve (CFR) and index of microvascular resistance (IMR)) are operator-dependent and mandate the use of adenosine to induce hyperemia. In recent years, a new thermodilution-based method for measurement of absolute coronary blood flow and microvascular resistance has been proposed and initial procedural problems have been overcome. Presently, the technique is easy to perform using the Rayflow infusion catheter and the Coroventis software. The method is accurate, reproducible, and completely operator-independent. This method has been validated noninvasively against the current golden standard for flow assessment: Positron Emission Tomography-Computed Tomography (PET-CT). In addition, absolute flow and resistance measurements have proved to be safe, both periprocedurally and at long-term follow-up. With an increasing number of studies being performed, this method has great potential for better understanding and quantification of microvascular disease.

Global Fractional Flow Reserve Value Predicts 5-Year Outcomes in Patients With Coronary Atherosclerosis But Without Ischemia.

Background Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long-term clinical outcome of patients with stable coronary artery disease but no ischemia-inducing stenosis. Methods and Results We studied major adverse cardiovascular events (MACEs: all-cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post-percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80-2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5-year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log-rank P=0.040). The higher 5-year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log-rank P=0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977-0.998; P=0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966-0.998; P=0.032), and revascularization (HR, 0.985; 95% CI, 0.972-0.999; P=0.040). Conclusions Even in the absence of ischemia-producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5-year follow-up.

Coronary Microcirculation in Aortic Stenosis: Pathophysiology, Invasive Assessment, and Future Directions.

With the increasing prevalence of aortic stenosis (AS) due to a growing elderly population, a proper understanding of its physiology is paramount to guide therapy and define severity. A better understanding of the microvasculature in AS could improve clinical care by predicting left ventricular remodeling or anticipate the interplay between epicardial stenosis and myocardial dysfunction. In this review, we combine five decades of literature regarding microvascular, coronary, and aortic valve physiology with emerging insights from newly developed invasive tools for quantifying microcirculatory function. Furthermore, we describe the coupling between microcirculation and epicardial stenosis, which is currently under investigation in several randomized trials enrolling subjects with concomitant AS and coronary disease. To clarify the physiology explained previously, we present two instructive cases with invasive pressure measurements quantifying coexisting valve and coronary stenoses. Finally, we pose open clinical and research questions whose answers would further expand our knowledge of microvascular dysfunction in AS. These trials were registered with NCT03042104, NCT03094143, and NCT02436655.

Assessment of exercise-induced changes in von Willebrand factor as a marker of severity of aortic stenosis.

Background: Loss of high-molecular-weight multimers (HMWMs) of von Willebrand factor (vWF) occurs due to high shear stress in patients with aortic stenosis. As symptoms of aortic stenosis occur during exercise, measurement of vWF during exercise might identify patients with aortic stenosis of clinical importance. The aim of this pilot study is to evaluate whether vWF changes over time as a result of exercise in patients with asymptomatic moderate or severe aortic stenosis. Methods: Ten subjects were analysed for changes in vWF by measuring HMWMs and closure time with adenosine diphosphate (CT-ADP). All subjects underwent a full stress test on a bicycle ergometer. At rest and at peak exercise, a transthoracic echocardiogram was performed. HMWMs and CT-ADP were assessed at baseline, during and after exercise. Results: HMWMs and CT-ADP did not change significantly during exercise, p=0.45 and p=0.65, respectively. HMWMs and CT-ADP correlated well, Spearman's rho -0.621, p<0.001. HMWMs during peak exercise did not correlate with maximal velocity measured, p=0.21. CT-ADP during exercise correlated well with the maximal echocardiographic velocity over the aortic valve (AV), rho 0.82, p=0.04. Conclusions: In a cohort of 10 patients with moderate or severe aortic stenosis, we observed no significant change in vWF biomarkers during exercise. Peak CT-ADP during exercise showed a good correlation with peak AV velocity measured with echo. Although CT-ADP is an easy test to perform and could be an alternative for peak AV velocity measured during exercise, our results suggest that it can only detect large changes in shear stress.

Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve.

BACKGROUND: The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 2 trial demonstrated a significant reduction in subsequent coronary revascularization among patients with stable angina and at least 1 coronary lesion with a fractional flow reserve ≤0.80 who were randomized to percutaneous coronary intervention (PCI) compared with best medical therapy. The economic and quality-of-life implications of PCI in the setting of an abnormal fractional flow reserve are unknown. METHODS AND RESULTS: We calculated the cost of the index hospitalization based on initial resource use and follow-up costs based on Medicare reimbursements. We assessed patient utility using the EQ-5D health survey with US weights at baseline and 1 month and projected quality-adjusted life-years assuming a linear decline over 3 years in the 1-month utility improvements. We calculated the incremental cost-effectiveness ratio based on cumulative costs over 12 months. Initial costs were significantly higher for PCI in the setting of an abnormal fractional flow reserve than with medical therapy ($9927 versus $3900, P<0.001), but the $6027 difference narrowed over 1-year follow-up to $2883 (P<0.001), mostly because of the cost of subsequent revascularization procedures. Patient utility was improved more at 1 month with PCI than with medical therapy (0.054 versus 0.001 units, P<0.001). The incremental cost-effectiveness ratio of PCI was $36 000 per quality-adjusted life-year, which was robust in bootstrap replications and in sensitivity analyses. CONCLUSIONS: PCI of coronary lesions with reduced fractional flow reserve improves outcomes and appears economically attractive compared with best medical therapy among patients with stable angina.

VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): a multicenter study in consecutive patients.

OBJECTIVES: This study sought to compare fractional flow reserve (FFR) with the instantaneous wave-free ratio (iFR) in patients with coronary artery disease and also to determine whether the iFR is independent of hyperemia. BACKGROUND: FFR is a validated index of coronary stenosis severity. FFR-guided percutaneous coronary intervention (PCI) improves clinical outcomes compared to angiographic guidance alone. iFR has been proposed as a new index of stenosis severity that can be measured without adenosine. METHODS: We conducted a prospective, multicenter, international study of 206 consecutive patients referred for PCI and a retrospective analysis of 500 archived pressure recordings. Aortic and distal coronary pressures were measured in duplicate in patients under resting conditions and during intravenous adenosine infusion at 140 µg/kg/min. RESULTS: Compared to the FFR cut-off value of ≤0.80, the diagnostic accuracy of the iFR value of ≤0.80 was 60% (95% confidence interval [CI]: 53% to 67%) for all vessels studied and 51% (95% CI: 43% to 59%) for those patients with FFR in the range of 0.60 to 0.90. iFR was significantly influenced by the induction of hyperemia: mean ± SD iFR at rest was 0.82 ± 0.16 versus 0.64 ± 0.18 with hyperemia (p < 0.001). Receiver operating characteristics confirmed that the diagnostic accuracy of iFR was similar to resting Pd/Pa and trans-stenotic pressure gradient and significantly inferior to hyperemic iFR. Analysis of our retrospectively acquired dataset showed similar results. CONCLUSIONS: iFR correlates weakly with FFR and is not independent of hyperemia. iFR cannot be recommended for clinical decision making in patients with coronary artery disease.

Functional SYNTAX score for risk assessment in multivessel coronary artery disease.

OBJECTIVES: This study was aimed at investigating whether a fractional flow reserve (FFR)-guided SYNTAX score (SS), termed "functional SYNTAX score" (FSS), would predict clinical outcome better than the classic SS in patients with multivessel coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). BACKGROUND: The SS is a purely anatomic score based on the coronary angiogram and predicts outcome after PCI in patients with multivessel CAD. FFR-guided PCI improves outcomes by adding functional information to the anatomic information obtained from the angiogram. METHODS: The SS was prospectively collected in 497 patients enrolled in the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study. FSS was determined by only counting ischemia-producing lesions (FFR ≤ 0.80). The ability of each score to predict major adverse cardiac events (MACE) at 1 year was compared. RESULTS: The 497 patients were divided into tertiles of risk based on the SS. After determining the FSS for each patient, 32% moved to a lower-risk group as follows. MACE occurred in 9.0%, 11.3%, and 26.7% of patients in the low-, medium-, and high-FSS groups, respectively (p < 0.001). Only FSS and procedure time were independent predictors of 1-year MACE. FSS demonstrated a better predictive accuracy for MACE compared with SS (Harrell's C of FSS, 0.677 vs. SS, 0.630, p = 0.02; integrated discrimination improvement of 1.94%, p < 0.001). CONCLUSIONS: Recalculating SS by only incorporating ischemia-producing lesions as determined by FFR decreases the number of higher-risk patients and better discriminates risk for adverse events in patients with multivessel CAD undergoing PCI.

Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease.

BACKGROUND: The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study demonstrated significantly improved health outcomes at 1 year in patients randomized to multivessel percutaneous coronary intervention guided by fractional flow reserve (FFR) compared with percutaneous coronary intervention guided by angiography alone. The economic impact of routine measurement of FFR in this setting is not known. METHODS AND RESULTS: In this study, 1005 patients were randomly assigned to FFR-guided or angiography-guided percutaneous coronary intervention and followed up for 1 year. A prospective cost-utility analysis comparing costs and quality-adjusted life-years was performed with a time horizon of 1 year. Quality-adjusted life-years were calculated with the use of utilities determined by the EuroQuol 5 dimension health survey with US weights. Direct medical costs included those of the index procedure and hospitalization and costs for major adverse cardiac events during follow-up. Confidence intervals for both quality-adjusted life-years and costs were estimated by the bootstrap percentile method. Major adverse cardiac events at 1 year occurred in 13.2% of those in the FFR-guided arm and 18.3% of those in the angiography-guided arm (P=0.02). Quality-adjusted life-years were slightly greater in the FFR-guided arm (0.853 versus 0.838; P=0.2). Mean overall costs at 1 year were significantly less in the FFR-guided arm ($14 315 versus $16 700; P<0.001). Bootstrap simulation indicated that the FFR-guided strategy was cost-saving in 90.74% and cost-effective at a threshold of US $50 000 per quality-adjusted life-years in 99.96%. Sensitivity analyses demonstrated robust results. CONCLUSION: Economic evaluation of the FAME study reveals that FFR-guided percutaneous coronary intervention in patients with multivessel coronary disease is one of those rare situations in which a new technology not only improves outcomes but also saves resources. Clinical Trial Registration- URL: http://ClinicalTrials.gov. Unique identifier: NCT00267774.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention.

BACKGROUND: In patients with multivessel coronary artery disease who are undergoing percutaneous coronary intervention (PCI), coronary angiography is the standard method for guiding the placement of the stent. It is unclear whether routine measurement of fractional flow reserve (FFR; the ratio of maximal blood flow in a stenotic artery to normal maximal flow), in addition to angiography, improves outcomes. METHODS: In 20 medical centers in the United States and Europe, we randomly assigned 1005 patients with multivessel coronary artery disease to undergo PCI with implantation of drug-eluting stents guided by angiography alone or guided by FFR measurements in addition to angiography. Before randomization, lesions requiring PCI were identified on the basis of their angiographic appearance. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions, whereas those assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was 0.80 or less. The primary end point was the rate of death, nonfatal myocardial infarction, and repeat revascularization at 1 year. RESULTS: The mean (+/-SD) number of indicated lesions per patient was 2.7+/-0.9 in the angiography group and 2.8+/-1.0 in the FFR group (P=0.34). The number of stents used per patient was 2.7+/-1.2 and 1.9+/-1.3, respectively (P<0.001). The 1-year event rate was 18.3% (91 patients) in the angiography group and 13.2% (67 patients) in the FFR group (P=0.02). Seventy-eight percent of the patients in the angiography group were free from angina at 1 year, as compared with 81% of patients in the FFR group (P=0.20). CONCLUSIONS: Routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year. (ClinicalTrials.gov number, NCT00267774.)