Fractional flow reserve to guide percutaneous coronary intervention in multivessel coronary artery disease

Coronary heart disease is a leading cause of death, morbidity, and substantial economic costs in the United States and Europe. The pathological process responsible for coronary heart disease is atherosclerosis. It can cause diffuse disease or local narrowings in the coronary arteries, which impair blood flow and therefore oxygen supply to the myocardium. In case oxygen demand by the heart, for instance during exercise, exceeds oxygen supply through the narrowed coronary arteries, myocardial ischemia is induced, resulting in chest discomfort known as angina pectoris. In patients with coronary artery disease, the presence of inducible myocardial ischemia not only causes symptoms, but it also has significant prognostic implications i.e. increased chance for myocardial infarction or sudden death. Restoring blood flow and therefore oxygen supply to the myocardium reliefs myocardial ischemia, improves symptoms, and reduces the risk of death and myocardial infarction. Revascularization by percutaneous coronary intervention (PCI) with stent placement or by coronary bypass surgery, should therefore be targeted at relieving myocardial ischemia. In chapter 1, the introduction of this thesis, it is explained that non-invasive stress testing and coronary angiography will not always provide adequate or complete information about the functional importance of coronary artery narrowings. Particularly in patients with multivessel disease, it can therefore be difficult to determine which out of several lesions cause myocardial ischemia and therefore warrant revascularization. Because of the low restenosis rate, some investigators have proposed stenting of all intermediate lesions with drug-eluting stents, irrespective of their physiological significance. However, drug-eluting stents are expensive and are associated with potential late serious complications, occurring in 2 to 3% of stents per year. Therefore, a more judicious use of stents is paramount. The index of fractional flow reserve (FFR) is considered as the gold standard for the detection of myocardial ischemia, related to a particular stenosis. The concept and practical application of this diagnostic tool in the catheterization laboratory are described in chapter 2. By using FFR in patients with multivessel disease, the interventional cardiologist is able to accurately distinguish between coronary stenoses that induce myocardial ischemia and stenoses that do not induce myocardial ischemia. Consequently, it is possible to selectively treat those functionally significant stenoses (those responsible for reversible ischemia, also called ‘ischemic stenoses’) by stent placement and leave the non-ischemic stenoses for medical treatment in such patients. This led to the hypothesis that, compared to commonly practiced angiography-guided stenting, a strategy of FFR-guided stenting would decrease the number of stents deployed and typically stent-related complications, but still result in complete relief of myocardial ischemia, thereby improving clinical outcome and decreasing health care expenditure. The ‘windtunnel’ for testing a novel strategy or treatment is a randomized trial, in which the new treatment can be tested against the treatment that is commonly used in daily practice. That was the rationale to perform the Fractional Flow Reserve versus Angiography in Multivessel Evaluation (FAME) study. Chapter 3 describes the design of the FAME study. This international, multicenter study compares angiography-guided PCI with FFR-guided PCI in patients with multivessel coronary disease. In both treatment arms the coronary intervention is performed with drug-eluting stents. In little more than a year, 1005 patients were randomized in 20 centers in Europe and in the USA. Only a limited number of in- and exclusion criteria were applied and an exceptionally high percentage of 53% of all screened patients entered into the study Amongst others, these two factors paved the way for an unselected patient population with complex and severe multivessel coronary artery disease, truly reflecting daily practice as much as possible. The results after 1 year of follow-up are discussed in chapter 4, and showed a significant reduction in the primary, combined endpoint of death, myocardial infarction, and repeat revascularization for the FFR-guided strategy. In fact not only the primary endpoint, but also the rates of all its individual components were decreased consistently by roughly 30% with this strategy. Moreover, while using less stents per patient, the FFR-guided approach results in a similar relief of myocardial ischemia and subsequent anginal symptoms, as with the common angiography-guided approach. It is important to stress that the use of FFR in these patients does not prolong procedure time and even reduces the amount of contrast agent used. In chapter 5, an in-depth analysis of the patients in the FFR-guided treatment arm of the FAME study confirms the poor performance of coronary angiography in predicting the presence of inducible myocardial ischemia, related to a coronary stenosis. Generally, coronary narrowings with a stenosis percentage of 50% or more of the vessel diameter on the angiogram are defined as clinically significant and are therefore revascularized. However, this analysis shows that of all coronary stenoses with an angiographic severity of 50-70%, two-thirds are functionally non-significant and only one-third is functionally significant. Even in more severe stenoses between 71 and 90% angiographic stenosis severity, 20% of all lesions are not functionally significant. Therefore, in patients with multivessel CAD, one cannot rely on the angiogram to identify ischemia-producing lesions when assessing stenoses between 50 and 90%. In fact, this is probably one of the key explanations for the superior clinical outcome of FFR-guided stenting in the FAME study; by selectively stenting ischemic stenoses, ‘collateral damage’ from unnecessary stenting of non-ischemic coronary stenoses is prevented, with similar relief of myocardial ischemia as with angiography-guided stenting. Coronary heart disease not only effects clinical outcome, but it also consumes large parts of health care budgets. An extensive economic evaluation of the FAME study is described in chapter 6. This evaluation shows that a FFR-guided strategy also saves health care resources and improves health outcomes at 1 year. The cost savings occurs at the index procedure due to a decrease in drug-eluting stent use, and it occurs during follow-up as a result of a decrease in events and re-hospitalization. Combining the economic and clinical outcome results of the FAME study reveals that FFR-guided placement of drug-eluting stents 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. After 2 years of follow-up in the FAME study, the favorable results of an FFR-guided strategy were maintained, as discussed in chapter 7. The combination of death and myocardial infarction, but also the rate of myocardial infarction alone, both very important endpoints from a clinical and patient’s perspective, were significantly reduced at 2 years when compared to the common angiography-guided approach. The high percentage of patients free from anginal symptoms was maintained after 2 years for both treatment strategies. This chapter also describes the outcome of the 513 stenoses in the FFR-guided treatment arm, that were deferred from stenting, because they were functionally non-significant at the index procedure. After 2 years, only 0.2% of the deferred stenoses led to a myocardial infarction and only 3.2% of these stenoses needed revascularization because of progression of atherosclerosis. These findings confirm the excellent long-term safety of deferral of non-ischemic stenoses from stenting. The 2-year results of the FAME study show durability of the improved outcomes noted at 1 year. Thereby they continue to support the evolving paradigm of functionally complete revascularization, or in other words revascularization of ischemic stenoses and medical treatment of non-ischemic stenoses. It is intended to collect data up to a follow-up of 5 years for the FAME study In chapter 8, the findings in this thesis are presented in a general discussion and the following conclusions are drawn: 1. In patients with multivessel coronary artery disease undergoing PCI with drug-eluting stents, routine measurement of FFR in addition to angiographic guidance, as compared with PCI guided by angiography alone, results in a significant reduction of all major adverse events at 1 year by 30-35%. 2. This is achieved without prolonging the procedure time and with less contrast agent. 3. Performing PCI guided by FFR in patients with multivessel coronary artery disease also saves health care resources and improves health outcomes at 1 year compared to a traditional strategy of angiographic guidance. Thus, PCI guided by FFR in patients with multivessel disease is one of those rare situations in medicine in which a new technology not only improves outcomes, but also saves resources. 4. This advantage of an FFR-guided strategy is maintained at 2 years. Although there is a mild catch up for repeat revascularization, the difference between both strategies in the combined rate of death and myocardial infarction, and also in the rate of myocardial infarction alone, further increases in favour of the FFR-guided strategy. 5. In patients with multivessel coronary artery disease one cannot rely on the angiogram to identify ischemia-producing lesions when assessing stenoses between 50 and 90%. 6. The findings in this thesis support the evolving paradigm of ‘functionally complete revascularization’; stenting of ischemic lesions and medical treatment of non-ischemic lesions. Finally, the FAME study and its implications for the treatment of multivessel coronary disease are discussed within a wide scope in chapter 8 and appendix I, and reflected to other recent landmark studies in the field of treatment of patients with multivessel coronary artery disease: the COURAGE and the SYNTAX trial. These recent, large trials compared PCI with medical therapy and coronary bypass surgery, respectively. In the COURAGE trial PCI did not show better results than medical therapy, and in the SYNTAX trial PCI was inferior to coronary bypass surgery. However, PCI in those trials was performed with the standard angiography-guided strategy and not with an FFR-guided strategy. Although great caution should be taken when comparing different studies, due to the many similarities in patient populations and characteristics, it might be speculated that the results and even conclusions of these studies might have significantly changed in favour of PCI if performed with the guidance of FFR, like in the FAME study (figure 4 in chapter 8). To prove this standpoint definitely, this theme has resulted in starting two new prospective, large, multicenter trials to show the superiority of FFR-guided PCI over medical treatment (FAME II study) and equality to coronary bypass surgery in patients with multivessel coronary disease (FAME III study). With the unequalled support of the excellent group of investigators and institutions who perform the FAME study, an extensive but exciting future task is waiting for us. In appendix II of this thesis, all authors and members of the FAME Study Group, and their affiliations are listed

Generation of synthetic aortic valve stenosis geometries for in silico trials

In silico trials are a promising way to increase the efficiency of the development, and the time to market of cardiovascular implantable devices. The development of transcatheter aortic valve implantation (TAVI) devices, could benefit from in silico trials to overcome frequently occurring complications such as paravalvular leakage and conduction problems. To be able to perform in silico TAVI trials virtual cohorts of TAVI patients are required. In a virtual cohort, individual patients are represented by computer models that usually require patient‐specific aortic valve geometries. This study aimed to develop a virtual cohort generator that generates anatomically plausible, synthetic aortic valve stenosis geometries for in silico TAVI trials and allows for the selection of specific anatomical features that influence the occurrence of complications. To build the generator, a combination of non‐parametrical statistical shape modeling and sampling from a copula distribution was used. The developed virtual cohort generator successfully generated synthetic aortic valve stenosis geometries that are comparable with a real cohort, and therefore, are considered as being anatomically plausible. Furthermore, we were able to select specific anatomical features with a sensitivity of around 90%. The virtual cohort generator has the potential to be used by TAVI manufacturers to test their devices. Future work will involve including calcifications to the synthetic geometries, and applying high‐fidelity fluid–structure‐interaction models to perform in silico trials

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).</p

Functional SYNTAX Score for Risk Assessment in Multivessel Coronary Artery Disease

ObjectivesThis 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).BackgroundThe 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.MethodsThe 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.ResultsThe 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).ConclusionsRecalculating 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. (Fractional Flow Reserve versus Angiography for Multivessel Evaluation [FAME]; NCT00267774

Wearable devices can predict the outcome of standardized 6-minute walk tests in heart disease

Wrist-worn devices with heart rate monitoring have become increasingly popular. Although current guidelines advise to consider clinical symptoms and exercise tolerance during decision-making in heart disease, it remains unknown to which extent wearables can help to determine such functional capacity measures. In clinical settings, the 6-minute walk test has become a standardized diagnostic and prognostic marker. We aimed to explore, whether 6-minute walk distances can be predicted by wrist-worn devices in patients with different stages of mitral and aortic valve disease. A total of n = 107 sensor datasets with 1,019,748 min of recordings were analysed. Based on heart rate recordings and literature information, activity levels were determined and compared to results from a 6-minute walk test. The percentage of time spent in moderate activity was a predictor for the achievement of gender, age and body mass index-specific 6-minute walk distances (p < 0.001; R2 = 0.48). The uncertainty of these predictions is demonstrated

Refining Our Understanding of the Flow Through Coronary Artery Branches; Revisiting Murray's Law in Human Epicardial Coronary Arteries

Background: Quantification of coronary blood flow is used to evaluate coronary artery disease, but our understanding of flow through branched systems is poor. Murray’s law defines coronary morphometric scaling, the relationship between flow (Q) and vessel diameter (D) and is the basis for minimum lumen area targets when intervening on bifurcation lesions. Murray’s original law (Q α D(P)) dictates that the exponent (P) is 3.0, whilst constant blood velocity throughout the system would suggest an exponent of 2.0. In human coronary arteries, the value of Murray’s exponent remains unknown. Aim: To establish the exponent in Murray’s power law relationship that best reproduces coronary blood flows (Q) and microvascular resistances (Rmicro) in a bifurcating coronary tree. Methods and Results: We screened 48 cases, and were able to evaluate inlet Q and Rmicro in 27 branched coronary arteries, taken from 20 patients, using a novel computational fluid dynamics (CFD) model which reconstructs 3D coronary anatomy from angiography and uses pressure-wire measurements to compute Q and Rmicro distribution in the main- and side-branches. Outputs were validated against invasive measurements using a Rayflow™ catheter. A Murray’s power law exponent of 2.15 produced the strongest correlation and closest agreement with inlet Q (zero bias, r = 0.47, p = 0.006) and an exponent of 2.38 produced the strongest correlation and closest agreement with Rmicro (zero bias, r = 0.66, p = 0.0001). Conclusions: The optimal power law exponents for Q and Rmicro were not 3.0, as dictated by Murray’s Law, but 2.15 and 2.38 respectively. These data will be useful in assessing patient-specific coronary physiology and tailoring revascularisation decisions

Validation of a novel numerical model to predict regionalized blood flow in the coronary arteries

Aims: Ischaemic heart disease results from insufficient coronary blood flow. Direct measurement of absolute flow (mL/min) is feasible, but has not entered routine clinical practice in most catheterization laboratories. Interventional cardiologists, therefore, rely on surrogate markers of flow. Recently, we described a computational fluid dynamics (CFD) method for predicting flow that differentiates inlet, side branch, and outlet flows during angiography. In the current study, we evaluate a new method that regionalizes flow along the length of the artery. Methods and results: Three-dimensional coronary anatomy was reconstructed from angiograms from 20 patients with chronic coronary syndrome. All flows were computed using CFD by applying the pressure gradient to the reconstructed geometry. Side branch flow was modelled as a porous wall boundary. Side branch flow magnitude was based on morphometric scaling laws with two models: a homogeneous model with flow loss along the entire arterial length; and a regionalized model with flow proportional to local taper. Flow results were validated against invasive measurements of flow by continuous infusion thermodilution (Coroventis™, Abbott). Both methods quantified flow relative to the invasive measures: homogeneous (r 0.47, P 0.006; zero bias; 95% CI -168 to +168 mL/min); regionalized method (r 0.43, P 0.013; zero bias; 95% CI -175 to +175 mL/min). Conclusion: During angiography and pressure wire assessment, coronary flow can now be regionalized and differentiated at the inlet, outlet, and side branches. The effect of epicardial disease on agreement suggests the model may be best targeted at cases with a stenosis close to side branches.</p

Rationale and design of SAVI-AoS:A physiologic study of patients with symptomatic moderate aortic valve stenosis and preserved left ventricular ejection fraction

Background: Moderate aortic valve stenosis occurs twice as often as severe aortic stenosis (AS) and carries a similarly poor prognosis. Current European and American guidelines offer limited insight into moderate AS (MAS) patients with unexplained symptoms. Measuring valve physiology at rest while most patients experience symptoms during exertion might represent a conceptual limitation in the current grading of AS severity. The stress aortic valve index (SAVI) may delineate hemodynamically significant AS among patients with MAS. Objectives: To investigate the diagnostic value of SAVI in symptomatic MAS patients with normal left ventricular ejection fraction (LVEF ≥ 50%): aortic valve area (AVA) > 1 cm2 plus either mean valve gradient (MG) 15–39 mmHg or maximal aortic valve velocity (AOV max) 2.5–3.9 m/s. Short-term objectives include associations with symptom burden, functional capacity, and cardiac biomarkers. Long-term objectives include clinical outcomes. Methods and results: Multicenter, non-blinded, observational cohort. AS severity will be graded invasively (aortic valve pressure measurements with dobutamine stress testing for SAVI) and non-invasively (echocardiography during dobutamine and exercise stress). Computed tomography (CT) of the aortic valve will be scored for calcium, and hemodynamics simulated using computational fluid dynamics. Cardiac biomarkers and functional parameters will be serially monitored. The primary objective is to see how SAVI and conventional measures (MG, AVA and Vmax) correlate with clinical parameters (quality of life survey, 6-minute walk test [6MWT], and biomarkers). Conclusions: The SAVI-AoS study will extensively evaluate patients with unexplained, symptomatic MAS to determine any added value of SAVI versus traditional, resting valve parameters

Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial

In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcome compared with angiography-guided PCI for up to 2 years of follow-up. The aim in this study was to investigate whether the favourable clinical outcome with the FFR-guided PCI in the FAME study persisted over a 5-year follow-up

Dedicated plug based closure for large bore access -The MARVEL prospective registry

Objectives To study safety and performance of the MANTA Vascular closure device (VCD) under real world conditions in 10 centers. Background The MANTA is a novel plug-based device for large bore arteriotomy closure. Methods We included all eligible patients who underwent transfemoral large bore percutaneous procedures. Exclusion criteria were per operator's discretion and included severe calcification or marked tortuosity of the access vessel, presence of marked obesity/cachexia or a systolic blood pressure above 180 mmHg. The primary performance endpoint was time to hemostasis. Primary and secondary safety endpoints were major and minor access site related vascular complications up to 30 days, respectively. Vascular complications were adjudicated by an independent clinical event committee according to VARC-2 criteria. We performed multivariable logistic regression to estimate the effect of baseline and procedural characteristics on any and major vascular complications. Results Between February 2018 and July 2019 500 patients were enrolled undergoing Transcatheter aortic valve replacement (TAVR, N = 496), Balloon aortic valvuloplasty (BAV, N = 2), Mechanical circulatory support (MCS, N = 1) or Endovascular aneurysm repair (EVAR, N = 1). Mean age was 80.8 +/- 6.6 years with a median STS-score of 2.7 [IQR 2.0-4.3] %. MANTA access site complications were major in 20 (4%) and minor in 28 patients (5.6%). Median time to hemostasis was 50 [IQR 20-120] sec. Severe femoral artery calcification, scar presence in groin, longer procedure duration, female gender and history of hypertension were independent predictors for vascular complications. Conclusion In this study, MANTA appeared to be a safe and effective device for large bore access closure under real-world conditions.Peer reviewe