The challenge of risk stratification in suspected angina, in myocardial infarction without risk factors, and in frail patients

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 Viewpoint article ‘Coronary artery disease in the absence of traditional risk factors: a call for action’ by Suzanne Avis from the University of Tasmania in Australia, and colleagues.1 The key role of hypertension, hypercholesterolaemia, diabetes mellitus, and smoking in causing coronary artery disease (CAD) has been well recognized at a population level and has been the target of highly effective primary and secondary prevention strategies for >50 years. However, a substantial, and increasing, proportion of patients presenting with life-threatening acute coronary syndrome (ACS) have none of these standard modifiable cardiovascular risk factors (SMuRFs). Whilst this remains a relatively small proportion of the ‘pie’, the global burden of CAD makes their absolute number substantial, estimated conservatively to impact 29.6 million, and to account for 1.4 million deaths per annum. Despite this, SMuRF-less CAD patients appear to be an invisible group in current clinical trials and guidelines, with little known about their outcomes or the best approach to their management and secondary prevention strategies.2–4 Thus, the authors assessed both the European Society of Cardiology and the American College of Cardiology/American Heart Association guidelines to determine the proportion of trials underpinning the guideline recommendations that reported the number or percentage of participants with no SMuRFs. The second Viewpoint article entitled ‘Physical activity and exercise in patients with spontaneous coronary artery dissection and fibromuscular dysplasia’ is by Marysia Tweet from the Mayo Clinic in Rochester, MN, USA, and colleagues.5 The authors note that spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic aetiology of acute myocardial infarction and sudden cardiac arrest for which research, awareness, and diagnosis have increased substantially over the past 5 years.6–9 Co-existent in 45–86% of SCAD patients, fibromuscular dysplasia (FMD) is a non-atherosclerotic and non-inflammatory disease of the medium and small calibre arteries that is associated with arterial aneurysms, dissections, and stenoses. SCAD recurs in ∼10–29% of SCAD patients, arterial dissections are reported in up to 28% of FMD patients, and cervical FMD is associated with recurrent spontaneous cervical artery dissections. Risk for future arterial dissections and the safety of physical activity/exercise after a diagnosis of SCAD or FMD is poorly understood. As current recommendations are based on clinical ‘gestalt’ and often an abundance of caution, there is a need for future attention to be focused on this topic in research, and clearly distinguishing between physical activities vs. structured exercise will help to refine recommendations. Further mechanistic research is needed regarding safe cardiorespiratory fitness and strength training thresholds in this patient population. While increased cardiopulmonary fitness is anticipated to be associated with better outcomes, this is not known for SCAD/FMD due to the concern for recurrent arterial dissection or rupture at high exercise intensity levels. As exercise strategies within cardiac rehabilitation continue to be refined, randomized controlled trials of restricted and non-restricted/facilitated exercise assessing for differences in outcomes such as vascular events, mental health status, and physiological fitness would greatly inform clinical practice. Graphical Abstract (from Hildick-Smith D, Egred M, Banning A, Brunel P, Ferenc M, Hovasse T, Wlodarczak A, Pan M, Schmitz T, Silvestri M, Erglis A, Kretov E, Flensted Lassen J, Chieffo A, Lefevre T, Burzotta F, Cockburn J, Darremont O, Stankovic G, Morice MC, Louvard Y. The European Bifurcation Club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN). See pages 3829–3839). Graphical Abstract (from Hildick-Smith D, Egred M, Banning A, Brunel P, Ferenc M, Hovasse T, Wlodarczak A, Pan M, Schmitz T, Silvestri M, Erglis A, Kretov E, Flensted Lassen J, Chieffo A, Lefevre T, Burzotta F, Cockburn J, Darremont O, Stankovic G, Morice MC, Louvard Y. The European Bifurcation Club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN). See pages 3829–3839). Patients with non-left main coronary bifurcation lesions are usually best treated with a stepwise provisional approach. However, patients with true left main stem bifurcation lesions have been shown in one dedicated randomized study to benefit from systematic dual stent implantation.10 In a Fast Track clinical research article entitled ‘The European Bifurcation Club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN)’, David Hildick-Smith from the Brighton and Sussex University Hospitals in the UK, and colleagues looked into this issue further.11 A total of 467 patients with true left main stem bifurcation lesions requiring intervention were recruited to the EBC MAIN study in 11 European countries. Patients were randomly allocated to a stepwise layered provisional strategy or a systematic dual stent approach. The primary endpoint (a composite of death, myocardial infarction, and target lesion revascularization at 12 months) occurred in 14.7% of the stepwise provisional group vs. 17.7% of the systematic dual stent group (hazard ratio 0.8, 95% confidence interval 0.5–1.3; P = 0.34). Secondary endpoints were death (3.0% vs. 4.2%, P = 0.48), myocardial infarction (10.0% vs. 10.1%, P = 0.91), target lesion revascularization (6.1% vs. 9.3%, P = 0.16), and stent thrombosis (1.7% vs. 1.3%, P = 0.90), respectively (Figure 1). Procedure time, X-ray dose, and consumables favoured the stepwise provisional approach. Symptomatic improvement was excellent and equal in each group. Hildick-Smith et al. conclude that among patients with true bifurcation, left main stem stenosis requiring intervention, fewer major adverse cardiac events occur with a stepwise layered provisional approach than with planned dual stenting, although the difference is not statistically significant. The stepwise provisional strategy should remain the default for distal left main stem bifurcation intervention. The manuscript is accompanied by an Editorial by Farouc Jaffer from the Massachusetts General Hospital in Boston, MA, USA, and colleagues.12 The authors congratulate the EBC MAIN investigators for bringing forth this new study that will undoubtedly increase interest in provisional stenting for left main distal true bifurcation disease. Yet the story is probably not complete. In trying to harmonize an approach based on these pivotal left main studies, they propose a strategy based on integration of currently accepted best practices, including careful assessment of the complexity of the side branch, image- and physiology-based guidance, and plaque preparation. Jaffer et al. anticipate that long-term outcomes from ongoing trials will help us understand if we can truly ‘simplify, simplify, simplify’ stenting of the left main bifurcation. Fractional flow reserve obtained by computed tomography coronary angiography (FRCTCA) determines both the presence of CAD and vessel-specific ischaemia. In a Clinical Research article entitled ‘Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial’, Nick Curzen from the University of Southampton in the UK, and colleagues tested whether an evaluation strategy based on FFRCTCA would improve economic and clinical outcomes compared with standard care.13 Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with FFRCTCA (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months. Secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Mean total cardiac costs were higher by £114 (+8%) in the experimental group though the difference was not significant. Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group), and angina and quality of life improved to a similar degree during follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01). The authors conclude that a strategy of FFRCT in patients with stable angina does not differ significantly from standard clinical care pathways in cost or clinical outcomes, but does reduce the use of invasive coronary angiography. This manuscript is accompanied by an Editorial by Charalambos Antoniades and Henry West from the University of Oxford in the UK.14 The authors conclude that CTCA can guide revascularization procedures, allowing simultaneous extraction of information not achievable by any other non-invasive test.15 This includes information about plaque composition and plaque/arterial inflammation which can facilitate re-allocation of resources and treatments to the vulnerable plaque and the vulnerable patient. CTCA has great potential to render redundant other widely used tests for ischaemia and significantly reduce the number of unnecessary invasive diagnostic procedures. The complete health, economic, and socioeconomic consequences of CTCA can only be evaluated when CTCA is used as a ‘one-stop shop’, to provide information about ischaemia, the vulnerable plaque, but—most importantly—the vulnerable patient. The ageing of the US population and the influence of frailty on the incidence of cardiovascular outcomes in over 6 years of follow-up. (A) Estimates on the projected number (%) of all older adults in 2040 were obtained from https://www.census.gov. (B) The cumulative incidence of each cardiovascular outcome during 6 years of follow-up were derived from the National Health and Aging and Trends Study (from Damluji AA, Chung SE, Xue QL, Hasan RK, Moscucci M, Forman DE, Bandeen-Roche K, Batchelor W, Walston JD, Resar JR, Gerstenblith G. Frailty and cardiovascular outcomes in the National Health and Aging Trends Study. See pages 3856–3865). The ageing of the US population and the influence of frailty on the incidence of cardiovascular outcomes in over 6 years of follow-up. (A) Estimates on the projected number (%) of all older adults in 2040 were obtained from https://www.census.gov. (B) The cumulative incidence of each cardiovascular outcome during 6 years of follow-up were derived from the National Health and Aging and Trends Study (from Damluji AA, Chung SE, Xue QL, Hasan RK, Moscucci M, Forman DE, Bandeen-Roche K, Batchelor W, Walston JD, Resar JR, Gerstenblith G. Frailty and cardiovascular outcomes in the National Health and Aging Trends Study. See pages 3856–3865). Physical frailty is a commonly encountered geriatric syndrome among older adults without CAD. The impact of frailty on the incidence of long-term cardiovascular outcomes is not known. In a clinical research article entitled ‘Frailty and cardiovascular outcomes in the National Health and Aging Trends Study’, Abdulla Damluji from the Johns Hopkins School of Medicine in Baltimore, MD, USA, and colleagues aimed to evaluate the long-term association of frailty, measured by the Fried frailty phenotype, with all-cause mortality and major adverse cardiovascular events (MACE) among 3259 older adults without a history of CAD at baseline.16 They used the National Health and Aging Trends Study, a prospective cohort study linked to a Medicare sample. Frailty was measured during the baseline visit using the Fried physical frailty phenotype. Compared with those without frailty, subjects with frailty were older (mean age 82 vs. 75 years, P < 0.001), and more likely to be female (68% vs. 55%, P < 0.001) and to belong to an ethnic minority. The prevalence of hypertension, falls, disability, anxiety/depression, and multimorbidity was much higher in the frail and pre-frail than in the non-frail participants. In a Cox time-to-event multivariable model and during 6 years of follow-up, the incidences of death and of each individual cardiovascular outcome were all significantly higher in the frail than in the non-frail patients including MACE [hazard ratio (HR) 1.77], death (HR 2.7), acute myocardial infarction (HR 1.95), stroke (HR 1.71), peripheral vascular disease (HR 1.80), and CAD (HR 1.35) (Figure 2). The authors conclude that in patients without CAD, frailty is a risk factor for the development of MACE. Efforts to identify frailty in patients without CAD and interventions to limit or reverse frailty status are needed and, if successful, may limit subsequent adverse cardiovascular events. The contribution is accompanied by an Editorial by Ariela Orkaby from Harvard Medical School in Boston, MA, USA.17 The author concludes that the work by Damluji and colleagues represents an important step forward to individualizing care for older adults that does not simply extrapolate from younger populations. Prevention of cardiovascular disease is often considered in two broad categories: non-modifiable (age, sex, race, and genetics) and modifiable (smoking, hypertension, diabetes, cholesterol, diet, and weight). Chronological age is the single dominant non-modifiable risk factor that makes it challenging to practise precision medicine in older adults. The addition of frailty to the risk toolbox for the prevention of cardiovascular disease is critical to developing a more precise and quantitative estimate of risk for older adults that moves beyond non-modifiable chronological age. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in the left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. Step A is the only sign established in guidelines and recommendations.18 In a Clinical Research article entitled ‘Prognostic value of stress echocardiography assessed by the ABCDE protocol’, Quirino Ciampi from the Fatebenefratelli Hospital in Benevento, Italy, and colleagues sought to assess the prognostic value of ABCDE-SE in a prospective, large-scale, multicentre, international, effectiveness study.19 From July 2016 to November 2020, they enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise or pharmacological. SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. During a median follow-up of 21 months, 73 deaths occurred. The annual mortality rate significantly increased from 0.4% per person-year for score 0 up to 2.7% per person-year for score 5. The authors conclude that ABCDE-SE allows an effective prediction of survival in patients with chronic coronary syndromes. The manuscript is accompanied by an Editorial by Roxy Senior and Rajdeep Khattar from the Royal Brompton & Harefield NHS Trust in London, UK.20 The authors observe that the ABCDE-SE protocol for the investigation of suspected CAD may be further refined by (i) optimizing the detection of ischaemia by incorporating information on myocardial perfusion during step A and (ii) adding a step for the assessment of atherosclerosis by carotid ultrasound to target the preventative treatment of non-obstructive atherosclerotic plaque. Abnormal findings in step C, D, or E in the absence of myocardial ischaemia, although of prognostic significance, are likely to have low specificities for the diagnosis of CAD. Furthermore, therapies targeted towards pathophysiological abnormalities in these steps have not been established and certainly there are no data to show that therapy improves prognosis. In contrast, the ABCDE-SE protocol in known CAD and absence of myocardial ischaemia may be very useful for risk stratification, providing reassurance for low-risk patients and for taking an informed decision regarding the need for invasive investigation in high risk patients. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘In the pool: dilution or drowning’, Victor Dayan from the Universidad de la Republica, Montevideo, Uruguay and colleagues comment on the recent publication ‘Cardiac mortality in patients randomized to elective coronary revascularization plus medical therapy or medical therapy alone: a systematic review and meta-analysis’ by Eliano P. Navarese from the University of Alberta in Edmonton (Canada).21,22 Navarese et al. respond in a separate comment.23 The editors hope that this issue of the European Heart Journal will be interest to its readers. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.