Frontiers in today’s chronic coronary syndromes: detecting obstructive disease, role of beta-blockers and of anticoagulants

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The management of stable coronary artery disease or, to use a more modern term, chronic coronary syndromes, remains a challenge. The diagnosis is more difficult compared with the standardized algorithms in acute patients. In addition, the value of percutaneous coronary intervention (PCI) has been repeatedly questioned in such patients.1,2 Most drug studies are decades old and thus their effectiveness in today’s patients is uncertain and often driven by beliefs3 rather than evidence.4 This issue is addressed by Philippe Gabriel Steg and colleagues from the INSERM U698 and Hôpital Bichat-Cl. Bernard in Paris in their article entitled ‘Beta-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study’.5 They analysed the effect of the use of beta-blockers or calcium antagonists on outcomes in 22 006 stable coronary patients followed-up for 5 years in the CLARIFY registry. After multivariable adjustment, baseline beta-blocker use was not associated with lower all-cause death, cardiovascular death, or cardiovascular death and non-fatal myocardial infarction (Figure 1). Sensitivity analyses according to beta-blocker use over time and to prescribed dose produced similar results. Among patients enrolled in the year following their myocardial infarction, baseline beta-blocker use was associated with lower all-cause death with a hazard ratio of 0.68, cardiovascular death with a hazard ratio of 0.52, and cardiovascular death and non-fatal infarction with a hazard ratio of 0.69. Calcium antagonists were not associated with any difference in mortality. Thus, in contemporary stable coronary artery disease, beta-blocker use is associated with lower mortality only following a myocardial infarction, while calcium antagonists are not protective regardless of a history of infarction. These highly relevant findings are put into perspective in a comprehensive Editorial by Steven E. Nissen from the Cleveland Clinic Foundation in Cleveland, Ohio (USA).6 Cumulative hazard of all-cause mortality according to β-blocker use at baseline, categorized by the time elapsed since the index myocardial infarction prior to enrolment. P-values, hazard ratios, and confidence intervals are derived from comparing β-blocker users with non-users at baseline in a survival analysis from Cox proportional hazards models with multivariable adjustment for the REACH cardiovascular event risk score, systolic/blood pressure, left ventricular ejection fraction, histories of coronary revascularization, peripheral artery disease, and asthma/chronic obstructive pulmonary disease. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction (from Sorbets E, Steg PG, Young R, Danchin N, Greenlaw N, Ford I, Tendera M, Ferrari R, Merkely B, Parkhomenko A, Reid C, Tardif J-C, Fox KM. β-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study. See pages 1399--1407). Atherosclerotic plaques are not homogenously distributed in the coronary circulation, suggesting that local biomechanical forces7,8 influence plaque development. This is of great clinical importance as bifurcation and complex lesions are associated with unfavourable outcomes.9,10 In their article ‘Impact of combined plaque structural stress and wall shear stress on coronary plaque progression, regression, and changes in composition’, Charis Costopoulos and colleagues from the University of Cambridge School of Clinical Medicine in the UK studied this using virtual histology intravascular ultrasound and bi-plane coronary angiography.11 In areas with progression, high plaque structural stress was associated with larger increases in the necrotic core and small increases in fibrous tissue compared with low plaque stress areas. In areas with regression, high plaque stress was associated with increased necrotic core and decreased fibrous tissue. Low wall shear stress was associated with increased plaque burden compared with those exposed to high wall shear stress. Thus, areas with high plaque stress are associated with increased plaque vulnerability, while those with low wall shear stress are more prone to plaque growth or less regression. These novel and complex findings are further explained in an informative Editorial by Peter H. Stone from the Brigham and Women’s Hospital in Boston, Massachusetts in the USA.12 The modified Diamond Forrester prediction model is commonly used to predict the presence of obstructive coronary artery disease in patients submitted to an exercise test.13–15 However, its precision has been repeatedly debated. Eva Prescott and colleagues from the Bispebjerg University Hospital in Copenhagen, Denmark analysed this further in their article entitled ‘Prediction of obstructive coronary artery disease and prognosis in patients with suspected stable angina’.16 They included 3903 patients free of coronary artery disease and heart failure and suspected of angina. Obstructive coronary artery disease was defined at angiography by the presence of lesions requiring revascularization, >70% stenosis, or fractional flow reserve <0.8. The updated Diamond Forrester prediction model overestimated probability considerably: mean pre-test probability was 31.4%, while only 7% had obstructive coronary disease. In contrast, a basic prediction model with age, gender, and symptoms demonstrated good discrimination, with C-statistics of 0.86, while a clinical prediction model adding diabetes, family history, and dyslipidaemia slightly improved the C-statistic to 0.88. Quartiles of probability provided good diagnostic and prognostic stratification: in the lowest quartiles, there were no cases of obstructive coronary disease and the cumulative risk of the composite endpoint was <3% at 2 years (Figure 2). Thus, the pre-test probability model recommended by current ESC guidelines substantially overestimates the likelihood of coronary disease in a contemporary all-comer population. These provocative findings are further discussed in a thought-provoking Editorial by Felicita Andreotti from the Catholic University Medical School in Rome, Italy.17 The observed proportion of obstructive coronary artery disease in 3786 patients age 30 or above by gender, age, and angina typicality vs. the expected proportion from the updated Diamond Forrester prediction model. There are no expected values for dyspnoea since this symptom is not included in the Diamond Forrester prediction model (from Reeh J, Therming CB, Heitmann M, Højberg S, Sørum C, Bech J, Husum D, Dominguez H, Sehestedt T, Hermann T, Hansen KW, Simonsen L, Galatius S, Prescott E. Prediction of obstructive coronary artery disease and prognosis in patients with suspected stable angina. See pages 1426--1435). This topic is further discussed in a clinical review entitled ‘Should NICE guidelines be universally accepted for the evaluation of stable coronary disease? A debate’ by Harvey Hecht and colleagues from the Mount Sinai Medical Center in New York in the USA, who note that the 2016 National Institute for Health and Care Excellence guideline for the assessment and diagnosis of chest pain positions coronary computed tomography angiography as the first test for all stable chest pain patients without confirmed coronary artery disease and discards the previous emphasis on calculation of pre-test likelihood recommended in their 2012 edition of the guidelines.18 On the other hand, the American College of Cardiology Foundation/American Heart Association continue to present stress testing as the tests of choice, while the most recent ESC Guidelines on Revascularization prefer non-invasive tests to the classical exercise test.19 The authors discuss the pros and cons of these paradigm-changing recommendations, with the current evidence and future needs. Narrowing of the left main coronary artery jeopardizes a large area of myocardium and increases the risk of major adverse cardiac events.20,21 In their review entitled ‘Management of left main disease: an update’, Davide Capodanno from Ferrarotto in Catania, Italy and colleagues update us on this field and discuss current management strategies for left main coronary artery disease.22 In general, PCI offers more rapid recovery and a lower early adverse event rate, whereas coronary artery bypass grafting (CABG) provides a more durable procedure. In the largest of six trials comparing PCI with CABG, patients with low or intermediate anatomical complexity contemporary PCI did similarly well to those undergoing CABG as regards death, stroke, or myocardial infarction at 3 years. The authors discuss the current management of left main coronary artery disease, with an emphasis on clinical data and procedural knowledge supporting the use of PCI in a growing proportion of patients. With the publication of ATLAS TIMI 5123 and, more recently, the COMPASS trial,24 anticoagulation is increasingly considered in coronary patients in addition to dual antiplatelet therapy. Excessive fibrin formation and, in turn, a high thrombus firmness25,26 has been recognized as a major outcome variable after myocardial infarction. In their Current Opinion ‘Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add?’, John W. Eikelboom et al. from the McMaster University in Hamilton, Ontario in Canada27 discuss the potential for clinically worthwhile improvements in outcomes, in the context of currently proven secondary prevention measures, and also highlight the therapeutic implications of atherothrombotic disease across different vascular territories. Can one extrapolate from secondary prevention in acute vascular disease to long-term chronic stable disease? What does the COMPASS regimen add to current secondary prevention for chronic arterial vascular disease? Besides providing answers to these questions, they look at how the benefits and risks of the combination of a very low dose of a non-vitamin K antagonist oral anticoagulant and aspirin compare with those seen with other anti-thrombotic combinations. Finally, they discuss the new dual pathway anti-thrombotic therapy compared with the impact of other accepted pharmacological secondary prevention measures in stable vascular disease. This issue is complemented by two Discussion Forum contributions. In a contribution entitled ‘The time has come to use coronary computed tomography angiography in patients with multivessel coronary artery disease’, Patrick W. Serruys and colleagues from Imperial College in London in the UK comment on an Editorial entitled ‘Is it time to replace conventional angiography with coronary computed tomography?’ authored by Antonio Colombo from the EMO GVM Centro Cuore Columbus and Francesco Giannini from the IRCCS San Raffaele Scientific Institute in Milano, Italy.28,29 The authors of the Editorial article also respond to the raised criticism.30 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.