A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis.

AIMS: This meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies. METHODS AND RESULTS: We systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39-5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92-3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04-1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04-1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78-7.83) and MACE (HR: 3.56, 95% CI: 2.14-5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35-6.00), heart failure (HR: 6.38, 95% CI: 1.95-20.90), heart transplant (HR: 3.32, 95% CI: 2.34-4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37-16.55). CONCLUSION: Reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk.

Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial.

AIMS: Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine 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 percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients with severe single-vessel coronary artery disease (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 higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (-0.07; 95% CI: -0.12 to -0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. CONCLUSION: 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.

Quality of Life Assessment in Trials of Revascularization for Chronic Stable Angina: Insights from ORBITA and the Implications of Blinding.

The main aims of therapy in chronic stable angina are to reduce the risk of myocardial infarction and death and improve symptoms and quality of life (QoL). Unblinded trials have shown that revascularization does not reduce the risk of myocardial infarction or death but does appear to improve symptoms. However, symptoms are susceptible to the placebo effect which can bias therapies to appear more effective than they are. To assess the true physical impact of a treatment on symptoms, placebo-controlled trials with patients and medical and research teams blinded to treatment allocation are necessary. Symptoms and QoL can be reported directly by the patient or indirectly by the physician. Patient-reported outcome measures in angina trials can include angina frequency, frequency of nitrate use, exercise capacity, and questionnaires such as the Seattle Angina Questionnaire (SAQ) and the generic EuroQOL-5D-5L (EQ-5D-5L) QoL questionnaire. Physician-assessed outcome measures include Canadian Cardiovascular Society Class. The Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial was the first blinded placebo-controlled study investigating the role of percutaneous coronary intervention (PCI) in chronic stable angina. The trial showed a smaller than expected and not statistically significant effect of placebo-controlled PCI on the primary endpoint of change in exercise time at 6 weeks follow-up in single-vessel coronary artery disease. There was also no significant placebo-controlled treatment effect of PCI for the prespecified secondary endpoints of SAQ or EQ-5D-5L, although PCI did result in 20% more patients becoming free from angina than placebo in a non-prespecified secondary analysis. ORBITA has demonstrated the need for symptomatic and QoL effects of PCI to be studied using placebo control. Here, we describe ways of measuring QoL, the impact of the unblinded and blinded trials to date, what we have learned from ORBITA, and what is next for this common and complex condition.

Dobutamine Stress Echocardiography Ischemia as a Predictor of the Placebo-Controlled Efficacy of Percutaneous Coronary Intervention in Stable Coronary Artery Disease: The Stress Echocardiography-Stratified Analysis of ORBITA.

BACKGROUND: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina). METHODS: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling. RESULTS: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426). CONCLUSIONS: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Development of artificial intelligence tools for invasive Doppler-based coronary microvascular assessment.

Aims: Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. Methods and results: A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman's rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias -1.68 cm/s, 95% confidence interval (CI) -2.13 to -1.23 cm/s, P < 0.001 with limits of agreement (LOA) -4.03 to 0.68 cm/s; console flow vs. expert flow bias -2.63 cm/s, 95% CI -3.74 to -1.52, P < 0.001, 95% LOA -8.45 to -3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). Conclusion: An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.

A double-blind randomised placebo-controlled trial of percutaneous coronary intervention for the relief of stable angina without antianginal medications: design and rationale of the ORBITA-2 trial.

Percutaneous coronary intervention (PCI) is frequently performed for stable angina. However, the first blinded trial, ORBITA, did not show a placebo-controlled increment in exercise time in patients with single-vessel disease, at 6 weeks, on maximal antianginal therapy. ORBITA-2 will assess the placebo-controlled efficacy of PCI on angina frequency in patients with single- or multivessel disease, at 12 weeks, on no antianginal therapy. ORBITA-2 is a double-blind placebo-controlled trial randomising participants with (i) angina at presentation, (ii) documented angina during the 2-week pre-randomisation symptom assessment phase, (iii) objective evidence of ischaemia, (iv) single- or multivessel disease, and (v) clinical eligibility for PCI. At enrolment, antianginals will be stopped, and angina questionnaires completed. Participants will record their symptoms on a smartphone application daily throughout the trial and will undergo exercise treadmill testing and stress echocardiography at pre-randomisation. They will then undergo coronary angiography with unblinded invasive physiology assessment. Eligible participants will then be sedated to a deep level of conscious sedation and randomised 1:1 between PCI and placebo. After the 12-week blinded follow-up period, they will return for questionnaires, exercise testing and stress echocardiography assessment. If angina becomes intolerable, antianginals will be introduced using a prespecified medication protocol. The primary outcome is an angina symptom score using an ordinal clinical outcome scale for angina. Secondary outcomes include exercise treadmill time, angina frequency, angina severity and quality of life. Trial registration: ClinicalTrials.gov: NCT03742050.

Mechanical thrombectomy with retrievable stents and aspiration catheters for acute ischaemic stroke: a meta-analysis of randomised controlled trials.

BACKGROUND: Retrievable stents and aspiration catheters have been developed to provide more effective arterial recanalisation in acute ischaemic stroke. AIMS: The aim of this analysis was to test the effect of mechanical thrombectomy on mortality and long-term neurological outcome in patients presenting with acute large-vessel anterior circulation ischaemic stroke. METHODS: A structured search identified randomised controlled trials of thrombectomy (using a retrievable stent or aspiration catheter) versus control on a background of medical therapy which included intravenous thrombolysis if appropriate. The primary endpoint was disability at 90-day follow-up as assessed by the modified Rankin scale (mRS). Secondary endpoints included all-cause mortality and symptomatic intracranial haemorrhage. A Bayesian mixed-effects model was used for analysis. RESULTS: Twelve trials met the inclusion criteria, comprising a total of 1,276 patients randomised to thrombectomy and 1,282 patients to control. Randomisation to thrombectomy significantly reduced disability at 90 days (odds ratio [OR] 0.52, 95% credible interval [CrI] 0.46 to 0.61, probability(control better)<0.0001). Furthermore, thrombectomy reduced the odds of functional dependence at 90 days, indicated by an mRS score >2 (OR 0.44, CrI 0.37 to 0.52, p<0.0001). Thrombectomy reduced all-cause mortality at 90 days (16.1% vs 19.2%, OR 0.81, 95% CrI 0.66 to 0.99, p=0.024). The frequency of symptomatic intracranial haemorrhage was similar between thrombectomy (4.2%) and control (4.0%) (OR 1.12, 95% CrI 0.76 to 1.68, p=0.72). CONCLUSIONS: In patients with an acute anterior circulation stroke, modern device thrombectomy significantly reduces death and subsequent disability. The magnitude of these effects suggests that universal access to this treatment strategy should be the standard of care.

Daily angina documentation versus subsequent recall: development of a symptom smartphone app.

Aims: The traditional approach to documenting angina outcomes in clinical trials is to ask the patient to recall their symptoms at the end of a month. With the ubiquitous availability of smartphones and tablets, daily contemporaneous documentation might be possible. Methods and results: The ORBITA-2 symptom smartphone app was developed with a user-centred iterative design and testing cycle involving a focus group of previous ORBITA participants. The feasibility and acceptability were assessed in an internal pilot of participants in the ongoing ORBITA-2 trial. Seven days of app entries by ORBITA-2 participants were compared with subsequent participant recall at the end of the 7-day period. The design focus group tested a prototype app. They reported that the final version captured their symptoms and was easy to use. In the completion assessment group, 141 of 142 (99%) completed the app in full and 47 of 141 (33%) without reminders. In the recall assessment group, 29 of 29 (100%) participants said they could recall the previous day's symptoms, and 82% of them recalled correctly. For 2 days previously, 88% said they could recall and of those, 87% recalled correctly. The proportion saying they could recall their symptoms fell progressively thereafter: 89, 67, 61, 50%, and at 7 days, 55% (P < 0.001 for trend). The proportion of recalling correctly also fell progressively to 55% at 7 days (P = 0.04 for trend). Conclusion: Episode counts of angina are difficult to recall after a few days. For trials such as ORBITA-2 focusing on angina, daily symptom collection via a smartphone app will increase the validity of the results.

Controversies in revascularisation for stable coronary artery disease.

Recent randomised controlled trials, such as ISCHEMIA and ORBITA, have overturned most of what we were taught in medical school about hospital procedures considered necessary for patients with stable coronary artery disease. In this article, we discuss what these trials mean for physicians and patients considering revascularisation procedures with the hope of reducing the risk of death or alleviating angina.

The Placebo-Controlled Effect of Percutaneous Coronary Intervention on Exercise Induced Changes in Anti-Malondialdehyde-LDL Antibody Levels in Stable Coronary Artery Disease: A Substudy of the ORBITA Trial.

Aim: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) forms a significant component of oxidised LDL. The effects of exercise on levels of MDA-LDL and anti-MDA-LDL antibodies are not well-understood. Furthermore, it is not known whether these can be modified in patients with coronary artery disease by percutaneous coronary intervention (PCI). Methods: The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial was the first blinded, multi-centre randomised trial of PCI vs. placebo procedure for angina relief. Serum samples were available at four time-points: pre-randomisation pre- (P1) and post- (P2) exercise and post-randomisation (6-weeks following the PCI or placebo procedure), pre- (P3) and post- (P4) exercise. ELISAs were performed using laboratory-developed assays for MDA-LDL (adjusted for Apolipoprotein B) and anti-MDA-LDL antibodies. Results: One hundred ninety-six of the 200 patients (age 66.1 [SD 8.99] years, 28% female) with severe single vessel coronary artery disease suitable for PCI enrolled in the ORBITA trial had blood available for analysis. With exercise at pre-randomisation (P2-P1) there was no significant change in adjusted MDA-LDL (-0.001, 95% CI -0.004 to 0.001; p = 0.287); however, IgG and IgM anti-MDA-LDL significantly declined (-0.022, 95% CI -0.029 to -0.014, p < 0.0001; -0.016, 95% CI -0.024 to -0.008, p = 0.0002, respectively). PCI did not have a significant impact on either the pre-exercise values (P3 controlling for P1) of MDA-LDL (p = 0.102), IgG (p = 0.444) or IgM anti-MDA-LDL (p = 0.909). Nor did PCI impact the exercise induced changes in these markers (P4 controlling for P1, P2, and P3) for MDA-LDL (p = 0.605), IgG (p = 0.725) or IgM anti-MDA-LDL (p = 0.171). Pre-randomisation ischaemia on stress echo did not impact these interactions. Conclusions: Exercise results in an acute reduction in anti-oxLDL antibodies in patients with severe single vessel coronary disease, possibly indicating an induction in homoeostatic clearance via the innate immune system. However, PCI did not ameliorate this effect.

Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.

BACKGROUND: Most people who begin statins abandon them, most commonly because of side effects. OBJECTIVES: The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. METHODS: Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the "nocebo" ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. RESULTS: A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. CONCLUSIONS: The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016).

Achieving Optimal Medical Therapy: Insights From the ORBITA Trial.

Background In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo-controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline-directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results After enrollment into the ORBITA trial, all 200 patients entered a 6-week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2-4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0-1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions In the 12-week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer-term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02062593.

Gender-Related Differences in Clinical Presentation and Angiographic Findings in Patients with Ischemia and No Obstructive Coronary Artery Disease (INOCA): A Single-Center Observational Registry.

Ischemia and no obstructive coronary arteries (INOCA) is a common clinical presentation, with a variety of causes that are often not fully investigated in routine clinical practice. The goal of our study was to characterize a real-world population of patients with INOCA, with a deeper focus on symptoms and stress test findings. The study population consisted of 435 patients who underwent diagnostic coronary angiography for anginal symptoms and/or evidence of myocardial ischemia at non-invasive imaging. In all patients angiography demonstrated nonobstructive coronary artery disease (CAD, less than 30% luminal diameter stenosis or fractional flow reserve > 0.8 and/or instantaneous wave-free ratio > 0.89). Fifty-four percent of the patients were women. Atypical clinical presentation was more common in women (59.5 vs. 49.5%, p = 0.037). Women were more likely to have normal coronary arteries than men (41.8 vs. 16.2%, p < 0.001), and less likely than men to have hemodynamically non-significant CAD (32.1 vs. 55.1%, p < 0.001). No significant correlation between typicality of symptoms and evidence of ischemia was found in those patients (244/435, 56.1%) who had either dobutamine stress echocardiography or electrocardiogram stress test. INOCA is a common clinical condition, prevalent in women often presenting with atypical symptoms.

Effects of Percutaneous Coronary Intervention on Death and Myocardial Infarction Stratified by Stable and Unstable Coronary Artery Disease: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: In patients presenting with ST-segment-elevation myocardial infarction, percutaneous coronary intervention (PCI) reduces mortality when compared with fibrinolysis. In other forms of coronary artery disease (CAD), however, it has been controversial whether PCI reduces mortality. In this meta-analysis, we examine the benefits of PCI in (1) patients post-myocardial infarction (MI) who did not receive immediate revascularization; (2) patients who have undergone primary PCI for ST-segment-elevation myocardial infarction but have residual coronary lesions; (3) patients who have suffered a non-ST-segment-elevation acute coronary syndrome; and (4) patients with truly stable CAD with no recent infarct. This analysis includes data from the recently presented International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) and Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI (COMPLETE) trials. METHODS AND RESULTS: We systematically identified all randomized trials of PCI on a background of medical therapy for the treatment of CAD. The ISCHEMIA trial, presented in November 2019, was eligible for inclusion. Data were combined using a random-effects meta-analysis. The primary end point was all-cause mortality. Forty-six trials, including 37 757 patients, were eligible. In the 3 unstable scenarios, PCI had the following effects on mortality: unrevascularized post-MI relative risk (RR) 0.68 (95% CI, 0.45-1.03); P=0.07; multivessel disease following ST-segment-elevation myocardial infarction (RR, 0.84 [95% CI, 0.69-1.04]; P=0.11); non-ST-segment-elevation acute coronary syndrome (RR, 0.84 [95% CI, 0.72-0.97]; P=0.02). Overall, in these unstable scenarios PCI was associated with a significant reduction in mortality (RR, 0.84 [95% CI, 0.75-0.93]; P=0.02). In unstable CAD, PCI also reduced cardiac death (RR, 0.69 [95% CI, 0.53-0.90]; P=0.007) and MI (RR, 0.74 [95% CI, 0.62-0.90]; P=0.002). For stable CAD, PCI did not reduce mortality (RR, 0.98 [95% CI, 0.87-1.11]), cardiac death (RR, 0.89 [95% CI, 0.71-1.12]; P=0.33), or MI (RR, 0.96 [95% CI, 0.86-1.08]; P=0.54). CONCLUSIONS: PCI prevents death, cardiac death, and MI in patients with unstable CAD. For patients with stable CAD, PCI shows no evidence of an effect on any of these outcomes.

Improving ultrasound video classification: an evaluation of novel deep learning methods in echocardiography.

Echocardiography is the commonest medical ultrasound examination, but automated interpretation is challenging and hinges on correct recognition of the 'view' (imaging plane and orientation). Current state-of-the-art methods for identifying the view computationally involve 2-dimensional convolutional neural networks (CNNs), but these merely classify individual frames of a video in isolation, and ignore information describing the movement of structures throughout the cardiac cycle. Here we explore the efficacy of novel CNN architectures, including time-distributed networks and two-stream networks, which are inspired by advances in human action recognition. We demonstrate that these new architectures more than halve the error rate of traditional CNNs from 8.1% to 3.9%. These advances in accuracy may be due to these networks' ability to track the movement of specific structures such as heart valves throughout the cardiac cycle. Finally, we show the accuracies of these new state-of-the-art networks are approaching expert agreement (3.6% discordance), with a similar pattern of discordance between views.

Percutaneous coronary intervention for stable coronary artery disease.

The adverse consequences of stable coronary artery disease (CAD) are death, myocardial infarction (MI) and angina. Trials in stable CAD show that percutaneous coronary intervention (PCI) does not reduce mortality. PCI does appear to reduce spontaneous MI rates but at the expense of causing some periprocedural MI. Therefore, the main purpose of PCI is to relieve angina. Indeed, patients and physicians often choose PCI rather than first attempting to control symptoms with anti-anginal medications as recommended by guidelines. Nevertheless, it is unclear how effective PCI is at relieving angina. This is because, whereas anti-anginal medications are universally required to be tested against placebo, there is no such requirement for procedural interventions such as PCI. The first placebo-controlled trial of PCI showed a surprisingly small effect size. This may be because it is overly simplistic to assume that the presence of a stenosis and inducible ischaemia in a patient means that the clinical chest pain they report is caused by ischaemia. In this article, we review the evidence base and argue that if we as a medical specialty wish to lead the science of procedures for symptom control, we should recognise the special merit of placebo-controlled experiments.

Mortality From Ischemic Heart Disease.

Background Ischemic heart disease (IHD) has been considered the top cause of mortality globally. However, countries differ in their rates and there have been changes over time. Methods and Results We analyzed mortality data submitted to the World Health Organization from 2005 to 2015 by individual countries. We explored patterns in relationships with age, sex, and income and calculated age-standardized mortality rates for each country in addition to crude death rates. In 5 illustrative countries which provided detailed data, we analyzed trends of mortality from IHD and 3 noncommunicable diseases (lung cancer, stroke, and chronic lower respiratory tract diseases) and examined the simultaneous trends in important cardiovascular risk factors. Russia, United States, and Ukraine had the largest absolute numbers of deaths among the countries that provided data. Among 5 illustrative countries (United Kingdom, United States, Brazil, Kazakhstan, and Ukraine), IHD was the top cause of death, but mortality from IHD has progressively decreased from 2005 to 2015. Age-standardized IHD mortality rates per 100 000 people per year were much higher in Ukraine (324) and Kazakhstan (97) than in United States (60), Brazil (54), and the United Kingdom (46), with much less difference in other causes of death. All 5 countries showed a progressive decline in IHD mortality, with a decline in smoking and hypertension and in all cases a rise in obesity and type II diabetes mellitus. Conclusions IHD remains the single largest cause of death in countries of all income groups. Rates are different between countries and are falling in most countries, indicating great potential for further gains. On the horizon, future improvements may become curtailed by increasing hypertension in some developing countries and more importantly global growth in obesity.