Coronary Revascularization Trial Research Articles

Underrepresentation of Women in Revascularization Trials

This Viewpoint discusses the unequal representation of women in coronary revascularization trials in the US, its negative effects on the cardiovascular health of both sexes, and potential mechanisms to ensure appropriate representation of women moving forward.

Correlation Between Periprocedural Myocardial Infarction, Mortality, and Quality of Life in Coronary Revascularization Trials: A Meta-analysis.

The prognostic importance of periprocedural myocardial infarction (pMI) and its inclusion in the composite outcomes of coronary revascularization trials are controversial. We assessed whether pMI is a surrogate for all-cause or cardiac mortality and quality of life (QoL) outcomes in coronary revascularization trials. All randomized trials comparing percutaneous coronary intervention vs coronary artery bypass grafting (MEDLINE, EMBASE, Cochrane Library) were identified. Trials were included if they reported data for pMI and mortality. Trial-level associations between pMI and all-cause or cardiac mortality and QoL were assessed using the coefficient of determination (R 2 ). The criterion for surrogacy was set at 0.7. Subgroup analyses based on pMI definition and on key clinical/procedural variables were performed. Twelve trials were included (11,549 patients; weighted mean follow-up: 5.6 years). There was a positive correlation between pMI and all-cause mortality (slope, 1.81; 95% CI, 1.00-2.63; R 2 = 0.72). In the trials that defined pMI as a rise in cardiac biomarkers >5 times the upper reference limit, pMI positively correlated with both all-cause (slope, 2.07; 95% CI, 1.00-3.14; R 2 = 0.93) and cardiac mortality (slope, 0.70; 95% CI, 0.20-1.19; R 2 = 0.87); no such relationships were present in trials that used a lower biomarker threshold. An inverse correlation was found between pMI and long-term changes in the Short Form Health Survey Physical Component score (slope, -4.66; 95% CI, -5.75 to -3.57; R 2 =0.99). In the published coronary revascularization trials, pMI defined by larger biomarker elevations was associated with subsequent mortality and reduced QoL. These findings suggest that large pMI should be included as an outcome measure in coronary revascularization trials.

Reconsidering the Direction of Coronary Revascularization Trials

Reconsidering the Direction of Coronary Revascularization Trials

Is the world ready for the STICH 3.0 trial?

Coronary artery disease (CAD) is responsible for >50% of heart failures cases. Patients with ischemic left ventricular systolic dysfunction (iLVSD) are known to have poorer outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) compared to patients with a normal ejection fraction. Nevertheless, <1% of patients in coronary revascularization trials to date had iLVSD. The purpose of this review is to describe coronary revascularization modalities in patients with iLVSD and highlight the need for randomized controlled trial evidence comparing these treatments in this patient population. Network meta-analytic findings of observational studies suggest that PCI is associated with higher rates of mortality, cardiac death, myocardial infarction, and repeat revascularization but not stroke compared to CABG in iLVSD. In recent years, outcomes for patients undergoing PCI have improved as a result of advances in technologies and techniques. The optimal coronary revascularization modality in patients with iLVSD remains unknown. In observational studies, CABG appears superior to PCI; however, direct randomized evidence is absent and developments in PCI techniques have improved post-PCI outcomes in recent years. The Surgical Treatment for Ischemic Heart Failure 3.0 consortium of trials will seek to address the clinical equipoise in coronary revascularization in patients with iLVSD.

Insights into the Role of Fractional Flow Reserve in Clinical Practice

The early trials of fractional flow reserve (FFR), such as the Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischaemia, FFR versus angiography for multivessel evaluation (FAME), and FAME 2 trials, established the role of FFR in the practice of interventional cardiology. These trials led proponents of FFR to propose making FFR a routine procedure before percutaneous coronary intervention (PCI) and to give preference to PCI over optimal medical therapy (OMT) in those with FFR-positive coronary stenoses. Follow-up results of these trials have given more insights. Some of the benefits of FFR-guided strategy over angiography-guided strategy disappeared over time, and beyond revascularization, the FFR strategy did not show benefit over OMT when considering death and myocardial infarction as endpoints. The FUnctional Testing Underlying Coronary REvascularization trial did not demonstrate the superiority of the FFR-guided strategy over angiography-guided strategy. The ORBITA and the ISHEMIA trials gave strength to the lifestyle modification and OMT approach in stable ischemic heart disease patients with moderate-to-severe ischemia. The role of FFR has to be defined in light of the evolving clinical advances in medicine and new evidence. An in-depth review of all current evidence provides no compelling evidence for the routine use of FFR in cardiac interventions. However, FFR can play a role in coronary stenoses where there is uncertainty in the hemodynamic impact of the lesions.

Noninferiority Margins in Trials of Thrombectomy Devices for Acute Ischemic Stroke: Is the Bar Being Set Too Low?

Background and Purpose- Novel endovascular thrombectomy (EVT) devices for acute ischemic stroke are often cleared by regulatory agencies on the basis of noninferiority trials. The relation between the noninferiority margins used in trials and the minimal clinically important differences (MCIDs) determined by experts have not been systematically investigated. Methods- Systematic searches were performed to identify (1) all noninferiority design or noninferiority-presented stroke-EVT trials for acute ischemic stroke, (2) all studies determining the MCIDs for the same outcomes, and (3) all noninferiority coronary revascularization trials. Stroke-EVT trial results were reanalyzed using the broad noninferiority margins originally used and narrower noninferiority margins derived from formal MCID studies. Results- We identified 7 noninferiority-designed or noninferiority-interpreted stroke-EVT controlled trials, enrolling 1766 patients, variously comparing coil retrievers, first- and second-generation stent retrievers, and aspiration devices. In 6 trials, the primary outcome was achievement of reperfusion, using noninferiority margins of 15% (3 trials), 10% (2 trials), and 8% (1 trial). In contrast, a stroke expert survey identified the MCID for reperfusion as 3.1% to 5%, and cardiac trials used noninferiority margins of 3.5% to 4.4%. In one stroke-EVT trial, the primary outcome was functional independence, using a noninferiority margin of 15%. However, 2 stroke expert survey studies identified MCIDs for functional independence as having lower values, 5% and 1% to 1.5%. For both reperfusion and functional independence outcomes, all 7 trials demonstrated noninferiority with the broadest noninferiority margin, but only 4 and 3 trials demonstrated noninferiority with actual expert-derived margins for reperfusion and functional independence, respectively. Conclusions- Noninferiority margins used in EVT device trials have regularly exceeded the MCIDs determined by stroke experts, as well as margins used for cardiac devices. New approaches, such as the use of reasonably adequate performance margins, rather than noninferiority margins, are needed to optimize stroke-EVT trial design integrity and trial performance feasibility.

Type 1 diabetes mellitus and coronary revascularization.

Over the last three decades, trials of coronary revascularization have taken into account whether populations did or did not have diabetes. What has not been considered is whether or not patients with diabetes in these studies have type 1 or type 2 diabetes. 'Diabetes' appears to be largely used as a synonym for type 2 diabetes. The number of patients with type 1 diabetes has not been reported in most trials. Many questions remain unanswered. Do patients with type 1 diabetes have the same response to various modes of revascularization as those with type 2 diabetes? We know type 2 diabetes affects coronary endothelial function and the coronary artery wall but to what extent does type 1 diabetes affect these? Any response to revascularization does not just depend on the coronary artery but also on the myocardium. How does type 1 diabetes affect the myocardium? To what extent do patients with type 1 diabetes have viable or ischaemic myocardium or scar? What does 'diabetic cardiomyopathy' refer to in the context of type 1 diabetes? This manuscript reviews the evidence for revascularization in type 1 diabetes. We conclude that there has been a near absence of investigation of the pros and cons of revascularization in this population. Investigations to establish both the nature and extent of coronary and myocardial disease in these populations are necessary. Clinical trials of the pros and cons of revascularization in type 1 diabetes are necessary; many will declare that these will be too challenging to perform.

What is the state of hybrid coronary revascularization in 2018?

Hybrid coronary revascularization (HCR) combines minimally invasive surgical bypass with percutaneous coronary intervention (PCI) using drug-eluting stents, the goal being to leverage the strengths of each approach. Here we provide an update on HCR from the past 12 months. HCR represents a minority of surgical revascularization cases from a small number of highly experienced surgical centers. Most single-center observational series show no differences in major cardiovascular outcomes comparing HCR and coronary artery bypass graft (CABG) or HCR and PCI. The 5-year results of the first randomized study comparing HCR to CABG reported no difference in all-cause mortality, myocardial infarction, and repeat revascularization. Comparing HCR with multivessel PCI, a large, prospective observational study reported no difference in risk-adjusted major adverse cardiovascular events at 12 months. The Hybrid Coronary Revascularization Trial is an international, multicenter, randomized controlled trial to compare HCR versus PCI for patients with proximal left anterior descending disease or left main disease. This trial is currently recruiting patients. HCR is a potentially attractive alternative to both surgical revascularization and multivessel PCI when performed in experienced centers for highly selected patients. The results of a large, multicenter, prospective trial will provide greater clarity on the clinical role and optimal coronary anatomy for this third revascularization option.

Regional, Artery-Specific Thresholds of Quantitative Myocardial Perfusion by PET Associated with Reduced Myocardial Infarction and Death After Revascularization in Stable Coronary Artery Disease.

Because randomized coronary revascularization trials in stable coronary artery disease (CAD) have shown no reduced myocardial infarction (MI) or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI, or stroke after revascularization within 90 d after PET. Methods: In a prospective long-term cohort of stable CAD, regional, artery-specific, quantitative myocardial perfusion by PET, coronary revascularization within 90 d after PET, and all-cause death, MI, and stroke (DMS) at 9-y follow-up (mean ± SD, 3.0 ± 2.3 y) were analyzed by multivariate Cox regression models and propensity analysis. Results: For 3,774 sequential rest–stress PET scans, regional, artery-specific, severely reduced coronary flow capacity (CFC) (coronary flow reserve ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 d after PET (P = 0.0369), compared with moderate or mild CFC, coronary flow reserve, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Conclusion: CFC by PET provides objective, regional, artery-specific, size–severity physiologic quantification of CAD severity associated with high risk of DMS that is significantly reduced after revascularization within 90 d after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone.

Compliance With Guideline-Directed Medical Therapy in Contemporary Coronary Revascularization Trials

BackgroundDespite the well-established benefits of secondary cardiovascular prevention, the importance of concurrent medical therapy in clinical trials of coronary revascularization is often overlooked. ObjectivesThe goal of this study was to assess compliance with guideline-directed medical therapy (GDMT) in clinical trials and its potential impact on the comparison between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). MethodsThe Cochrane Central Register of Controlled Trials and MEDLINE were searched from 2005 to August 2017. Clinical trial registries and reference lists of relevant studies were also searched. Randomized controlled trials comparing PCI with drug-eluting stents versus CABG and reporting medical therapy after revascularization were included. The study outcome was compliance with GDMT, defined as the following: 1) any antiplatelet agent plus beta-blocker plus statin (GDMT1); and 2) any antiplatelet agent plus beta-blocker plus statin plus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (GDMT2). Data collection and analysis were performed according to the methodological recommendations of The Cochrane Collaboration. ResultsFrom a total of 439 references, 5 trials were included based on our inclusion and exclusion criteria. Overall, compliance with GDMT1 was low and decreased over time from 67% at 1 year to 53% at 5 years. Compliance with GDMT2 was even lower and decreased from 40% at 1 year to 38% at 5 years. Compliance with both GDMT1 and GDMT2 was higher in PCI than in CABG at all time points. Meta-regression suggested an association between lower use of GDMT1 and adverse clinical outcomes in PCI versus CABG at 5 years. ConclusionsCompliance with GDMT in contemporary clinical trials remains suboptimal and is significantly lower after CABG than after PCI, which may influence the comparison of clinical trial endpoints between those study groups.

Evolution of Reperfusion Therapies for Acute Brain and Acute Myocardial Ischemia

Early reperfusion is the most effective therapy for both acute brain and cardiac ischemia. However, the cervicocephalic circulatory bed offers more challenges to recanalization interventions. The historical development of reperfusion interventions has not previously been systematically compared. Medline search identified all multi-arm, controlled trials of coronary revascularization for acute myocardial infarction and multicenter trials of cerebral revascularization for acute ischemic stroke reporting angiographic reperfusion rates. Thirty-seven trials of coronary reperfusion enrolled 10 908 patients from 1983 to 2009, and 10 trials of cerebral reperfusion enrolled 1064 patients from 1992 to 2009. Coronary reperfusion trials included 10 of intravenous fibrinolysis alone, 8 combined intravenous fibrinolysis and percutaneous transluminal coronary angioplasty with or without stenting, 3 intra-arterial fibrinolysis, and 16 percutaneous transluminal coronary angioplasty with or without stenting. Cerebral reperfusion trials included 1 of intravenous fibrinolysis alone, 3 intra-arterial fibrinolysis, 3 endovascular device alone, and 3 of endovascular treatment ± intravenous fibrinolysis. In both circulatory beds, endovascular treatments were more efficacious at achieving reperfusion than peripherally administered fibrinolytics. In the coronary bed, rates of achieved reperfusion began at high levels in the 1980s and improved modestly over the subsequent 3 decades. In the cerebral bed, reperfusion rates began at modest levels in the early 1990s and increased more slowly. Most recently, in 2005 to 2009, cardiac reperfusion rates substantially exceeded cerebral, partial reperfusion 86.1% versus 61.1%, complete reperfusion 78.6% versus 23.4%. Reperfusion therapies developed more slowly and remain less effective for cerebral than cardiac ischemia. Further, cerebral circulation-specific technical advances are required for physicians to become as capable at safely restoring blood flow to the ischemic brain as the ischemic heart.

Weighting Composite Endpoints in Clinical Trials: Essential Evidence for the Heart Team

Coronary revascularization trials often use a composite endpoint of major adverse cardiac and cerebrovascular events (MACCE). The usual practice in analyzing data with a composite endpoint is to assign equal weights to each of the individual MACCE elements. Noninferiority margins are used to offset effects of presumably less important components, but their magnitudes are subject to bias. This study describes the relative importance of MACCE elements from a patient perspective. A discrete choice experiment was conducted. Survey respondents were presented with a scenario that would make them eligible for the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial three-vessel disease cohort. Respondents chose among pairs of procedures that differed on the 3-year probability of MACCE, potential for increased longevity, and procedure/recovery time. Conjoint analysis derived relative weights for these attributes. In all, 224 respondents completed the survey. The attributes did not have equal weight. Risk of death was most important (relative weight 0.23), followed by stroke (0.18), potential increased longevity and recovery time (each 0.17), myocardial infarction (0.14), and risk of repeat revascularization (0.11). Applying these weights to the SYNTAX 3-year endpoints resulted in a persistent, but decreased margin of difference in MACCE favoring coronary artery bypass graft surgery compared to percutaneous coronary intervention. When labeled only as "procedure A" and "procedure B," 87% of respondents chose coronary artery bypass graft surgery over percutaneous coronary intervention. When procedures were labeled as "coronary stent" and "coronary bypass surgery," only 73% chose coronary artery bypass graft surgery. Procedural preference varied with demographics, sex, and familiarity with the procedures. The MACCE elements do not carry equal weight in a composite endpoint, from a patient perspective. Using a weighted composite endpoint increases the validity of statistical analyses and trial conclusions. Patients are subject to bias by labels when considering coronary revascularization.

Repeat Revascularization Is a Faulty End Point for Clinical Trials

Coronary revascularization is performed to reduce myocardial ischemia and its sequelae of death, myocardial infarction, and anginal symptoms. A successful procedure increases the patient's quality of life, length of life, or both. Clinical trials of coronary revascularization should measure these outcomes to assess progress toward the goals of therapy. Death is an important and unequivocal outcome but, fortunately, is uncommon, and hence, very large studies are needed to assess differences in mortality. Myocardial infarction is also an objective outcome because it requires laboratory measures such as electrocardiography, biomarker levels, and imaging results, but it too is uncommon and can be assessed only in large trials. In contrast to these hard outcomes, angina is a symptom, and its subjectivity has made it less desirable to clinical investigators as an outcome measure. Angina can be measured using standardized approaches, however, and its effect on health status and quality of life has been quantified in many clinical trials. Article see p 267 In addition to these standard outcomes, repeat coronary revascularization has been adopted as an end point in many trials of percutaneous coronary intervention (PCI). Early balloon angioplasty procedures had high rates of restenosis and, consequently, of repeat revascularization procedures, typically another angioplasty. In the early 1980s, most interventional cardiologists accepted repeat procedures as an inevitable consequence of PCI because restenosis proved very difficult to tame, at least by using drug therapy. The disease process of restenosis could be measured using coronary angiography, but the angiographic measures were of uncertain clinical importance. Repeat revascularization became a …

No “I” in Heart Team

The landmark Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, comparing drug-eluting stents with coronary bypass surgery in patients with complex coronary artery disease, was published in 2009.1 Although the trial continues to provide valuable insights regarding selection of coronary revascularization procedures, a particular aspect of its protocol has also generated considerable attention: the “Heart Team.” Although not the first to suggest it, the Heart Team concept was recently popularized by the SYNTAX investigators in their attempt to accommodate an “all-comers” design, streamlining the process for patient selection that had burdened coronary revascularization trials in the past. Instead of using an exhaustive list of explicit inclusion and exclusion criteria, the study protocol simply required that, for the most part, a cardiac surgeon and an interventional cardiologist came together in consensus about the appropriateness of enrolling a patient. Although the idea of using Heart Teams in this manner did not originate with the SYNTAX trial, the special emphasis placed on it by the investigators was unique and identified as such, even early on, by editorialists and prominent clinicians.2,3 As a result, the notion of encouraging multidisciplinary care in cardiovascular medicine, exemplified by the Heart Team concept, has gained increasing traction in the context of a broad range of procedures that encompass coronary revascularization, transcatheter aortic valve replacement (TAVR), and other complex endovascular interventions. It is widely discussed in the published literature, highlighted at scientific conferences, and, most prominently, incorporated into professional society guidelines. In recent guidelines for coronary revascularization, for example, use of a Heart Team is a class I recommendation during the decision-making process for patients with complex coronary artery disease.4,5 So, what exactly is a Heart Team? In the SYNTAX trial, the idea simply referred to the requirement that, at …

The Impact of Revascularization on Mortality in Patients with Nonacute Coronary Artery Disease

Background Although early revascularization improves outcomes for patients with acute coronary syndromes, the role of revascularization for patients with nonacute coronary artery disease is controversial. The objective of this meta-analysis was to compare surgical or percutaneous revascularization with medical therapy alone to determine the impact of revascularization on death and nonfatal myocardial infarction in patients with coronary artery disease. Methods The Medline and Cochrane Central Register of Controlled Trials databases were searched to identify randomized trials of coronary revascularization (either surgical or percutaneous) versus medical therapy alone in patients with nonacute coronary disease reporting the individual outcomes of death or nonfatal myocardial infarction reported at a minimum follow-up of 1 year. A random effects model was used to calculate odds ratios (OR) for the 2 prespecified outcomes. Results Twenty-eight studies published from 1977 to 2007 were identified for inclusion in the analysis; the revascularization modality was percutaneous coronary intervention in 17 studies, coronary bypass grafting in 6 studies, and either strategy in 5 studies. Follow-up ranged from 1 to 10 years with a median of 3 years. The 28 trials enrolled 13,121 patients, of whom 6476 were randomized to revascularization and 6645 were randomized to medical therapy alone. The OR for revascularization versus medical therapy for mortality was 0.74 (95% confidence interval [CI], 0.63-0.88). A stratified analysis according to revascularization mode revealed both bypass grafting (OR 0.62; 95% CI, 0.50-0.77) and percutaneous intervention (OR 0.82; 95% CI, 0.68-0.99) to be superior to medical therapy with respect to mortality. Revascularization was not associated with a significant reduction in nonfatal myocardial infarction compared with medical therapy (OR 0.91; 95% CI, 0.72-1.15). Conclusion Revascularization by coronary bypass surgery or percutaneous intervention in conjunction with medical therapy in patients with nonacute coronary artery disease is associated with significantly improved survival compared with medical therapy alone.

Confusion in Coronary Revascularization in Women

Some of the confusion surrounding the role of coronary revascularization in women relates to differences in study design, the large number of reported end points, and the multitude of comparisons. This article presents current results from randomized coronary revascularization trials as well as contemporary observational data from a large regional experience. It is suggested that a structured approach to data reporting can better track the emerging data on coronary revascularization in women.

Clinical trials of coronary revascularization for chronic stable angina: medical treatment versus coronary revascularization

For patients with chronic stable angina, several randomized trials have been performed comparing medical management with surgery, medical management with angioplasty, and angioplasty with surgery. Data from the medical versus revascularization trials (either surgery or angioplasty) support the following contentions: For patients with multivessel disease, particularly involving the proximal left anterior descending coronary artery, survival is superior to surgical treatment. Symptom relief with either type of revascularization is superior to medical management. The subsequent rate of myocardial infarction is not affected by the initial treatment strategy, whether medical, angioplasty, or surgery. In individual patients the potential benefits of any revascularization strategy must be weighed against its initial risks. Further study is needed, particularly with multifaceted pharmacologic therapy and with updated angioplasty techniques, to evaluate relative survival benefits in these patients. The studies supporting these conclusions are highlighted in this paper.

The benefit of abciximab in percutaneous coronary revascularization is not device-specific

Abciximab has been shown to decrease adverse outcomes after percutaneous coronary interventions, but it is unclear whether this beneficial effect is more or less pronounced with specific devices. This study sought to determine the relative magnitude of the benefit of abciximab among different interventional devices. Data from the 5 placebo-controlled trials of abciximab during coronary intervention were pooled. Patients were divided into groups based on whether they received balloon angioplasty alone, elective stenting, bailout stenting, or directional coronary atherectomy. In the patients undergoing balloon angioplasty, the 30-day hazard ratio for death or myocardial infarction (MI) in the group randomized to abciximab versus the placebo-treated group was 0.52 (p <0.001), for elective stenting the hazard ratio was 0.51 (p <0.001), for bailout stenting the hazard ratio was 0.38 (p <0.001), and for directional coronary atherectomy the hazard ratio was 0.38 (p = 0.007). A Cox proportional-hazards model revealed that overall, the use of abciximab decreased the composite end point of 30-day death or MI rates (hazard ratio 0.55, 95% confidence interval 0.43 to 0.69, p <0.001). However, bailout stenting and directional coronary atherectomy were associated with increased rates of death or MI compared with balloon angioplasty, as was elective stenting in women compared with men. There was no significant increase in major bleeding episodes associated with abciximab in any of the device categories. These findings from all the controlled coronary revascularization trials using abciximab demonstrate that a decrease in death and MI is achieved with abciximab regardless of the type of device used, without an increase in significant bleeding complications.