Dealing With Nonproportional Hazards in Coronary Revascularisation Studies.

The Cox proportional hazards model is one of the most popular statistical tools to model time to event outcomes without the need for specifying the hazards or survival time distributions. The Cox model requires that the ratio of the hazards of the occurrence of the outcome for any 2 individuals remains constant during the entire follow-up. Studies comparing coronary revascularisation strategies, however, might be prone to violations of proportionality by the crossing of the hazard functions over time. Early increases in the risk of cardiovascular outcomes are commonly observed when comparing coronary artery bypass grafting vs percutaneous coronary intervention, whereas decreased risk might be observed later during the follow-up. The same is valid for comparisons between invasive vs conservative coronary revascularisation strategies. In these situations, the statistical power of the Cox model is reduced, and hazard ratios might not be an informative summary measure of treatment effect. In this article, we discuss methods to identify and account for nonproportionality. We illustrate the use of these methods in a case study based on reconstructed data from a coronary revascularisation clinical trial. And finally, we review the cardiovascular literature to estimate how the proportionality assumption has been reported in coronary revascularisation studies recently.

Coronary atherosclerotic burden assessed by SYNTAX scores and outcomes in surgical, percutaneous or medical strategies: a retrospective cohort study.

INTRODUCTION: Coronary atherosclerotic burden and SYNTAX Score (SS) are predictors of cardiovascular events. OBJECTIVES: To investigate the value of SYNTAX scores (SS, SYNTAX Score II (SSII) and residual SYNTAX Score (rSS)) for predicting cardiovascular events in patients with coronary artery disease (CAD). DESIGN: Retrospective cohort study. SETTING: Single tertiary centre. PARTICIPANTS: Medicine, Angioplasty or Surgery Study database patients with stable multivessel CAD and preserved ejection fraction. INTERVENTIONS: Patients with CAD undergoing coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or medical treatment (MT) alone from January 2002 to December 2015. PRIMARY AND SECONDARY OUTCOMES: Primary: 5-year all-cause mortality. Secondary: composite of all-cause death, myocardial infarction, stroke and subsequent coronary revascularisation at 5 years. RESULTS: A total of 1719 patients underwent PCI (n=573), CABG (n=572) or MT (n=574) alone. The SS was not considered an independent predictor of 5-year mortality in the PCI (low, intermediate and high SS at 6.5%, 6.8% and 4.3%, respectively, p=0.745), CABG (low, intermediate and high SS at 5.7%, 8.0% and 12.1%, respectively, p=0.194) and MT (low, intermediate and high SS at 6.8%, 6.9% and 6.5%, respectively, p=0.993) cohorts. The SSII (low, intermediate and high SSII at 3.6% vs 7.9% vs 10.5%, respectively, p<0.001) was associated with a higher mortality risk in the overall population. Within each treatment strategy, SSII was associated with a significant 5-year mortality rate, especially in CABG patients with higher SSII (low, intermediate and high SSII at 1.8%, 9.7% and 10.0%, respectively, p=0.004) and in MT patients with high SSII (low, intermediate and high SSII at 5.0%, 4.7% and 10.8%, respectively, p=0.031). SSII demonstrated a better predictive accuracy for mortality compared with SS and rSS (c-index=0.62). CONCLUSIONS: Coronary atherosclerotic burden alone was not associated with significantly increased risk of all-cause mortality. The SSII better discriminates the risk of death. TRIAL REGISTRATION NUMBER: ISRCTN66068876.

Outcomes with revascularization and medical therapy in patients with coronary disease and chronic kidney disease: A meta-analysis.

BACKGROUND AND AIMS: Chronic kidney disease (CKD) confers a high risk for poor cardiovascular outcomes. We conducted a systematic review and meta-analysis to estimate the effects of revascularization as the initial management strategy compared with medical therapy among patients with CKD and coronary artery disease. METHODS: A Medline/PubMed literature research was conducted to identify randomized studies comparing early coronary revascularization with optimal medical therapy or medical therapy alone in patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 or maintenance dialysis). The primary outcome was myocardial infarction. The secondary outcomes were all-cause mortality or progression to kidney failure. The risk ratio (RR) was estimated using a random-effects model. RESULTS: Eleven randomized trials were included (3422 patients). Revascularization was associated with lower incidence of myocardial infarction compared with medical therapy in patients with CKD: RR 0.71 (95% confidence interval [CI] 0.54-0.94; p=0.02). This result was mainly driven from a significantly lower incidence of myocardial infarction with early revascularization among patients with stable coronary artery disease: RR 0.59; 95% CI 0.37-0.93. A similar incidence of all-cause mortality was observed with both treatment strategies: RR 0.88 (95% CI 0.72-1.08; p=0.22). A trend towards lower incidence of all-cause mortality was observed with revascularization in the subgroup of patients presenting with NSTE-ACS: RR 0.73 (95% CI 0.51-1.04; p=0.08) but not among patients with stable coronary disease. There was no difference in progression to kidney failure between the two strategies. CONCLUSIONS: Coronary revascularization may be superior to medical therapy among patients with CKD and coronary disease.

Revascularization Strategies in Patients with Diabetes and Acute Coronary Syndromes.

PURPOSE OF REVIEW: To review the current evidence for coronary revascularization in patients with diabetes mellitus (DM) in the setting of an acute coronary syndrome (ACS). RECENT FINDINGS: In patients with DM and stable multivessel ischemic heart disease, coronary artery bypass graft surgery (CABG) has been observed to be superior to percutaneous coronary intervention (PCI) in long-term follow-up, leading to lower rates of all-cause mortality, myocardial infarction, and repeat revascularization. In the ACS setting, PCI remains the most frequently performed procedure. In patients with an ST-segment-elevation myocardial infarction (STEMI), primary PCI should be the revascularization method of choice, whenever feasible. Controversy still exists regarding when and how to deal with possible residual lesions. In the non-ST-segment-elevation (NSTE) ACS setting, although there are no data from randomized controlled trials (RCTs), recent observational data and sub-analyses of randomized studies have suggested that CABG may be the preferred approach for patients with DM and multivessel coronary disease. There is a paucity of RCTs evaluating revascularization strategies (PCI and CABG) in patients with DM and ACS. CABG may be a viable strategy, leading to improved outcomes, especially following NSTE-ACS.

Association between time to therapeutic INR and length of stay following mechanical heart valve surgery.

BACKGROUND: Warfarin is the only oral anticoagulant approved for use following mechanical valve surgery (MeVS). Patients may experience prolonged hospital length of stay (LOS) following MeVS awaiting an appropriate warfarin effect. We aimed to determine whether an association exists between time to achieve the first therapeutic international normalized ratio (INR) and LOS following MeVS. MATERIALS AND METHODS: Retrospective single center cohort study. We included consecutive adult patients undergoing elective MeVS from 2013 to 2018. Landmark analyses and multivariable regression with time-updated INR were used to estimate the association between time to therapeutic INR (TTI) and LOS. RESULTS: Among 384 patients (median age: 51 years, interquartile range [IQR]: 41-57; 58.3% male), the median TTI was 4 days (IQR: 2-5). Thirty seven percent of patients were discharged with a subtherapeutic INR, many on bridging anticoagulation or with an INR close to target. Those achieving therapeutic INR had an increased rate of hospital discharge (adjusted hazard ratio: 2.17; 95% confidence interval: 1.71-2.76; p < .0001). Attainment of a therapeutic INR anytime between postoperative Days 4 and 13 was significantly associated with a shorter LOS. CONCLUSIONS: Prolonged time to achieve a therapeutic INR was independently associated with prolonged LOS. Future strategies aimed at improving attainment of therapeutic INR following MeVS may reduce hospital LOS.

Association of Adverse Childhood Experiences With Cardiovascular Disease Later in Life: A Review.

Importance: Adverse childhood experiences (ACEs) are potentially harmful events that occur during childhood, spanning neglect, physical or sexual abuse, parental separation, or death, among others. At least 50% of the US adult population has experienced 1 or more ACEs before the age of 18 years, but in clinical practice, ACEs remain underrecognized. Adults who have experienced ACEs are at increased risk of developing health risk behaviors and, ultimately, cardiovascular disease (CVD). This review summarizes the evidence regarding the association of ACEs with CVD and the accompanying diagnostic and therapeutic approaches in the adult population. Observations: ACEs are commonly classified into 3 domains: abuse (psychological, physical, or sexual), household dysfunction (eg, substance use by household members, mental illness, parental separation), and neglect. These experiences elicit chronic activation of the stress response system, leading to autonomic, neuroendocrine, and inflammatory dysfunction. The subsequent development of traditional risk factors, such as diabetes, hypertension, smoking, and obesity, results in the onset of CVD and premature mortality. Adults with 4 or more ACEs compared with those with none have a more than 2-fold higher risk of developing CVD and an almost 2-fold higher risk of premature mortality. Conclusions and Relevance: Identifying methods of mitigating the health consequences of ACEs may lead to better cardiovascular outcomes. Inquiry into ACE exposure during clinical encounters and subsequent referral to psychological services when appropriate may be helpful, but strategies aimed at CVD prevention via management of ACEs in adults continue to lack adequate evidence.

ECG changes after non-cardiac surgery: a prospective observational study in intermediate-high risk patients.

BACKGROUND: Efforts to mitigate the risk for perioperative cardiac events focus on both patient's and operation's risk and often include a preprocedural electrocardiogram (ECG). The merits of postprocedural ECG for detection of occult cardiac events occurring during surgery are unknown. We aim to explore the incidence of pre, and new postprocedural ECG pathologies in an intermediate-high risk population undergoing non-cardiac surgery. METHODS: This single-center, prospective, observational study, included patients older than 18 years with at least two cardiovascular risk factors who were scheduled for non-cardiac surgery. All patients had pre, and postprocedural ECG. The ECG was analyzed and coded according to the Minnesota criteria. A multivariable logistic regression analysis was performed for indices associated with new postoperative ECG pathologies. RESULTS: A total of 217 patients were enrolled. Preoperative pathologic ECG changes were recorded in 62.2% of the patients. Postoperatively, new ECG pathologies were documented in 49.8% of patients, most commonly T-wave changes (36.4% of changes). Pathologic ECG changes at baseline (OR 3.15, 95% CI [1.61-6.17]; P<0.01), diabetes (OR 1.93, 95% CI [1.02-3.64]; P=0.04), history of ischemic heart disease (OR 2.14, 95% CI [1.03-4.47]; P=0.04), higher volumes of fluid replacement (OR 1.70, 95% CI [1.10-2.61]; P=0.01) and higher levels of preoperative hemoglobin (OR 1.24, 95% CI [1.04-1.47]; P=0.01) were all independently associated with postoperative ECG changes. CONCLUSIONS: Pre-, but most importantly, postoperative ECG changes are common in intermediate-high risk surgical patients. Postoperative ECG may be valuable to disclose silent cardiovascular events that occurred during surgery.

Influence of LDL-Cholesterol Lowering on Cardiovascular Outcomes in Patients With Diabetes Mellitus Undergoing Coronary Revascularization.

BACKGROUND: Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased cardiovascular events, especially in high-risk populations. OBJECTIVES: This study sought to evaluate the influence of LDL-C on the incidence of cardiovascular events either following a coronary revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or optimal medical therapy alone in patients with established coronary heart disease and type 2 diabetes (T2DM). METHODS: Patient-level pooled analysis of 3 randomized clinical trials was undertaken. Patients with T2DM were categorized according to the levels of LDL-C at 1 year following randomization. The primary endpoint was major adverse cardiac or cerebrovascular events ([MACCE] the composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke). RESULTS: A total of 4,050 patients were followed for a median of 3.9 years after the index 1-year assessment. Patients whose 1-year LDL-C remained ≥100 mg/dl experienced higher 4-year cumulative risk of MACCE (17.2% vs. 13.3% vs. 13.1% for LDL-C between 70 and <100 mg/dl and LDL-C <70 mg/dl, respectively; p = 0.016). When compared with optimal medical therapy alone, patients with PCI experienced a MACCE reduction only if 1-year LDL-C was <70 mg/dl (hazard ratio: 0.61; 95% confidence interval: 0.40 to 0.91; p = 0.016), whereas CABG was associated with improved outcomes across all 1-year LDL-C strata. In patients with 1-year LDL-C ≥70 mg/dl, patients undergoing CABG had significantly lower MACCE rates as compared with PCI. CONCLUSIONS: In patients with coronary heart disease with T2DM, lower LDL-C at 1 year is associated with improved long-term MACCE outcome in those eligible for either PCI or CABG. When compared with optimal medical therapy alone, PCI was associated with MACCE reductions only in those who achieved an LDL-C <70 mg/dl.

Weighing Coronary Revascularization Options in Patients With Type 2 Diabetes Mellitus.

Patients with diabetes mellitus (DM) are at increased risk for developing coronary artery disease. Choosing the optimal revascularization strategy, such as coronary artery bypass grafting or percutaneous coronary intervention (PCI), may be difficult in this population. A large body of evidence suggests that, for patients with DM and stable multivessel ischemic heart disease, coronary artery bypass grafting is usually superior to PCI, leading to lower rates of all-cause mortality, myocardial infarction and repeat revascularization in the long term. In patients with less complex coronary anatomy (2- or single-vessel disease, especially without involvement of the proximal left anterior descendent artery), PCI may be a viable option. Because these anatomic patterns are less frequent in patients with DM, there is less evidence to guide revascularization in these cases. Patients with DM and left main disease and those in the acute coronary syndrome setting are also underrepresented in randomized trials, and the best revascularization strategy for these patients is not clear. Once the revascularization procedure is performed, patients should be kept engaged in controlling the risk factors for progression of cardiovascular disease. Avoidance of smoking, control of cholesterol, blood pressure and glycemic levels; regular practice of physical activity of at least moderate intensity; and a balanced diet are of key importance in the post-revascularization period. In this study, we review the current literature in the management of patients with DM and coronary artery disease undergoing a revascularization procedure.

Urgent Revascularization Strategies in Patients With Diabetes Mellitus and Acute Coronary Syndrome.

The prevalence of diabetes mellitus (DM) is rising globally and in Canada. Besides being a risk factor for the development of coronary artery disease, DM is also a marker of poor prognosis in patients with acute coronary syndrome (ACS), increasing the risks for ischemic and bleeding complications. Patients with DM have a high prevalence of multivessel coronary artery disease (MVD) and robust evidence has supported coronary artery bypass surgery (CABG) as the optimal revascularization strategy in the setting of stable ischemic heart disease. In the acute scenario, particularly in patients with non-ST-segment elevation (NSTE) ACS (NSTE-ACS), there are many uncertainties regarding the best revascularization strategy. Most guidelines suggest an invasive and timely approach (that is, performing coronary catheterization within 72 hours after the onset of the NSTE-ACS) and make recommendations about choosing between percutaneous coronary intervention (PCI) or CABG on the basis of data for patients with stable ischemic heart disease. Recent observational and subgroup analyses suggest that CABG might be the preferential method of revascularization for patients with DM and MVD also in the NSTE-ACS setting; however, dedicated randomized clinical trials are lacking. Finally, in patients who present with an ST-segment elevation myocardial infarction, the initial revascularization method of choice is generally PCI, instead of fibrinolysis or CABG, and DM status most often does not influence this decision. The management of residual MVD after primary PCI for ST-segment elevation myocardial infarction, however, remains controversial.

The role of coronary artery bypass surgery versus percutaneous intervention in patients with diabetes and coronary artery disease.

Patients with diabetes mellitus (DM) often exhibit a complex coronary anatomy, making coronary revascularization challenging. Coronary artery bypass grafting surgery (CABG) is currently considered the preferred revascularization method in patients with DM and multivessel disease. Percutaneous coronary intervention (PCI) has advanced with new stent generations having been developed in the recent years, but they have not yet been adequately compared against CABG in the population with DM. Comorbidities, such as renal disease and heart failure, lead to worse prognosis following a revascularization procedure and require especial consideration when choosing between CABG versus PCI. The presence of significant left main disease may also impose additional challenges to coronary revascularization, particularly when accompanied by the involvement of multivessel disease. Most of the evidence regarding revascularization in patients with DM is compiled from studies enrolling patients with stable ischemic heart disease, and trials with patients in the acute coronary syndrome setting are lacking.

Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes: The FREEDOM Follow-On Study.

BACKGROUND: The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. OBJECTIVES: The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. METHODS: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. RESULTS: A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). CONCLUSIONS: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).