Statistical primer: basics of survival analysis for the cardiothoracic surgeon.

Survival analysis incorporates various statistical methods specific to data on time until an event of interest. While the event is often death, giving rise to the phrase 'survival analysis', the event might also be, for example, a reoperation. As such, it is sometimes referred to as 'time-to-event analysis'. Censoring sets survival analysis apart from other analyses: at the end of the follow-up period, not all subjects have experienced the event of interest, and some subjects may drop out of the study prior to completion. Survival data for a group of subjects is usually visualized by the Kaplan-Meier estimator, representing the probability of a subject remaining free of the event during follow-up. There are several methods to compare survival between the study groups, for example, treatment arms, including the log-rank test and the Cox proportional hazards model. The log-rank test is an unadjusted non-parametric method, whereas the Cox proportional hazards model allows comparison while adjusting for multiple covariates. A principal assumption of the Cox proportional hazards model is that the relative hazard stays constant over time-the so-called proportionality. Specific methods exist for comparison of survival with the general population. This article describes the fundamental concepts every cardiothoracic surgeon should be aware of when analysing survival data and are illustrated with a clinical example.

Statistical primer: a cost-effectiveness analysis.

Cost-effectiveness analyses (CEAs) of new treatment strategies are increasingly reported. This can be a part of a clinical trial or as a separate study. Governments and healthcare payers frequently require a CEA to decide whether a new treatment strategy will be reimbursed. CEA is a framework to assess the effectiveness and costs of a new treatment strategy (e.g. a drug or intervention) when compared with a reference strategy. Effectiveness is often measured in life-years or quality-adjusted life-years, whereas costs consist of direct costs (the costs of the treatment), induced costs (downstream costs and cost offsets) and indirect costs. In this statistical primer, the rationale for assessing the economic consequences of new therapies is explained, followed by the fundamental concepts of CEAs, the different types of CEAs and an introduction to interpretation of CEAs. Finally, a real-world example of a CEA is discussed, comparing cost-effectiveness of transcatheter versus surgical aortic valve replacement in patients with severe aortic stenosis at intermediate surgical risk.

Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections.

Aims: The number of transcatheter aortic valve implantation (TAVI) procedures is rapidly increasing. This has a major impact on health care resource planning. However, the annual numbers of TAVI candidates per country are unknown. The aim of this study was to estimate current and future number of annual TAVI candidates in 27 European countries, the USA and Canada. Methods and results: Systematic literature searches and meta-analyses were performed on aortic stenosis (AS) epidemiology and decision-making in severe symptomatic AS. The incidence rate of severe AS was determined. Findings were combined with population statistics and integrated into a model employing Monte Carlo simulations to predict the annual number of TAVI candidates. Various future scenarios and sensitivity analyses were explored. Data from 37 studies (n = 26 402) informed the model. The calculated incidence rate of severe AS was 4.4‰/year [95% confidence interval (95% CI) 3.0-6.1‰] in patients ≥65 years. AS-related symptoms were present in 68.3% (95% CI 60.8-75.9%) of patients with severe AS. Despite having severe symptomatic AS, 41.6% (95% CI 36.9-46.3%) did not undergo surgical aortic valve replacement. Of the non-operated patients, 61.7% (95% CI 42.0-81.7%) received TAVI. The model predicted 114 757 (95% CI 69 380-172 799) European and 58 556 (95% CI 35 631-87 738) Northern-American TAVI candidates annually. Conclusion: Currently, approximately 180 000 patients can be considered potential TAVI candidates in the European Union and in Northern-America annually. This number might increase up to 270 000 if indications for TAVI expand to low-risk patients. These findings have major implications for health care resource planning in the 29 individual countries.

Long-term outlook for transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) revolutionized the treatment of severe symptomatic aortic stenosis (AS). TAVR is increasingly offered for lower-risk patients. The role and place of TAVR in the future treatment of AS is not clear yet. In this review, we discuss the long-term outlook for TAVR, its challenges and its relationship to conventional surgical aortic valve replacement.

Quality of Life After Surgery or DES in Patients With 3-Vessel or Left Main Disease.

BACKGROUND: In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, patients with 3-vessel or left main coronary artery disease (CAD) had improved long-term outcomes with coronary artery bypass graft (CABG) surgery compared with percutaneous coronary intervention (PCI) with drug-eluting stents (DES), improvements driven mainly by differences in myocardial infarction and repeat revascularization. OBJECTIVES: This study compared the long-term quality-of-life benefits of DES-PCI versus CABG for patients with 3-vessel or left main CAD. METHODS: Between 2005 and 2007, the SYNTAX trial randomized 1,800 patients with 3-vessel or left main CAD to either CABG or DES-PCI. Health status was assessed at baseline and at 1, 6, 12, 36, and 60 months by using the Seattle Angina Questionnaire (SAQ) and the 36-Item Short Form Health Survey. RESULTS: At 5-year follow-up, CABG was superior to DES-PCI on several SAQ domains including angina frequency and physical function, as well as the role physical and role emotional scales of the 36-Item Short Form Health Survey. Subgroup analysis demonstrated a significant interaction between angiographic complexity (as assessed by the SYNTAX score) and angina relief (mean difference in the SAQ angina frequency score for CABG vs. PCI of -0.9, 3.3, and 3.9 points for low, intermediate, and high SYNTAX score patients, respectively; p = 0.048 for interaction). CONCLUSIONS: Among patients with 3-vessel or left main CAD, both CABG and DES-PCI were associated with substantial and sustained quality-of-life benefits over 5 years of follow-up. In general, CABG resulted in greater angina relief, although the absolute treatment benefit was small. Angina relief at 5 years was enhanced with CABG among patients with high SYNTAX scores, a finding reinforcing the recommendation that CABG should be strongly preferred for such patients. (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery [SYNTAX]; NCT00114972).

Cost-effectiveness of percutaneous coronary intervention versus bypass surgery from a Dutch perspective.

AIMS: Recent cost-effectiveness analyses of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) have been limited by a short time horizon or were restricted to the US healthcare perspective. We, therefore, used individual patient-level data from the SYNTAX trial to evaluate the cost-effectiveness of PCI versus CABG from a European (Dutch) perspective. METHODS AND RESULTS: Between 2005 and 2007, 1800 patients with three-vessel or left main coronary artery disease were randomised to either CABG (n=897) or PCI with drug-eluting stents (DES; n=903). Costs were estimated for all patients based on observed healthcare resource usage over 5 years of follow-up. Health state utilities were evaluated with the EuroQOL questionnaire. A patient-level microsimulation model based on Dutch life-tables was used to extrapolate the 5-year in-trial data to a lifetime horizon. Although initial procedural costs were lower for CABG, total initial hospitalisation costs per patient were higher (€17 506 vs €14 037, p<0.001). PCI was more costly during the next 5 years of follow-up, due to more frequent hospitalisations, repeat revascularisation procedures and higher medication costs. Nevertheless, total 5-year costs remained €2465/patient higher with CABG. When the in-trial results were extrapolated to a lifetime horizon, CABG was projected to be economically attractive relative to DES-PCI, with gains in both life expectancy and quality-adjusted life expectancy. The incremental cost-effectiveness ratio (ICER) (€5390/quality-adjusted life year (QALY) gained) was favourable and remained <€80 000/QALY in >90% of the bootstrap replicates. Outcomes were similar when incorporating the prognostic impact of non-fatal myocardial infarction and stroke, as well as across a broad range of assumptions regarding the effect of CABG on post-trial survival and costs. However, DES-PCI was economically dominant compared with CABG in patients with a SYNTAX Score ≤22 or in those with left main disease. In patients for whom the SYNTAX Score II favoured PCI based on lower predicted 4-year mortality, PCI was also economically dominant, whereas in those patients for whom the SYNTAX Score II favoured surgery, CABG was highly economically attractive (ICER range, €2967 to €3737/QALY gained). CONCLUSIONS: For the broad population with three-vessel or left main disease who are candidates for either CABG or PCI, we found that CABG is a clinically and economically attractive revascularisation strategy compared with DES-PCI from a Dutch healthcare perspective. The cost-effectiveness of CABG versus PCI differed according to several anatomic factors, however. The newly developed SYNTAX Score II provides enhanced prognostic discrimination in this population, and may be a useful tool to guide resource allocation as well. TRIAL REGISTRATION NUMBER: Clinical trial unique identifier: NCT00114972 (http://www.clinical-trials.gov).

Health status after transcatheter aortic valve replacement in patients at extreme surgical risk: results from the CoreValve U.S. trial.

OBJECTIVES: The purpose of this study was to characterize health status outcomes after transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis among patients at extreme surgical risk and to identify pre-procedural patient characteristics associated with a poor outcome. BACKGROUND: For many patients considering TAVR, improvement in quality of life may be of even greater importance than prolonged survival. METHODS: Patients with severe, symptomatic aortic stenosis who were considered to be at prohibitive risk for surgical aortic valve replacement were enrolled in the single-arm CoreValve U.S. Extreme Risk Study. Health status was assessed at baseline and at 1, 6, and 12 months after TAVR using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Short Form-12, and the EuroQol-5D. The overall summary scale of the KCCQ (range 0 to 100; higher scores = better health) was the primary health status outcome. A poor outcome after TAVR was defined as death, a KCCQ overall summary score (OS) <45, or a decline in KCCQ-OS of 10 points at 6-month follow-up. RESULTS: A total of 471 patients underwent TAVR via the transfemoral approach, of whom 436 (93%) completed the baseline health status survey. All health status measures demonstrated considerable impairment at baseline. After TAVR, there was substantial improvement in both disease-specific and generic health status measures, with an increase in the KCCQ-OS of 23.9 points (95% confidence interval [CI]: 20.3 to 27.5 points) at 1 month, 27.4 points (95% CI: 24.2 to 30.6 points) at 6 months, 27.4 points (95% CI: 24.1 to 30.8 points) at 12 months, along with substantial increases in Short Form-12 scores and EuroQol-5D utilities (all p < 0.003 compared with baseline). Nonetheless, 39% of patients had a poor outcome after TAVR. Baseline factors independently associated with poor outcome included wheelchair dependency, lower mean aortic valve gradient, prior coronary artery bypass grafting, oxygen dependency, very high predicted mortality with surgical aortic valve replacement, and low serum albumin. CONCLUSIONS: Among patients with severe aortic stenosis, TAVR with a self-expanding bioprosthesis resulted in substantial improvements in both disease-specific and generic health-related quality of life, but there remained a large minority of patients who died or had very poor quality of life despite TAVR. Predictive models based on a combination of clinical factors as well as disability and frailty may provide insight into the optimal patient population for whom TAVR is beneficial. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902).

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users.

We systematically investigated how 11 overlapping meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel could yield contradictory outcomes. The results of the meta-analyses differed because more recent meta-analyses included more primary studies and some had not included conference abstracts. Conclusions differed because between-study heterogeneity and publication bias were handled differently across meta-analyses. All meta-analyses on the clinical end point observed significant heterogeneity and several reported evidence for publication bias, but only one out of eight statistically significant meta-analyses concluded that therefore the association was unproven and one other refrained from quantifying a pooled estimate because of heterogeneity. For the end point stent thrombosis, all meta-analyses reported statistically significant associations with CYP2C19 loss-of-function alleles with no statistically significant evidence for heterogeneity, but only three had investigated publication bias and also found evidence for it. One study therefore concluded that there was no evidence for an association, and one other doubted the association because of a high level of heterogeneity. In summary, meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel differed widely with regard to assessment and interpretation of heterogeneity and publication bias. The substantial heterogeneity and publication bias implies that personalized antiplatelet management based on genotyping is not supported by the currently available evidence.Genet Med advance online publication 19 June 2014.

Role of percutaneous coronary intervention in the treatment of left main coronary artery disease.

Revascularization with coronary artery bypass graft surgery is the choice of therapy in patients with left main (LM) coronary artery stenosis. During the last decade, the introduction of drug-eluting stents, together with antiplatelet and antithrombotic treatments, has improved the outcome of percutaneous coronary interventions (PCIs) by reducing the number of repeat revascularizations and the risk of stent thrombosis. Many institutions inside and outside the United States have adopted stent treatment of unprotected LM coronary artery disease as a more routine strategy. However, coronary bypass surgery has improved as well by using more arterial grafts, better perioperative care, and optimizing medical treatment postoperatively. The advances in stent technique may reduce the gap between coronary surgery and PCIs further, but the results of the Evaluation of Xience Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization study, randomizing patients with LM coronary artery disease between coronary bypass grafting and PCIs, will be needed to test whether PCIs is noninferior to coronary bypass surgery.

Patient selection for TAVI in 2014: is there a justification for treating low- or intermediate-risk patients? The surgeon's view.

The introduction of transcatheter aortic valve implantation (TAVI) has revolutionised the treatment of patients with symptomatic severe aortic valve stenosis (AS). In extreme and high-risk patients, randomised studies have shown the benefit of this new therapy. However, there are still a lot of unknowns, and the question has arisen whether it is justified to expand the indication of TAVI to other patient groups, especially intermediate-or even low-risk patients.

Cost, quality, and value in coronary artery bypass grafting.

OBJECTIVE: Pay-for-performance measures, part of the Affordable Care Act, aim to reduce health care costs by linking value with Medicare payments, but until now the concept of value has not been applied to specific procedures. We sought to define value in coronary artery bypass grafting (CABG) and provide a framework to identify high-value centers. METHODS: In a multiinstitutional statewide database, clinical patient-level data from 42,839 patients undergoing CABG were matched with cost data. Hierarchical models adjusting for relevant preoperative patient characteristics and comorbidities were used to estimate center-specific risk-adjusted costs and risk-adjusted postoperative length of stay. Variation in value across centers was assessed by the correlation between risk-adjusted measures of quality (mortality, morbidity/mortality) and resource use (costs and length of stay). RESULTS: There were no significant correlations between risk-adjusted costs and risk-adjusted mortality (r = 0.20, P = .45) or morbidity/mortality (r = 0.15, P = .57) across centers. Risk-adjusted costs and length of stay were not significantly associated (r = 0.23, P = .37) because of cost accounting differences across centers. This may explain the lack of correlation between risk-adjusted quality and risk-adjusted cost measures. When risk-adjusted length of stay and morbidity/mortality were used for the framework, there was a strong positive correlation (r = 0.67, P = .003), indicating that higher risk-adjusted quality is associated with shorter risk-adjusted length of stay. CONCLUSIONS: Risk-adjusted length of stay and risk-adjusted combined morbidity/mortality are important outcome measures for assessing value in cardiac surgery. The proposed framework can be used to define value in CABG and identify high-value centers, thereby providing information for quality improvement and pay-for-performance initiatives.

Prediction of costs and length of stay in coronary artery bypass grafting.

BACKGROUND: Although more than 200,000 bypass operations are performed in the United States annually, few data exist on the predictors of costs and resource use for this procedure. Questions related to clinical outcomes, costs, and resource use in coronary artery bypass grafting (CABG) were addressed. METHODS: In a multiinstitutional statewide database, patient level data from 42,839 patients undergoing isolated CABG were combined with cost data. After adjustment for cost-to-charge ratios and inflation, the association of length of stay and costs with the Society of Thoracic Surgeons-Predicted Risk of Mortality (STS-PROM) was analyzed. Patients were randomly divided into development (60%) and validation (40%) cohorts. Regression models were developed to analyze the impact of patient characteristics, comorbidities, and adverse events on postoperative length of stay and total costs. RESULTS: Postoperative length of stay and total direct costs for CABG averaged 6.9 days and $38,847. Length of stay and costs increased from 5.4 days and $33,275 in the lowest-risk decile (mean STS-PROM of 0.6%) to 13.8 days and $69,122 in the highest-risk decile (mean STS-PROM 19%). Compared with adverse events, patient characteristics had little impact on length of stay and costs. on validation, the models that combined preoperative and postoperative variables explained variance better (R(2) = 0.51 for length of stay; R(2) = 0.47 for costs) and were better calibrated than the preoperative models (R(2) = 0.10 for length of stay; R(2) = 0.14 for costs). CONCLUSIONS: The STS-PROM and preoperative regression models are useful for preoperative prediction of costs and length of stay for groups of patients, case-mix adjustment in hospital benchmarking, and pay for performance measures. The combined preoperative and postoperative models identify incremental costs and length of stay associated with adverse events and are more suitable for prioritizing quality improvement efforts.

Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with 3-vessel or left main coronary artery disease: final results from the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial.

BACKGROUND: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial demonstrated that in patients with 3-vessel or left main coronary artery disease, coronary artery bypass graft surgery (CABG) was associated with a lower rate of cardiovascular death, myocardial infarction, stroke, or repeat revascularization compared with percutaneous coronary revascularization with drug-eluting stents (DES-PCI)). The long-term cost-effectiveness of these strategies is unknown. METHODS AND RESULTS: Between 2005 and 2007, 1800 patients with left main or 3-vessel coronary artery disease were randomized to CABG (n=897) or DES-PCI (n=903). Costs were assessed from a US perspective, and health state utilities were evaluated with the EuroQOL questionnaire. A patient-level microsimulation model based on the 5-year in-trial data was used to extrapolate costs, life expectancy, and quality-adjusted life expectancy over a lifetime horizon. Although initial procedural costs were $3415 per patient lower with CABG, total hospitalization costs were $10 036 per patient higher. Over the next 5 years, follow-up costs were higher with DES-PCI as a result of more frequent hospitalizations, revascularization procedures, and higher medication costs. Over a lifetime horizon, CABG remained more costly than DES-PCI, but the incremental cost-effectiveness ratio was favorable ($16 537 per quality-adjusted life-year gained) and remained <$20 000 per quality-adjusted life-year in most bootstrap replicates. Results were consistent across a wide range of assumptions about the long-term effect of CABG versus DES-PCI on events and costs. In patients with left main disease or a SYNTAX score ≤22, however, DES-PCI was economically dominant compared with CABG, although these findings were less certain. CONCLUSIONS: For most patients with 3-vessel or left main coronary artery disease, CABG is a clinically and economically attractive revascularization strategy compared with DES-PCI. However, among patients with less complex disease, DES-PCI may be preferred on both clinical and economic grounds. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT00114972.

Influence of diabetes mellitus on long-term clinical and economic outcomes after coronary artery bypass grafting.

BACKGROUND: China has the most patients with diabetes mellitus (DM) in the world and, annually, approximately 1 million Chinese become diabetic. We investigated both clinical and economic outcomes in a large Chinese cohort of diabetic patients undergoing coronary artery bypass graft surgery (CABG). METHODS: All 9,240 consecutive patients who underwent isolated, primary, elective CABG between January 1999 and December 2008 were included and analyzed for long-term major adverse cardiovascular and cerebrovascular events and economic outcomes up to 2 years after the procedure. The DM patients were divided into DM subgroups controlled by diet (n = 375), medication (n = 1,826) or insulin (n = 481). RESULTS: During the study period, the proportion of patients undergoing CABG who have DM increased from 20.1% to 31.8% in China. None of the DM subgroups was independently associated with in-hospital death, but DM was an independent predictor for long-term major adverse cardiovascular and cerebrovascular events (hazard ratio 1.29, 95% confidence interval: 1.14 to 1.46). Medically controlled DM and insulin-dependent DM, but not diet-controlled DM were independent predictors of long-term outcomes after CABG. Cost for initial hospitalization was higher for DM patients (76,782 Ren Min Bi [RMB] versus 65,521 RMB, respectively; p < 0.001). At 2 years after CABG, costs for DM patients were 11,261 RMB (approximately US $1,623) higher than for non-DM patients (p < 0.001). CONCLUSIONS: CABG for patients with DM was significantly more expensive and was associated with worse long-term outcomes compared with non-DM patients. The rising incidence of DM, combined with the significant incremental costs represents significant clinical, economic, and social challenges for the Chinese healthcare system.