On clinical trial fragility due to patients lost to follow up

Wells ′ research was partially supported by NIH grant U19 AI111143, PCORI IHS-2017C3-8923, and Cornell’s Center for the Social Sciences project on Algorithms, Big Data, and Inequality.Background Clinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification. Methods We reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial’s statistical results with respect to patients lost to follow up. Results The analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness. Conclusions The LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.Peer reviewe

Disagreement Between Randomized and Observational Evidence on the Use of Bilateral Internal Thoracic Artery Grafting:A Meta-Analytic Approach

Background The ART (Arterial Revascularization Trial) showed no difference in survival at 10 years between patients assigned to the single versus bilateral internal thoracic artery grafting strategies. This finding is in contrast with the results of most observational studies, where the use of 2 internal thoracic arteries has been associated with improved survival. Methods and Results We selected propensity-matched studies from the most comprehensive observational meta-analysis on the long-term outcomes of patients receiving 1 versus 2 internal thoracic arteries. Individual participant survival data from each study and the ART were reconstructed using an iterative algorithm that was applied to solve the Kaplan-Meier equations. The reconstructed individual participant survival data were aggregated to obtain combined survival curves and Cox regression hazard ratios with 95% CIs. Individual participant survival data were obtained from 14 matched observational studies (24 123 patients) and the ART. The 10-year survival of the control group of ART was significantly higher than that of the matched observational studies (hazard ratio, 0.86; 95% CI, 0.80-0.93). The 10-year survival of the experimental group of ART was significantly lower than that of the bilateral internal thoracic artery group of the observational studies (hazard ratio, 1.11; 95% CI, 1.03-1.20). Conclusions Both the improved outcome of the control arm and the lower beneficial effect of the intervention had played a role in the difference between observational evidence and ART

Decision analysis in cardiac surgery:a scoping review and methodological primer

OBJECTIVES: Randomized controlled trials are the gold standard for evidence generation in medicine but are limited by their real-world generalizability, resource needs, shorter follow-up durations and inability to be conducted for all clinical questions. Decision analysis (DA) models may simulate trials and observational studies by using existing data and evidence- and expert-informed assumptions and extend analyses over longer time horizons, different study populations and specific scenarios, helping to translate population outcomes to patient-specific clinical and economic outcomes. Here, we present a scoping review and methodological primer on DA for cardiac surgery research. METHODS: A scoping review was performed using the PubMed/MEDLINE, EMBASE and Web of Science databases for cardiac surgery DA studies published until December 2021. Articles were summarized descriptively to quantify trends and ascertain methodological consistency.RESULTS: A total of 184 articles were identified, among which Markov models (N = 92, 50.0%) were the most commonly used models. The most common outcomes were costs (N = 107, 58.2%), quality-adjusted life-years (N = 96, 52.2%) and incremental cost-effectiveness ratios (N = 89, 48.4%). Most (N = 165, 89.7%) articles applied sensitivity analyses, most frequently in the form of deterministic sensitivity analyses (N = 128, 69.6%). Reporting of guidelines to inform the model development and/or reporting was present in 22.3% of articles. CONCLUSION: DA methods are increasing but remain limited and highly variable in cardiac surgery. A methodological primer is presented and may provide researchers with the foundation to start with or improve DA, as well as provide readers and reviewers with the fundamental concepts to review DA studies.</p

The role of vessel wall physiology in predicting coronary bypass graft patency

Not applicable

Are stentless valves hemodynamically superior to stented valves? Long-term follow-up of a randomized trial comparing Carpentier–Edwards pericardial valve with the Toronto Stentless Porcine Valve

ObjectiveThe benefit of stentless valves remains in question. In 1999, a randomized trial comparing stentless and stented valves was unable to demonstrate any hemodynamic or clinical benefits at 1 year after implantation. This study reviews long-term outcomes of patients randomized in the aforementioned trial.MethodsBetween 1996 and 1999, 99 patients undergoing aortic valve replacement were randomized to receive either a stented Carpentier–Edwards pericardial valve (CE) (Edwards Lifesciences, Irvine, Calif) or a Toronto Stentless Porcine Valve (SPV) (St Jude Medical, Minneapolis, Minn). Among these, 38 patients were available for late echocardiographic follow-up (CE, n = 17; SPV, n = 21). Echocardiographic analysis was undertaken both at rest and with dobutamine stress, and functional status (Duke Activity Status Index) was compared at a mean of 9.3 years postoperatively (range, 7.5–11.1 years). Clinical follow-up was 82% complete at a mean of 10.3 years postoperatively (range, 7.5–12.2 years).ResultsPreoperative characteristics were similar between groups. Effective orifice areas increased in both groups over time. Although there were no differences in effective orifice areas at 1 year, at 9 years, effective orifice areas were significantly greater in the SPV group (CE, 1.49 ± 0.59 cm2; SPV, 2.00 ± 0.53 cm2; P = .011). Similarly, mean and peak gradients decreased in both groups over time; however, at 9 years, gradients were lower in the SPV group (mean: CE, 10.8 ± 3.8 mm Hg; SPV, 7.8 ± 4.8 mm Hg; P = .011; peak: CE, 20.4 ± 6.5 mm Hg; SPV, 14.6 ± 7.1 mm Hg; P = .022). Such differences were magnified with dobutamine stress (mean: CE, 22.7 ± 6.1 mm Hg; SPV, 15.3 ± 8.4 mm Hg; P = .008; peak: CE, 48.1 ± 11.8 mm Hg; SPV, 30.8 ± 17.7 mm Hg; P = .001). Ventricular mass regression occurred in both groups; however, no differences were demonstrated between groups either on echocardiographic, magnetic resonance imaging, or biochemical (plasma B-type [brain] natriuretic peptide) assessment (P = .74). Similarly, Duke Activity Status Index scores of functional status improved in both groups over time; however, no differences were noted between groups (CE, 27.5 ± 19.1; SPV, 19.9 ± 12.0; P = .69). Freedom from reoperation at 12 years was 92% ± 5% in patients with CEs and 75% ± 5% in patients with SPVs (P = .65). Freedom from valve-related morbidity at 12 years was 82% ± 7% in patients with CEs and 55% ± 7% in patients with SPVs (P = .05). Finally, 12-year actuarial survival was 35% ± 7% in patients with CEs and 52% ± 7% in patients with SPVs (P = .37).ConclusionAlthough offering improved hemodynamic outcomes, the SPV did not afford superior mass regression or improved clinical outcomes up to 12 years after implantation

A randomized comparison of intraoperative indocyanine green angiography and transit-time flow measurement to detect technical errors in coronary bypass grafts

BackgroundEarly coronary bypass graft failures may be preventable if identified intraoperatively. The purpose of this investigation was to compare the diagnostic accuracy of two intraoperative graft assessment techniques, transit-time ultrasound flow measurement and indocyanine green fluorescent-dye graft angiography.MethodsPatents undergoing isolated coronary artery bypass grafting with no contraindications for postoperative angiography were enrolled in the study. Patients were randomly assigned to be evaluated with either indocyanine green angiography (Novadaq Spy angiography system; Novadaq Technologies Inc, Concord, Ontario, Canada) and then transit-time ultrasonic flow measurement (Medtronic Medi-Stim Butterfly Flowmeter TTF measurement system; Medtronic Inc, Minneapolis, Minn) or transit-time flow then indocyanine green angiography. Patients underwent x-ray angiography on postoperative day 4. The primary end point of the trial was to determine the sensitivity and specificity of the two techniques versus reference standard x-ray angiography to detect graft occlusion or greater than 50% stenosis in the graft or perianastomotic area.ResultsBetween February 2004 and March 2005, 106 patients were enrolled and x-ray angiography was performed in 46 patients. In total, 139 grafts were reviewed with all three techniques and 12 grafts (8.2%) were demonstrated to have greater than 50% stenosis or occlusion by the reference standard. The sensitivity and specificity of indocyanine green angiography to detect greater than 50% stenosis or occlusion was 83.3% and 100%, respectively. The sensitivity and specificity of transit-time ultrasonic flow measurement to detect greater than 50% stenosis or occlusion was 25% and 98.4%, respectively. The P value for the overall comparison of sensitivity and specificity between indocyanine green angiography and transit-time flow ultrasonography was .011. The difference between sensitivity for indocyanine green angiography and transit-time flow measurement was 58% with a 95% confidence interval of 30% to 86%, P = .023.ConclusionIndocyanine green angiography provides better diagnostic accuracy for detecting clinically significant graft errors than does transit-time ultrasound flow measurement

Validating the SMART2 Score in a Racially Diverse High-Risk Nationwide Cohort of Patients Receiving Coronary Artery Bypass Grafting

Background We tested the potential of the Secondary Manifestations of Arterial Disease (SMART2) risk score for use in patients undergoing coronary artery bypass grafting. Methods and Results We conducted an external validation of the SMART2 score in a racially diverse high-risk national cohort (2010-2019) that underwent isolated coronary artery bypass grafting. We calculated the preoperative SMART2 score and modeled the 5-year major adverse cardiovascular event (cardiovascular mortality+myocardial infarction+stroke) incidence. We evaluated SMART2 score discrimination at 5 years using c-statistic and calibration with observed/expected ratio and calibration plots. We analyzed the potential clinical benefit using decision curves. We repeated these analyses in clinical subgroups, diabetes, chronic kidney disease, and polyvascular disease, and separately in White and Black patients. In 27 443 (mean age, 65 years; 10% Black individuals) US veterans undergoing coronary artery bypass grafting (2010-2019) nationwide, the 5-year major adverse cardiovascular event rate was 25%; 27% patients were in high predicted risk (>30% 5-year major adverse cardiovascular events). SMART2 score discrimination (c-statistic: 64) was comparable to the original study (c-statistic: 67) and was best in patients with chronic kidney disease (c-statistic: 66). However, it underpredicted major adverse cardiovascular event rates in the whole cohort (observed/expected ratio, 1.45) as well as in all studied subgroups. The SMART2 score performed better in White than Black patients. On decision curve analysis, the SMART2 score provides a net benefit over a wide range of risk thresholds. Conclusions The SMART2 model performs well in a racially diverse coronary artery bypass grafting cohort, with better predictive capabilities at the upper range of baseline risk, and can therefore be used to guide secondary preventive pharmacotherapy