Tackling Challenges in Assessing the Economic Value of Tumor-Agnostic Therapies: A Cost-Effectiveness Analysis of Pembrolizumab as a Case Study.

OBJECTIVES: Assessing the value of tumor-agnostic drugs (TAD) is challenging given the potential variability in treatment effects, trials with small sample sizes, different standards of care (SoC), and lack of comparative data from single-arm basket trials. Our study developed and applied novel methods to assess the value of pembrolizumab compared with SoC to inform coverage decisions. METHODS: We developed a partitioned survival model to evaluate the cost-utility of pembrolizumab for previously treated patients with 8 advanced or metastatic microsatellite instability-high or mismatch repair-deficient cancers from a US commercial payer perspective. Efficacy of pembrolizumab was based on data from trials directly or with adjustment using Bayesian hierarchical models. Eight chemotherapy-based external control arms were constructed from the TriNetX electronic health record databases. Tumor-specific health-state utility values were applied. All costs were adjusted to 2022 US dollars. RESULTS: At a lifetime horizon, pembrolizumab was associated with increased effectiveness compared with chemotherapies in colorectal (quality-adjusted life years [QALYs]: +0.64, life years [LYs]: +0.64), endometrial (QALYs: +3.79, LYs: +5.47), and small intestine cancers (QALYs: +1.73, LYs: +2.48), but not for patients with metastatic gastric, cholangiocarcinoma, pancreatic, ovarian, and brain cancers. Incremental cost-effectiveness ratios varied substantially across tumor types. Pembrolizumab was found to be cost-effective in treating colorectal and endometrial cancers (incremental cost-effectiveness ratios: $121 967 and $139 257, respectively), and not cost-effective for other assessed cancers at a $150 000 willingness-to-pay/QALY threshold, compared with SoC chemotherapies. CONCLUSIONS: The cost-effectiveness of TADs can vary by cancers. Using analytic tools such as external controls and Bayesian hierarchical models can tackle several challenges in assessing the value of TADs and uncertainties from basket trials.

Relationship between sex, body size, and cardiac resynchronization therapy benefit: A patient-level meta-analysis of randomized controlled trials.

BACKGROUND: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations. OBJECTIVE: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD). METHODS: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality. RESULTS: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m2 vs 2.02 [1.89-2.16] m2; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; Pinteraction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality. CONCLUSION: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration.

Benefit of cardiac resynchronization therapy among older patients: A patient-level meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. METHODS: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. RESULTS: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35). CONCLUSION: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT.

Comorbidities and clinical response to cardiac resynchronization therapy: patient-level meta-analysis from eight clinical trials.

AIMS: Patients with heart failure usually have several other medical conditions that might alter the effects of interventions. We investigated whether the burden of comorbidity modified the clinical response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Original patient-level data from eight randomized trials exploring the effects of CRT versus no CRT were pooled (BLOCK-HF, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, RAFT, COMPANION, MADIT-CRT and REVERSE). A prior history of the following comorbidities was considered: episodic or persistent atrial fibrillation (n = 920), coronary artery disease (n = 3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were classified into three groups based on the number of comorbidities: 0, 1-2, or ≥3. The outcomes of interest were time to all-cause mortality and time to the composite outcome of heart failure hospitalization (HFH) or all-cause mortality. Outcomes were evaluated within each comorbidity group using a Bayesian hierarchical Weibull survival regression model. Of 6324 patients, 970 (15%) had no comorbidities, 4052 (64%) had 1-2 and 1302 (21%) had ≥3 comorbidities. The adjusted hazard ratio (aHR) for CRT versus no CRT for all-cause mortality in the overall cohort was 0.79 (95% credible interval [CI] 0.68-0.93) (p = 0.010); for no comorbidities the aHR was 0.54 (95% CI 0.34-0.86), for 1-2 comorbidities was 0.81 (95% CI 0.67-0.97) and for ≥3 comorbidities was 0.83 (95% CI 0.64-1.07) (no significant interaction between CRT and comorbidity burden: p = 0.13). For the endpoint of HFH or all-cause mortality, the aHR for the overall cohort was 0.74 (95% CI 0.65-0.84) (p = 0.001), for no comorbidities was 0.69 (95% CI 0.50-0.94), for 1-2 comorbidities was 0.77 (95% CI 0.66-0.90) and for ≥3 comorbidities was 0.68 (95% CI 0.55-0.82) (no significant interaction between CRT and comorbidity burden: p = 0.081). CONCLUSION: In a meta-analysis of patient-level data from eight major trials, the totality of evidence suggests that CRT reduces HFH and/or all-cause mortality even when several comorbid diseases are present. CLINICAL TRIAL REGISTRATION: NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Outcomes of Cardiac Resynchronization Therapy by New York Heart Association Class: A Patient-Level Meta-Analysis.

Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure (HF) symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory NYHA IV vs. III functional class at the time of device implantation. In this meta-analysis, we pooled patient-level data from the MIRACLE, MIRACLE-ICD, and COMPANION trials. Outcomes evaluated were time to the composite endpoint of first HF hospitalization (HFH) or all-cause mortality and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian Hierarchical Weibull survival regression model. We assessed if this association differs between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from the RAFT trial. Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to HFH or all-cause mortality (adjusted hazard ratio [aHR] 0.79, 95%CI 0.64 - 0.99, p = 0.044), with a similar association with time to all-cause mortality (aHR 0.78, 95% CI 0.59 - 1.03, p = 0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR 0.72, 95% CI 0.30 - 1.27, p = 0.23 for HFH/mortality; ratio of aHR 0.70, 95% CI 0.35 - 1.34, p = 0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Cardiac resynchronization therapy in patients with a prior history of atrial fibrillation: Insights from four major clinical trials.

AIMS: To investigate the association of cardiac resynchronization therapy (CRT) on outcomes among participants with and without a history of atrial fibrillation (AF). METHODS: Individual-patient-data from four randomized trials investigating CRT-Defibrillators (COMPANION, MADIT-CRT, REVERSE) or CRT-Pacemakers (COMPANION, MIRACLE) were analyzed. Outcomes were time to a composite of heart failure hospitalization or all-cause mortality or to all-cause mortality alone. The association of CRT on outcomes for patients with and without a history of AF was assessed using a Bayesian-Weibull survival regression model adjusting for baseline characteristics. RESULTS: Of 3964 patients included, 586 (14.8%) had a history of AF; 2245 (66%) were randomized to CRT. Overall, CRT reduced the risk of the primary composite endpoint (hazard ratio [HR]: 0.69, 95% credible interval [CI]: 0.56-0.81). The effect was similar (posterior probability of no interaction = 0.26) in patients with (HR: 0.78, 95% CI: 0.55-1.10) and without a history of AF (HR: 0.67, 95% CI: 0.55-0.80). In these four trials, CRT did not reduce mortality overall (HR: 0.82, 95% CI: 0.66-1.01) without evidence of interaction (posterior probability of no interaction = 0.14) for patients with (HR: 1.09, 95% CI: 0.70-1.74) or without a history of AF (HR: 0.70, 95% CI: 0.60-0.97). CONCLUSION: The association of CRT on the composite endpoint or mortality was not statistically different for patients with or without a history of AF, but this could reflect inadequate power. Our results call for trials to confirm the benefit of CRT recipients with a history of AF.

Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. METHODS: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. RESULTS: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; Pinteraction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. CONCLUSIONS: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single "non-LBBB" category when selecting patients for CRT should be reconsidered. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Estimation of Breast Cancer Overdiagnosis in a U.S. Breast Screening Cohort.

BACKGROUND: Mammography screening can lead to overdiagnosis-that is, screen-detected breast cancer that would not have caused symptoms or signs in the remaining lifetime. There is no consensus about the frequency of breast cancer overdiagnosis. OBJECTIVE: To estimate the rate of breast cancer overdiagnosis in contemporary mammography practice accounting for the detection of nonprogressive cancer. DESIGN: Bayesian inference of the natural history of breast cancer using individual screening and diagnosis records, allowing for nonprogressive preclinical cancer. Combination of fitted natural history model with life-table data to predict the rate of overdiagnosis among screen-detected cancer under biennial screening. SETTING: Breast Cancer Surveillance Consortium (BCSC) facilities. PARTICIPANTS: Women aged 50 to 74 years at first mammography screen between 2000 and 2018. MEASUREMENTS: Screening mammograms and screen-detected or interval breast cancer. RESULTS: The cohort included 35 986 women, 82 677 mammograms, and 718 breast cancer diagnoses. Among all preclinical cancer cases, 4.5% (95% uncertainty interval [UI], 0.1% to 14.8%) were estimated to be nonprogressive. In a program of biennial screening from age 50 to 74 years, 15.4% (UI, 9.4% to 26.5%) of screen-detected cancer cases were estimated to be overdiagnosed, with 6.1% (UI, 0.2% to 20.1%) due to detecting indolent preclinical cancer and 9.3% (UI, 5.5% to 13.5%) due to detecting progressive preclinical cancer in women who would have died of an unrelated cause before clinical diagnosis. LIMITATIONS: Exclusion of women with first mammography screen outside BCSC. CONCLUSION: On the basis of an authoritative U.S. population data set, the analysis projected that among biennially screened women aged 50 to 74 years, about 1 in 7 cases of screen-detected cancer is overdiagnosed. This information clarifies the risk for breast cancer overdiagnosis in contemporary screening practice and should facilitate shared and informed decision making about mammography screening. PRIMARY FUNDING SOURCE: National Cancer Institute.

Factors and outcomes associated with improved left ventricular systolic function in patients with cardiomyopathy.

BACKGROUND: Many patients in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a significant improvement (> 10%) in the left ventricular ejection fraction (LVEF) during the course of the study, but the factors and outcomes associated with such improvement are uncertain. METHODS: We examined factors and rates of mortality, cause-specific mortality, and implantable cardioverter-defibrillator (ICD) shocks associated with improvement in LVEF by analyzing patients in the SCD-HeFT who were randomized to placebo or an ICD and who had an LVEF checked during follow-up. RESULTS: During a median follow-up of 3.99 years, of 837 patients who had at least two follow-up LVEF measurements, 276 (33%) patients had > 10% improvement in LVEF and 561 (67%) patients had no significant change in LVEF. Factors significantly associated with LVEF improvement included female sex, white race, history of hypertension, a QRS duration < 120 ms, and beta-blocker use. Improvement in LVEF was associated with a significant improvement in survival. There was no significant association between improvement in LVEF and cause-specific death, but there was a significant association between improvement in LVEF and reduced risk of receiving appropriate ICD shocks. CONCLUSIONS: About a third of patients in this analysis, who were randomized to placebo or an ICD in SCD-HeFT, had a significant improvement in LVEF during follow-up; improvement in LVEF was associated with improved survival but not with cause-specific death, and with decreased likelihood of receiving appropriate ICD shocks.

Recalibration Methods for Improved Clinical Utility of Risk Scores.

BACKGROUND: An established risk model may demonstrate miscalibration, meaning predicted risks do not accurately capture event rates. In some instances, investigators can identify and address the cause of miscalibration. In other circumstances, it may be appropriate to recalibrate the risk model. Existing recalibration methods do not account for settings in which the risk score will be used for risk-based clinical decision making. METHODS: We propose 2 new methods for risk model recalibration when the intended purpose of the risk model is to prescribe an intervention to high-risk individuals. Our measure of risk model clinical utility is standardized net benefit. The first method is a weighted strategy that prioritizes good calibration at or around the critical risk threshold. The second method uses constrained optimization to produce a recalibrated risk model with maximum possible net benefit, thereby prioritizing good calibration around the critical risk threshold. We also propose a graphical tool for assessing the potential for recalibration to improve the net benefit of a risk model. We illustrate these methods by recalibrating the American College of Cardiology (ACC)-American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score within the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: New methods are implemented in the R package ClinicalUtilityRecal. Recalibrating the ACC-AHA-ASCVD risk score for a MESA subcohort results in higher estimated net benefit using the proposed methods compared with existing methods, with improved calibration in the most clinically impactful regions of risk. CONCLUSION: The proposed methods target good calibration for critical risks and can improve the net benefit of a risk model. We recommend constrained optimization when the risk model net benefit is paramount. The weighted approach can be considered when good calibration over an interval of risks is important.

A Value-of-Information Framework for Personalizing the Timing of Surveillance Testing.

BACKGROUND: Patient surveillance using repeated biomarker measurements presents an opportunity to detect and treat disease progression early. Frequent surveillance testing using biomarkers is recommended and routinely conducted in several diseases, including cancer and diabetes. However, frequent testing involves tradeoffs. Although surveillance tests provide information about current disease status, the complications and costs of frequent tests may not be justified for patients who are at low risk of progression. Predictions based on patients' earlier biomarker values may be used to inform decision making; however, predictions are uncertain, leading to decision uncertainty. METHODS: We propose the Personalized Risk-Adaptive Surveillance (PRAISE) framework, a novel method for embedding predictions into a value-of-information (VOI) framework to account for the cost of uncertainty over time and determine the time point at which collection of biomarker data would be most valuable. The proposed sequential decision-making framework is innovative in that it leverages the patient's longitudinal history, considers individual benefits and harms, and allows for dynamic tailoring of surveillance intervals by considering the uncertainty in current information and estimating the probability that new information may change treatment decisions, as well as the impact of this change on patient outcomes. RESULTS: When applied to data from cystic fibrosis patients, PRAISE lowers costs by allowing some patients to skip a visit, compared to an "always test" strategy. It does so without compromising expected survival, by recommending less frequent testing among those who are unlikely to be treated at the skipped time point. CONCLUSIONS: A VOI-based approach to patient monitoring is feasible and could be applied to several diseases to develop more cost-effective and personalized strategies for ongoing patient care. HIGHLIGHTS: In many patient-monitoring settings, the complications and costs of frequent tests are not justified for patients who are at low risk of disease progression. Predictions based on patient history may be used to individualize the timing of patient visits based on evolving risk.We propose Personalized Risk-Adaptive Surveillance (PRAISE), a novel method for personalizing the timing of surveillance testing, where prediction modeling projects the disease trajectory and a value-of-information (VOI)-based pragmatic decision-theoretic framework quantifies patient- and time-specific benefit-harm tradeoffs.A VOI-based approach to patient monitoring could be applied to several diseases to develop more personalized and cost-effective strategies for ongoing patient care.

Future research prioritization in cardiac resynchronization therapy.

BACKGROUND: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan. METHODS: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers. RESULTS: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD. CONCLUSIONS: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.

Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes.

AIM: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes. METHODS AND RESULTS: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015). CONCLUSION: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts.

Background: Active surveillance (AS) is increasingly accepted for managing low-risk prostate cancer, yet there is no consensus about implementation. This lack of consensus is due in part to uncertainty about risks for disease progression, which have not been systematically compared or integrated across AS studies with variable surveillance protocols and dropout to active treatment. Objective: To compare risks for upgrading from a Gleason score (GS) of 6 or less to 7 or more across AS studies after accounting for differences in surveillance intervals and competing treatments and to evaluate tradeoffs of more versus less frequent biopsies. Design: Joint statistical model of longitudinal prostate-specific antigen (PSA) levels and risks for biopsy upgrading. Setting: Johns Hopkins University (JHU); Canary Prostate Active Surveillance Study (PASS); University of California, San Francisco (UCSF); and University of Toronto (UT) AS studies. Patients: 2576 men aged 40 to 80 years with a GS between 2 and 6 and clinical stage T1 or T2 prostate cancer enrolled between 1995 and 2014. Measurements: PSA levels and biopsy GSs. Results: After variable surveillance intervals and competing treatments were accounted for, estimated risks for biopsy upgrading were similar in the PASS and UT studies but higher in UCSF and lower in JHU studies. All cohorts had a delay of 3 to 5 months in detecting upgrading with biennial biopsies starting after a first confirmatory biopsy versus annual biopsies. Limitation: The model does not account for possible misclassification of biopsy GS. Conclusion: Men in different AS studies have different risks for biopsy upgrading after variable surveillance protocols and competing treatments are accounted for. Despite these differences, the consequences of more versus less frequent biopsies seem to be similar across cohorts. Biennial biopsies seem to be an acceptable alternative to annual biopsies. Primary Funding Source: National Cancer Institute.

New York Heart Association class and the survival benefit from primary prevention implantable cardioverter defibrillators: A pooled analysis of 4 randomized controlled trials.

BACKGROUND: Primary prevention implantable cardioverter defibrillator (ICD) reduce all-cause mortality by reducing sudden cardiac death. There are conflicting data regarding whether patients with more advanced heart failure derive ICD benefit owing to the competing risk of nonsudden death. METHODS: We performed a patient-level meta-analysis of New York Heart Association (NYHA) class II/III heart failure patients (left ventricular ejection fraction ≤35%) from 4 primary prevention ICD trials (MADIT-I, MADIT-II, DEFINITE, SCD-HeFT). Bayesian-Weibull survival regression models were used to assess the impact of NYHA class on the relationship between ICD use and mortality. RESULTS: Of the 2,763 patients who met study criteria, 68% (n=1,867) were NYHA II and 52% (n=1,435) were randomized to an ICD. In a multivariable model including all study patients, the ICD reduced mortality (hazard ratio [HR] 0.65, 95% posterior credibility interval [PCI]) 0.40-0.99). The interaction between NYHA class and the ICD on mortality was significant (posterior probability of no interaction=.036). In models including an interaction term for the NYHA class and ICD, the ICD reduced mortality among NYHA class II patients (HR 0.55, PCI 0.35-0.85), and the point estimate suggested reduced mortality in NYHA class III patients (HR 0.76, PCI 0.48-1.24), although this was not statistically significant. CONCLUSIONS: Primary prevention ICDs reduce mortality in NYHA class II patients and trend toward reducing mortality in the heterogeneous group of NYHA class III patients. Improved risk stratification tools are required to guide patient selection and shared decision making among NYHA class III primary prevention ICD candidates.

Predicting appropriate shocks in patients with heart failure: Patient level meta-analysis from SCD-HeFT and MADIT II.

BACKGROUND: No precise tools exist to predict appropriate shocks in patients with a primary prevention ICD. We sought to identify characteristics predictive of appropriate shocks in patients with a primary prevention implantable cardioverter defibrillator (ICD). METHODS: Using patient-level data from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), we identified patients with any appropriate shock. Clinical and demographic variables were included in a logistic regression model to predict appropriate shocks. RESULTS: There were 1,463 patients randomized to an ICD, and 285 (19%) had ≥1 appropriate shock over a median follow-up of 2.59 years. Compared with patients without appropriate ICD shocks, patients who received any appropriate shock tended to have more severe heart failure. In a multiple logistic regression model, predictors of appropriate shocks included NYHA class (NYHA II vs. I: OR 1.65, 95% CI 1.07-2.55; NYHA III vs. I: OR 1.74, 95% CI 1.10-2.76), lower LVEF (per 1% change) (OR 1.04, 95% CI 1.02-1.06), absence of beta-blocker therapy (OR 1.61, 95% CI 1.23-2.12), and single chamber ICD (OR 1.67, 95% CI 1.13-2.45). CONCLUSION: In this meta-analysis of patient level data from MADIT-II and SCD-HeFT, higher NYHA class, lower LVEF, no beta-blocker therapy, and single chamber ICD (vs. dual chamber) were significant predictors of appropriate shocks.

Primary Prevention Implantable Cardioverter Defibrillators in Patients With Nonischemic Cardiomyopathy: A Meta-analysis.

Importance: Conflicting data have emerged on the efficacy of implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death (primary prevention ICDs) in patients with nonischemic cardiomyopathy. Objective: To investigate the association of primary prevention ICDs with all-cause mortality in patients with nonischemic cardiomyopathy. Data Sources: PubMed was searched from January 1, 2000, through October 31, 2016, for the terms implantable defibrillator OR implantable cardioverter defibrillator AND non-ischemic cardiomyopathy. Additional references were identified from bibliographies of pertinent articles and queries to experts in this field. Study Selection: Inclusion criteria consisted of a randomized clinical trial design and comparison of the ICD with medical therapy (control) in at least 100 patients with nonischemic cardiomyopathy. In addition, studies had to report on all-cause mortality during a follow-up period of at least 12 months and be published in English. The search yielded 10 studies, of which only 1 met the inclusion criteria. A search of bibliographies of pertinent articles and queries of experts in this field led to 3 additional studies. Data Extraction and Synthesis: The PRISMA guidelines were used to abstract data and assess data quality and validity. Data were pooled using fixed- and random-effects models. Main Outcomes and Measures: The primary end point was all-cause mortality. Before data collection started, primary prevention ICDs were hypothesized to reduce all-cause mortality among patients with nonischemic cardiomyopathy. Results: Four randomized clinical trials met the selection criteria and included 1874 unique patients; 937 were in the ICD group and 937 in the control group. Pooling data from these trials showed a significant reduction in all-cause mortality with an ICD (hazard ratio, 0.75; 95% CI, 0.61-0.93; P = .008; P = .87 for heterogeneity). Conclusions and Relevance: Primary prevention ICDs are efficacious at reducing all-cause mortality among patients with nonischemic cardiomyopathy. These findings support professional guidelines that recommend the use of ICDs in such patients.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials.

BACKGROUND: The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. METHODS AND RESULTS: Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53-70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged <55 years: hazard ratio 0.48, 95% posterior credible interval 0.33 to 0.69; among patients aged 55 to 64 years: hazard ratio 0.69, 95% posterior credible interval 0.53 to 0.90; among patients aged 65 to 74 years: hazard ratio 0.67, 95% posterior credible interval, 0.53 to 0.85; and among patients aged ≥75 years: hazard ratio 0.54, 95% posterior credible interval 0.37 to 0.78. Sample sizes were limited among patients aged ≥75 years. In adjusted Bayesian-Weibull modeling, point estimates indicate ICD efficacy persists but is attenuated with increasing age. There was evidence of an interaction between age and ICD treatment on survival (two-sided posterior tail probability of no interaction <0.01). Using an adjusted Bayesian logistic regression model, there was no evidence of an interaction between age and ICD treatment on rehospitalization (two-sided posterior tail probability of no interaction 0.44). CONCLUSIONS: In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

A joint model for multistate disease processes and random informative observation times, with applications to electronic medical records data.

Multistate models are used to characterize individuals' natural histories through diseases with discrete states. Observational data resources based on electronic medical records pose new opportunities for studying such diseases. However, these data consist of observations of the process at discrete sampling times, which may either be pre-scheduled and non-informative, or symptom-driven and informative about an individual's underlying disease status. We have developed a novel joint observation and disease transition model for this setting. The disease process is modeled according to a latent continuous-time Markov chain; and the observation process, according to a Markov-modulated Poisson process with observation rates that depend on the individual's underlying disease status. The disease process is observed at a combination of informative and non-informative sampling times, with possible misclassification error. We demonstrate that the model is computationally tractable and devise an expectation-maximization algorithm for parameter estimation. Using simulated data, we show how estimates from our joint observation and disease transition model lead to less biased and more precise estimates of the disease rate parameters. We apply the model to a study of secondary breast cancer events, utilizing mammography and biopsy records from a sample of women with a history of primary breast cancer.

Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials.

OBJECTIVES: The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity. BACKGROUND: Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated. METHODS: Original, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. RESULTS: Overall, 25% of patients (n = 830) had <2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (≥2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with ≥2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with <2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004). CONCLUSIONS: Patients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted.