Abraham, Ivo

Introduction: Physical activity (PA) is known to be effective in treating and preventing many lifestyle diseases including CVD, stroke, depression, type II diabetes, Alzheimer’s disease, as well as breast and colon cancer. To date the direct medical cost-savings of PA as a medical intervention are poorly understood. Hypothesis: We hypothesized that a 10% increase in the proportion of US citizens who meet the minimum weekly exercise requirements of 150 minutes per week would lead to savings in direct medical costs (DMC) and cases prevented, as related to the above diseases. Methods: Population Attributable Risk (PAR) was calculated as PAR= (1+Prf x (RR-1))/(Prf x(RR-1)), where Prf is the percentage of the U.S. population not meeting minimum exercise requirements and RR is the relative risk of disease for sedentary versus physically active individuals. Prf and RR data were retrieved from the most recent and comprehensive meta-analyses and systematic reviews. PAR was calculated for each disease under two conditions; first, Prf was equal to the current percent (9.6%) of the population estimated to achieve the minimum weekly PA requirements. Second, Prf was equal to the initial Prf plus 10 percent (19.6%). For each condition the following were calculated: Attributable DMC=(PAR x DMC), preventable cases=(PAR x Prevalence) and Savings=(Condition 2- Condition 1). Results: The Prevalence, RR, PAR and DMC are provided in Table 1. This table also describes the potential savings in DMC and new cases by improving the Prf by 10%. A 10% increase in US citizens who meet the minimum weekly exercise requirements could lead to a total savings of 10.78 billion USD in DMC and 2.1 million cases prevented related to the studied diseases. Conclusion: A healthcare system directed PA intervention that effectively leads to a 10% increase in US citizens that meet minimum weekly exercise requirements and costs less than 10.78 billion dollars has the potential to be cost-effective, and prevent and treat, millions of cases in the United States.

5583 Background: FDA has approved three novel AAs [Apalutamide(A), Darolutamide(D) and Enzalutamide(E)] in combination with Androgen deprivation therapy ( ADT) for treatment of (nmCRPC) patients (pts). We report the cost-effectiveness of these drugs from the US perspective to help facilitate the choice of these agents for clinical practice. Methods: A life time Markov state-transition model was constructed with three health states (Metastasis-Free Survival[MFS], Metastatic disease, and Death) to compare cost-effectiveness of AA therapies for treatment of nmCRPC based on US healthcare payer perspective. A network meta-analysis of MFS and OS was conducted due to the lack of head to head trials. An approximation of the original individual-level patient time-to-event data were derived from digitized Kaplan-Meier curves for OS and MFS. Weibull distributions was selected as the best fitted model fitted and extrapolated as per the NICE decision support unit recommendations. Medication costs were based on wholesale acquisition cost. Adverse event (AE) grades 3/4 management costs were incorporated in the model. Discount rate of 3% per year was applied to costs and effects. Life years (LYs) and quality adjusted life years (QALYs) for each treatment as well as the incremental cost effectiveness (ICER) and cost utility (ICUR) ratios were estimated. Base case analyses (BCA) and probabilistic sensitivity analyses (PSA) were estimated. Results: The table summarizes the results form BCA analyses. A+ADT offers best gain in LYs (8.37yrs) and QALYs (5.30 yrs) but at higher cost. Conclusions: Apalutamide was associated with gains in LYs and QALYs traded off with higher lifetime cost relative to other AA alternatives. ADT was associated with lower gains in LYs and QALYs traded off with lower lifetime cost relative to other alternatives. Based on a $150,000/QALY threshold pay off, A+ADT is likely more cost effective compared to E+ADT or ADT alone; while E+ ADT may be more cost effective compared to D+ ADT. [Table: see text]

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.

243 Background: AA and D have been shown in separate trials to increase overall survival in patients with mCSPC compared to Androgen Derivation Therapy (ADT). In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison of AA and D using network meta-analysis. Methods: We performed a search of MEDLINE, EMBASE, Cochrane Library, and Cochrane Central Register of Controlled Trials to identify relevant clinical trials. Collected data included hazard ratio and confidence interval (CI) for Overall Survival (OS) and number of adverse events in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparison of D and AA. Results: Five clinical trials were included in this analysis. Two trials (LATITUDE, STAMPEDE) compared AA to ADT and three trials (CHAARTED,STAMPEDE, GETUG-AFU 15 study) compared D to ADT. Results from both fixed effect and random effect network meta-analyses for the primary outcome (OS) revealed no statistical significance between AA and D (HR 0.81,95%CI 0.65-1.01; HR 0.81, 95%CI 0.40-1.82) respectively. Comparatively, abiraterone had statistically significant fewer events of anemia (OR 0.14,95%CI 0.08-0.23), neutropenia (OR 0.06,95%CI 0.03-0.12), peripheral edema (OR 0.21,95%CI 0.09-0.44), dyspnea (OR 0.22,95%CI 0.08-0.51), nausea (OR 0.09,95%CI 0.02-0.24), diarrhea (OR 0.06,95%CI 0.02-0.15), constipation (OR 0.25,95%CI 0.11-0.53), and fatigue (OR 0.12,95%CI 0.07-0.20). AA had statistically significant more events of hot flashes (OR 3.85, 95% CI2.33-6.25). For other adverse events, both drugs were statistically similar. Conclusions: There is no difference in OS using AA for longer periods in CSPC than a regimen of a limited number of cycles of D. There are significant differences in side effect profile of these drugs. Further analyses are needed to determine cost effectiveness of AA vs D under consideration of comparative efficacy and safety.

AbstractAnti‐cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) and anti‐programmed cell death‐1 (PD‐1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta‐analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti‐CTLA‐4 or anti‐PD‐1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression‐free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76–0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59–0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76–0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune‐related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65–9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti‐PD‐1 treatment compared to anti‐CTLA‐4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti‐PD‐1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients.

ABSTRACT Background Anthracyclines are commonly used chemotherapeutic agents with proven efficacy in such malignancies as breast cancer, Hodgkin and non-Hodgkin lymphomas. These agents are associated with irreversible accumulative dose-related cardiomyopathy. Many agents have been examined to reduce cardiotoxicity risk. Aims We performed a systematic review and meta-analysis to determine the efficacy of β-blockers and angiotensin antagonists to prevent early-onset anthracyclines-induced left ventricular dysfunction and cardiac events. Methods Relevant articles were searched in PubMed, EMBASE and Cochrane database of systematic reviews up to July 2015. Eligible studies were limited to randomised controlled trials comparing the efficacy of cardioprotective agents (β-blocker and angiotensin antagonist) with control (either no treatment or placebo) in adult patients (age &gt;18 years) treated with anthracyclines-based regimens. Results Pooled analysis showed an association of β-blockers and/or angiotensin antagonists treatment with higher post-chemotherapy left ventricular ejection fraction (LVEF) of 64.03% compared with 57.48% for control treatment. The mean difference estimate (95% CI) was 6.06% (0.54 to 11.58), p=0.03, with significant heterogeneity, I2 (95% CI)=96% (82.7 to 109.3). Though the point estimate for the relative rate of cardiac events was lower in the experimental arm, the difference was not statistically significant. In an exploratory subgroup analysis, the benefit of experimental agents on LVEF preservation was prominent in patients treated with higher accumulative dose of anthracyclines, but not in the lower dose group. Conclusions β-Blockers and angiotensin antagonists treatments were associated with better LVEF preservation, and the benefit was prominent in patients treated with higher anthracyclines accumulative dose. Unexplained heterogeneity remains, indicating the need for more controlled studies. This analysis provides some support for the routine use of β-blockers or angiotensin antagonists in patients undergoing anthracyclines treatment, especially when higher accumulative dose is expected.