Comparative Efficacy of Acalabrutinib in Frontline Treatment of Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-analysis.

PURPOSE: The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline treatments for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, through a network meta-analysis (NMA). METHODS: The efficacy of acalabrutinib from ELEVATE-TN (study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) was compared to bendamustine + rituximab, chlorambucil-based therapy, alemtuzumab, ibrutinib mono/combination therapy and venetoclax + obinutuzumab using data from eight randomized controlled trials (RCTs). Relevant RCTs were identified using a systematic literature review. Two evidence networks were constructed: Network A, composed solely of RCTs that met the inclusion criteria; and Network B, composed of 7 RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil + obinutuzumab from iLLUMINATE. Bayesian NMAs were conducted on progression-free survival (PFS) and overall survival (OS) endpoints; results were reported by using hazard ratios (HRs) and 95% credible intervals (CrIs). HRs were considered significant if their CrIs did not cross 1. Treatments were ranked by using the surface under the cumulative ranking area (SUCRA) values. Expert opinion from 2 hematologists was sought to validate results. FINDINGS: Both networks showed a significant improvement in PFS for acalabrutinib + obinutuzumab over all comparators. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B. Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax + obinutuzumab in Network B but not Network A. Although OS HRs all favored acalabrutinib, most were not significant and were characterized by wide CrIs, indicating a high level of uncertainty. Acalabrutinib + obinutuzumab ranked highest in terms of PFS improvement (SUCRA values, 98% and 100%) and OS improvement (SUCRA values, 92% and 94%), followed by acalabrutinib monotherapy (SUCRA values for PFS, 88% and 90%; OS, 83% and 87%) in Networks A and B, respectively. IMPLICATIONS: Acalabrutinib was associated with favorable PFS and OS compared with frontline CLL therapies and ranked highest in treatment efficacy over the other comparators. The NMA was limited by heterogeneity in patient baseline characteristics across trials, variable treatment regimens, and short study follow-up times. Despite these limitations, the NMA provides insights into the relative efficacy of acalabrutinib compared with frontline CLL therapies in the absence of head-to-head clinical trials.

Efficacy of ustekinumab vs. advanced therapies for the treatment of moderately to severely active ulcerative colitis: a systematic review and network meta-analysis.

Objective: To compare the relative efficacy of ustekinumab (UST) vs. other therapies for 1-year response and remission rates in patients with moderate-severe UC.Methods: Randomized controlled trials reporting induction and maintenance efficacy of anti-TNFs (infliximab [IFX], adalimumab [ADA], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOF) or UST were identified through a systematic literature review (SLR). Analyses were conducted for clinical response, clinical remission and endoscopic-mucosal healing for populations with and without failure of prior biologics (non-biologic failure [NBF]; biologic failure [BF]). Maintenance data from trials with re-randomized response designs were re-calculated to correspond to treat-through arms. Bayesian network meta-analyses (NMA) were conducted to obtain posterior distribution probabilities for UST to perform better than comparators.Results: Six trials included NBF patients and four included BF patients. In NBF patients, UST as a 1-year regimen showed higher probabilities of clinical response, remission and endoscopic-mucosal healing vs. all treatments: Bayesian probabilities of UST being better than active therapies ranged from 91% (VDZ) to 100% (ADA) for response; 82% (VDZ) to 99% (ADA) for remission and 82% (IFX) to 100% (ADA and GOL) for endoscopic-mucosal healing. In BF patients, UST was the most effective treatment (Q8W dose); however, effect sizes were smaller than in the NBF population.Conclusions: Results indicate a higher likelihood of response, remission and endoscopic-mucosal healing at 1 year with UST vs. comparators in the NBF population. In BF patients, a higher likelihood of response to UST vs. the most comparators was also observed, although results were more uncertain.

A Comparison of National Guidelines for Network Meta-Analysis.

BACKGROUND: Network meta-analysis (NMA) techniques allow the comparison of a complete set of interventions for patient groups. These meta-analysis techniques may be the only source of evidence to underpin estimates of comparative efficacy. Reimbursement agencies around the world are increasingly reliant upon meta-analysis techniques and assess their design and conduct with growing sophistication. OBJECTIVE: Our objective is to create a superset of requirements collated from available national guidelines for the conduct of network meta-analysis such that a single analysis may be conducted to satisfy all reimbursement bodies that have specified requirements in sufficient detail. METHODS: Published and draft guidelines documents from reimbursement bodies and health technology appraisal agencies were examined for their stipulations as to the conduct and design of network meta-analysis and measures to be taken to reduce bias and increase validity. RESULTS: Guidelines from 41 countries were reviewed, yielding a sample size of 13 countries' guideline documents: Australia, Belgium, Canada, China, Ireland, England and Wales, France, Germany, Scotland, South Africa, South Korea, Spain, Thailand, and a guideline document from the European Network of Health Technology Assessment, which contained explicit recommendations or requirements for conduct of NMA. CONCLUSION: This study expands the range of previous work that reviewed the guidelines for the use of indirect evidence from multiple national jurisdictions. These aggregate guidelines do not include requirements that are mutually prohibitive. It is possible to perform a single NMA for submission to an expanded list of national jurisdictions.

Economic value and cost-effectiveness of biventricular versus right ventricular pacing: results from the BLOCK-HF study.

Aims: The Biventricular vs Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) demonstrated that biventricular (BiV) pacing resulted in better clinical and structural outcomes compared to right ventricular (RV) pacing in patients with atrioventricular (AV) block and reduced left ventricular ejection fraction (LVEF; ≤50%). This study investigated the cost-effectiveness of BiV vs RV pacing in the patient population enrolled in the BLOCK-HF trial. Methods: All-cause mortality, New York Heart Association (NYHA) Class distribution over time, and NYHA-specific heart failure (HF)-related healthcare utilization rates were predicted using statistical models based on BLOCK-HF patient data. A proportion-in-state model calculated cost-effectiveness from the Medicare payer perspective. Results: The predicted patient survival was 6.78 years with RV and 7.52 years with BiV pacing, a 10.9% increase over lifetime. BiV pacing resulted in 0.41 more quality-adjusted life years (QALYs) compared to RV pacing, at an additional cost of $12,537. The "base-case" incremental cost-effectiveness ratio (ICER) was $30,860/QALY gained. Within the clinical sub-groups, the highest observed ICER was $43,687 (NYHA Class I). Patients receiving combined BiV pacing and defibrillation (BiV-D) devices were projected to benefit more (0.84 years gained) than BiV pacemaker (BiV-P) recipients (0.49 years gained), compared to dual-chamber pacemakers. Conclusions: BiV pacing in AV block patients improves survival and attenuates HF progression compared to RV pacing. ICERs were consistently below the US acceptability threshold ($50,000/QALY). From a US Medicare perspective, the additional up-front cost associated with offering BiV pacing to the BLOCK-HF patient population appears justified.

Economic Value and Cost-Effectiveness of Cardiac Resynchronization Therapy Among Patients With Mild Heart Failure: Projections From the REVERSE Long-Term Follow-Up.

OBJECTIVES: This study investigated the cost effectiveness of early cardiac resynchronization therapy (CRT) implantation among patients with mild heart failure (HF). The differential cost effectiveness between CRT using a defibrillator (CRT-Ds) and CRT using a pacemaker (CRT-P) was also assessed. BACKGROUND: Cardiac resynchronization has been shown to be cost effective in New York Heart Association (NYHA) functional classes III/IV but is less studied in class II HF. The incremental costs of early CRT implementation in mild HF compared with the costs potentially avoided because of delaying disease progression to advanced HF are also unknown. Finally, combined biventricular pacing and defibrillator (CRT-D) devices are more expensive than biventricular pacemakers (CRT-P), but the relative cost effectiveness is controversial. METHODS: Data from the 5-year follow-up phase of REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) were used. The economics were evaluated from the U.S. Medicare perspective based on published clinical projections. RESULTS: Probabilistic estimates yielded $8,840/quality-adjusted life year (QALY) gained (95% confidence interval [CI]: $6,705 to $10,804/QALY gained) for CRT-ON versus CRT-OFF (i.e., programmed "ON" or "OFF" at pre-specified post-implantation timings) and $43,678/QALY gained for CRT-D versus CRT-P (95% CI: $35,164 to $53,589/QALY gained) over the patient's lifetime. Results were robust to choice of patient subgroup and alterations of ±10% to key model parameters. An "early" CRT-D class II strategy totaled $95,292 compared with $91,511 for a "late" implantation. An "early" implant offered on average 1.00 year of additional survival for $3,781, resulting in an ICER of $3,795/LY gained. CONCLUSIONS: This study demonstrates CRT cost effectiveness in mild HF. The incremental CRT-D costs are justified by the anticipated benefits, despite increased procurement costs and shorter generator longevities. "Early" CRT-D implants have essential cost parity with "late" implants while increasing the patient's survival. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154).

Long-Term Extrapolation of Clinical Benefits Among Patients With Mild Heart Failure Receiving Cardiac Resynchronization Therapy: Analysis of the 5-Year Follow-Up From the REVERSE Study.

OBJECTIVES: This study sought to assess the lifelong extrapolated patient outcomes with cardiac resynchronization therapy (CRT) in mild heart failure (HF), beyond the follow-up of randomized clinical trials (RCTs). BACKGROUND: RCTs have demonstrated short-term survival and HF hospitalization benefits of CRT in mild HF. We used data from the 5-year follow-up of the REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) study to extrapolate survival and HF hospitalizations. We compared CRT-ON versus CRT-OFF and CRT defibrillators (CRT-D) versus CRT pacemakers (CRT-P). METHODS: Multivariate regression models were used to estimate treatment-specific all-cause mortality, disease progression, and HF-related hospitalization rates. Rank-preserving structural failure time (RPSFT) models were used to adjust for protocol-mandated crossover in the survival analysis. RESULTS: CRT-ON was predicted to increase survival by 22.8% (CRT-ON 52.5% vs. CRT-OFF 29.7%; hazard ratio [HR]: 0.45; p = 0.21), leading to an expected survival of 9.76 years (CRT-ON) versus 7.5 years (CRT-OFF). CRT-D showed a significant improvement in survival compared with CRT-P (HR: 0.47; 95% confidence interval [CI]: 0.25 to 0.88; p = 0.02) and were predicted to offer 2.77 additional life-years. New York Heart Association (NYHA) functional class II patients had a 30.6% higher HF hospitalization risk than class I (I vs. II incident rate ratio [IRR]: 0.69; 95% CI: 0.57 to 0.85; p < 0.001) and 3 times lower rate compared with class III (III vs. II IRR: 2.98; 95% CI: 2.29 to 3.87; p < 0.001). CONCLUSIONS: RPSFT estimates yielded results demonstrating clinically important long-term benefit of CRT in mild HF. CRT was predicted to reduce mortality, with CRT-D prolonging life more than CRT-P. NYHA functional class I/II patients were shown to have a significantly reduced risk of HF hospitalization compared with class III, leading to CRT reducing HF hospitalization rates.

Cost-utility of transcatheter aortic valve implantation for inoperable patients with severe aortic stenosis treated by medical management: a UK cost-utility analysis based on patient-level data from the ADVANCE study.

OBJECTIVE: To use patient-level data from the ADVANCE study to evaluate the cost-effectiveness of transcatheter aortic valve implantation (TAVI) compared to medical management (MM) in patients with severe aortic stenosis from the perspective of the UK NHS. METHODS: A published decision-analytic model was adapted to include information on TAVI from the ADVANCE study. Patient-level data informed the choice as well as the form of mathematical functions that were used to model all-cause mortality, health-related quality of life and hospitalisations. TAVI-related resource use protocols were based on the ADVANCE study. MM was modelled on publicly available information from the PARTNER-B study. The outcome measures were incremental cost-effectiveness ratios (ICERs) estimated at a range of time horizons with benefits expressed as quality-adjusted life-years (QALY). Extensive sensitivity/subgroup analyses were undertaken to explore the impact of uncertainty in key clinical areas. RESULTS: Using a 5-year time horizon, the ICER for the comparison of all ADVANCE to all PARTNER-B patients was £13 943 per QALY gained. For the subset of ADVANCE patients classified as high risk (Logistic EuroSCORE >20%) the ICER was £17 718 per QALY gained). The ICER was below £30 000 per QALY gained in all sensitivity analyses relating to choice of MM data source and alternative modelling approaches for key parameters. When the time horizon was extended to 10 years, all ICERs generated in all analyses were below £20 000 per QALY gained. CONCLUSION: TAVI is highly likely to be a cost-effective treatment for patients with severe aortic stenosis.