Routine Clinical Practice for Patients With Recurrent Ovarian Carcinoma: Results From the TROCADERO Study.

OBJECTIVE: Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. METHODS: Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. RESULTS: There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0-12.0] and 8.3 [range, 6.0-11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1-42.3), 20.5 (95% CI, 17.7-24.8), 12.7 (95% CI, 10.4-14.2), and 9.8 (95% CI, 6.6-14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4-37.3) and 18.7 (95% CI, 11.0-23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. CONCLUSIONS: Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records.

Network Meta-analysis of Ravulizumab and Alternative Interventions for the Treatment of Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) is a complement-mediated autoimmune disease in which unpredictable and relapsing attacks on the central nervous system cause irreversible and accumulating damage. Comparative efficacy of new NMOSD therapies, such as ravulizumab, with established therapies is critical in making informed treatment decisions. METHODS: Efficacy of ravulizumab relative to established AQP4-Ab+ NMOSD treatments, such as eculizumab, inebilizumab, and satralizumab, was evaluated in a Bayesian network meta-analysis (NMA). Data were extracted from trials identified by a systematic literature review. The final evidence base consisted of 17 publications representing five unique and global studies (PREVENT, N-MOmentum, SAkuraSky, SAkuraStar, and CHAMPION-NMOSD). The primary endpoint was time-to-first relapse; other outcomes included annualized relapse rates (ARRs). RESULTS: For patients receiving monotherapy (monoclonal antibody only), ravulizumab was associated with a lower risk of relapse than inebilizumab (hazard ratio [HR] 0.09, 95% credible interval [CrI] 0.02, 0.57) or satralizumab (HR 0.08, 95% CrI 0.01, 0.55) and was comparable to eculizumab (HR 0.86, 95% Crl 0.16, 4.52). Ravulizumab + immunosuppressive therapy (IST) was associated with a lower risk of relapse than satralizumab + IST (HR 0.15, 95% CrI 0.03, 0.78); the comparison with eculizumab + IST suggested no difference. No patients treated with inebilizumab received background IST and were thus excluded from analysis. The ARR with ravulizumab monotherapy was 98% lower compared with inebilizumab (rate ratio [RR] 0.02, 95% Crl 0.00, 0.38) and satralizumab (RR 0.02, 95% Crl 0.00, 0.42) monotherapies. The ARR with ravulizumab ± IST showed the strongest treatment-effect estimates compared with other interventions. CONCLUSION: In the absence of head-to-head randomized controlled trials, NMA results suggest ravulizumab, a C5 inhibitor, is likely to be more effective in preventing NMOSD relapse in patients with AQP4-Ab+ NMOSD when compared with other treatments having different methods of action.

Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, also called AQP4-Ab+ NMOSD, is a rare autoimmune disease that causes repeated episodes of symptoms such as blindness, arm/leg weakness, painful spasms, vomiting, and hiccups, among other symptoms. Each episode can cause nervous system damage to worsen, making it more difficult to recover back to regular abilities. Repeated episodes are likely to cause permanent damage, such as blindness and paralysis. Medical treatments that reduce episodes also reduce the damage and the chances symptoms will become permanent. One treatment, ravulizumab, is being studied to treat adults with AQP4-Ab+ NMOSD. This analysis looked at information from published clinical studies to compare ravulizumab with three other treatments (eculizumab, inebilizumab, and satralizumab) to determine how well each treatment reduced NMOSD episodes. There are no studies that have tested all four treatments in one study. Here, the treatments were compared by a method used to estimate the likelihood of a treatment being better than the others. While all four treatments successfully reduced episodes in their own studies, this analysis predicts that ravulizumab would likely be best in preventing episodes compared with inebilizumab or satralizumab when used alone or in combination with other immunosuppressive treatments. These findings, in consideration along with other relevant factors such as cost, safety, dosing delivery method, and frequency of treatment, may help doctors and patients decide what is the best treatment option for each individual patient to prevent attacks in adults with AQP4-Ab+ NMOSD.

Characterizing mortality in patients with AQP4-Ab+ neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder is an autoimmune disease, causing severe disability due to relapses, but recent mortality data are limited. Among 396 patients seropositive for anti-aquaporin-4 antibody from 2014 to 2020 in the United Kingdom, 39 deaths occurred: 19 (48.7%) were unrelated to disease; 14 (35.9%) were severe disability- or relapse-related; and 4 (10.3%) were attributed to malignancy/infection. Mean annual mortality was 1.92% versus 0.63% in the matched population. The standardized mortality ratio was 3.04 (95% confidence interval 1.67-5.30) with 1.29% excess mortality per year in patients. Median Expanded Disability Status Scale before death was 7.0. Results highlight the importance of preventing relapses that drive disability.

A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder.

Background: Cumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD. Methods: Post hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes. Results: In 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses. Conclusion: Findings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

Clinical burden of relapses in aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder: A single center cohort analysis.

A retrospective, observational analysis of 47 patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) enrolled at the University of Utah healthcare system was conducted. Visual acuity, neurological disability, and pain medication use were compared in relapsing versus non-relapsing patients. The median observation period was 3.6 years (range: 0.0-11.4 years); the annual relapse rate was 0.1376 (95% confidence interval: 0.0874, 0.191). Relapsing patients (n = 14) exhibited diminished visual acuity, clinically meaningful worsening of neurological disability, and greater pain medication use than non-relapsing patients (n = 33). Therapies that reduce the risk of relapses should be considered when making treatment decisions.

Network Meta-analysis of Food and Drug Administration-approved Treatment Options for Adults with Aquaporin-4 Immunoglobulin G-positive Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions. METHODS: A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs). RESULTS: In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98). CONCLUSION: The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD.

Neuromyelitis Optica Spectrum Disorder: Clinical Burden and Cost of Relapses and Disease-Related Care in US Clinical Practice.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition characterized by unpredictable relapses that affect the optic nerves and spinal cord, which can lead to blindness, paralysis, and increased mortality rates. Evidence on the clinical and economic burden of NMOSD in the USA is currently lacking. METHODS: A retrospective, observational cohort study was conducted using data from the IQVIA PharMetrics Plus Healthcare Claims Database between January 1, 2012 and March 31, 2019. Adults (aged 18 years or more) with evidence of NMOSD and a matched group of comparison patients were identified. Outcomes, including NMOSD relapses, healthcare utilization, and healthcare expenditure (reported in 2018 US dollars), were evaluated during the follow-up period (maximum 6 years). Healthcare utilization and expenditure were assessed overall (all-cause) and during NMOSD relapses. RESULTS: The study included 1363 patients with NMOSD; the mean age was 44.9 years, and 75.3% were female. During the follow-up period (median 2.0 years), 47.7% of patients with NMOSD had one or more relapses, corresponding to an annualized relapse rate of 0.8 (95% confidence interval [CI] 0.7-0.9). When analyzing healthcare expenditure per patient, the mean annualized all-cause healthcare expenditure among patients with NMOSD was $60,599 (95% CI $52,112-66,716) compared with $8912 (95% CI $7084-10,727) among comparison patients, representing a difference of $51,687 (95% CI $43,820-58,664) attributable to NMOSD. The mean annualized total expenditure for NMOSD relapses was $10,070 (95% CI $7726-12,660) per patient, with hospital/inpatient care requiring more expenditure than ambulatory/outpatient care. CONCLUSION: Findings of this large, retrospective, observational study indicate that relapses among patients with NMOSD are common in US clinical practice, leading to substantial healthcare utilization and expenditure. Therapies with the highest relapse risk reduction could lead to markedly lower relapse-associated healthcare utilization and clinical burden in patients with NMOSD.

Neuromyelitis optica spectrum disorder (NMOSD) is a severely debilitating neurological disease that affects the nerves in the brain and spinal cord. People who have NMOSD may experience recurrent attacks, or relapses, that can cause blindness and disability. These relapses may lead to hospitalizations, doctor's office visits, and pharmacy costs that are paid by health insurance plans. Overall, the cost of treating relapses in patients with NMOSD is substantial. Our study analyzed healthcare claims data from the USA. During a median follow-up time of 2.0 years, our study showed that 47.7% of patients with NMOSD experienced one or more relapses, resulting in hospital/inpatient admissions and ambulatory/outpatient treatments. In addition, the average healthcare cost among patients with NMOSD was $60,599 per year compared with $8912 per year for patients without NMOSD. This represents a difference of $51,687 per year, which can be attributed to NMOSD. Among patients with three or more relapses during the follow-up period, the average total healthcare cost was more than $83,000 per patient. Therefore, medicines that prevent relapses could lead to fewer relapse-associated hospitalizations and outpatient treatments for patients with NMOSD.

Economic burden of hospitalizations of Medicare beneficiaries with heart failure.

OBJECTIVE: The objective of this study was to assess the costs associated with the hospitalization and the cumulative 30-, 60-, and 90-day readmission rates in a cohort of Medicare beneficiaries with heart failure (HF). METHODS: This was a retrospective, observational study based on data from the national 5% sample of Medicare beneficiaries. Inpatient data were gathered for Medicare beneficiaries with at least one HF-related hospitalization between July 1, 2005, and December 31, 2011. The primary end point was the average per-patient cost of hospitalization for individuals with HF. Secondary end points included the cumulative rate of hospitalization, the average length of hospital stay, and the cumulative 30-, 60-, and 90-day readmission rates. RESULTS: Data from 63,678 patients with a mean age of 81.8 years were included in the analysis. All costs were inflated to $2,015 based on the medical care component of the Consumer Price Index. The mean per-patient cost of an HF-related hospitalization was $14,631. The mean per-patient cost of a cardiovascular (CV)-related or all-cause hospitalization was $16,000 and $15,924, respectively. The cumulative rate of all-cause hospitalization was 218.8 admissions per 100 person-years, and the median length of stay for HF-related, CV-related, and all-cause hospitalizations was 5 days. Also, 22.3% of patients were readmitted within 30 days, 33.3% were readmitted within 60 days, and 40.2% were readmitted within 90 days. CONCLUSION: The costs associated with hospitalization for Medicare beneficiaries with HF are substantial and are compounded by a high rate of readmission.

Financial impact of ivabradine on reducing heart failure penalties under the Hospital Readmission Reduction Program.

OBJECTIVE: The introduction of the Hospital Readmission Reduction Program (HRRP) has led to renewed interest in developing strategies to reduce 30 day readmissions among patients with heart failure (HF). In this study, a model was developed to investigate whether the addition of ivabradine to a standard-of-care (SoC) treatment regimen for patients with HF would reduce HRRP penalties incurred by a hypothetical hospital with excess 30 day readmissions. RESEARCH DESIGN: A model using a Monte Carlo simulation framework was developed. Model inputs included national hospital characteristics, hospital-specific characteristics, and the ivabradine treatment effect as quantified by a post hoc analysis of the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT). RESULTS: The model computed an 83% reduction in HF readmission penalty payments in a hypothetical hospital with a readmission rate of 22.95% (excess readmission ratio = 1.056 over the national average readmission rate of 21.73%), translating into net savings of $44,016. A sensitivity analysis indicated that the readmission penalty is affected by the specific characteristics of the hospital, including the readmission rate, size of the ivabradine-eligible population, and ivabradine utilization. CONCLUSIONS: The results of this study indicate that the addition of ivabradine to an SoC treatment regimen for patients with HF may lead to a reduction in the penalties incurred by hospitals under the HRRP. This highlights the role ivabradine can play as part of a wider effort to optimize the care of patients with HF.

Cost-Effectiveness of Ivabradine for Heart Failure in the United States.

BACKGROUND: Ivabradine is a heart rate-lowering agent approved to reduce the risk of hospitalization for worsening heart failure. This study assessed the cost-effectiveness of adding ivabradine to background therapy in the United States from the perspective of a commercial or Medicare Advantage payer. METHODS AND RESULTS: A cost-effectiveness, cohort-based Markov model using a state transition approach tracked a cohort of heart failure patients with heart rate ≥70 beats per minute in sinus rhythm who were treated with ivabradine+background therapy or background therapy alone. Model inputs, including adjusted hazard ratios, rates of hospitalization and mortality, adverse events, and utility-regression equations, were derived from a large US claims database and SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial). In the commercial population, ivabradine+background therapy was associated with a cost savings of $8594 versus the cost of background therapy alone over a 10-year time horizon, primarily because of reduced hospitalization. Ivabradine was associated with an incremental benefit of 0.24 quality-adjusted life years over a 10-year time horizon. In the Medicare Advantage population, the incremental cost-effectiveness ratio for ivabradine was estimated to be $24 920/quality-adjusted life years. CONCLUSIONS: The cost-effectiveness model suggests that for a commercial population, the addition of ivabradine to background therapy was associated with cost savings and improved clinical outcomes. For a Medicare Advantage population, the analysis indicates that the clinical benefit of ivabradine can be achieved at a reasonable cost.

Pharmacotherapy Treatment Patterns, Outcomes, and Health Resource Utilization Among Patients with Heart Failure with Reduced Ejection Fraction at a U.S. Academic Medical Center.

STUDY OBJECTIVE: To assess clinical characteristics, pharmacotherapy treatment patterns, resource utilization and associated charges, and morbidity and mortality outcomes among a real-world cohort of patients with heart failure with reduced ejection fraction (HFrEF) in an academic medical center setting. DESIGN: Retrospective analysis. DATA SOURCE: Electronic health record database that includes clinical, laboratory, and administrative data for all facilities of the University of Utah Health Care System. PATIENTS: A total of 989 adults with prevalent (preexisting) HFrEF, identified by using the International Classification of Diseases, Ninth Revision, Clinical Modification code 428.x (heart failure) between January 1, 2007, and June 30, 2013, and who had a left ventricular ejection fraction of 40% or lower. MEASUREMENTS AND MAIN RESULTS: The cohort had a mean age of 64 ± 15 years and was predominantly white (71%) and male (74%). Patients received ß-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), and aldosterone receptor antagonists (ARAs) at rates of 79%, 69%, and 29%, respectively. Patients achieved target doses of ß-blockers, ACEIs, and ARBs at rates of only 24%, 31%, and 13%, respectively. Overall, 58% of patients were prescribed dual therapy with a ß-blocker and an ACEI or ARB, and 19% were prescribed triple therapy (ß-blocker, an ACEI or ARB, and an ARA). Univariate and multivariate logistic regression models were used to assess the association between baseline characteristics with the presence of triple therapy. Two variables were statistically significant in both models: increasing age was associated with a lower odds of triple therapy (univariate: odds ratio [OR] 0.760, 95% confidence interval [CI] 0.673-0.857; multivariate: OR 0.768, 95% CI 0.625-0.942), whereas receipt of an implantable cardiac device was associated with a 2-fold increase in the odds of triple therapy (univariate: OR 2.1, 95% CI 1.4-3.1; multivariate: OR 2.1, 95% CI 1.3-3.5). During a mean ± SD follow-up of 36 ± 27 months, all-cause mortality was 0.12 per person-year. There were 1311 all-cause hospitalizations of which 611 (47%) were for worsening heart failure. The rate of all-cause and heart failure-specific hospitalizations was 0.44 and 0.21 per person-year of follow-up, respectively. The median length of stay was 6.4 ± 8.8 days, and the median charge was $22,310. The 30-day all-cause readmission rate was 20%, and the primary reason for readmission was heart failure in 65% of cases. CONCLUSION: This study demonstrates the continuing significant disease and economic burden for patients with HFrEF. Challenges remain in utilization of established disease-modifying therapy and in the treatment of patients with HFrEF and multiple comorbidities.

Budget Impact of Adding Ivabradine to Standard of Care in Patients with Chronic Systolic Heart Failure in the United States.

BACKGROUND: Heart failure (HF) costs $21 billion annually in direct health care costs, 80% of which is directly attributable to hospitalizations. The SHIFT clinical study demonstrated that ivabradine plus standard of care (SoC) reduced HF-related and all-cause hospitalizations compared with SoC alone. OBJECTIVE: To estimate the budget impact of ivabradine from a U.S. commercial payer perspective. METHODS: A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related = $37,507; non-HF CV = $28,951; and non-CV = $17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2%, increasing 2% per year. RESULTS: Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of $0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine's reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was $0.01 for the commercial population and $0.24 for the Medicare Advantage population. CONCLUSIONS: Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers. DISCLOSURES: This study was funded by Amgen. Patel is employed by Amgen; Kielhorn was employed by Amgen at the time of the study but is no longer affiliated with Amgen. Borer, Böhm, Ford, and Komajda have received scientific support, consultative fees, and/or speakers honoraria from Servier and Amgen in connection with SHIFT, the trial underlying this analysis. Borer also has received consultative fees from Celladon, Pfizer, ARMGO, Cardiorentis, Novartis, and Takeda USA. Kansal, Dorman, Krotneva, and Zheng are employees of Evidera, which was hired to assist with this study. Tavazzi has received research grants and consultation fees from Servier in connection with this study and has had advisory board memberships with Boston Scientific, Servier, Cardiorentis, Medtronic, St. Jude Medical, and CVie Therapeutics. Study concept and design were contributed by Dorman and Keilhorn, along with the other authors. Tavazzi, Komajda, Ford, BÖhm, and Borer oversaw collection of the data. Tavazzi, Komajda, Ford, BÖhm, and Borer (along with Karl Swedberg) formed the Executive Committee of SHIFT, the trial underlying this analysis. The manuscript was written by Kansal, along with the other authors, and revised by Borer and Patel, with assistance from the other authors.

Relation of Elevated Heart Rate in Patients With Heart Failure With Reduced Ejection Fraction to One-Year Outcomes and Costs.

There are limited data describing outcomes associated with an elevated heart rate in patients with heart failure with reduced ejection fraction (HFrEF) in routine clinical practice. We identified patients with HFrEF at Duke University Hospital undergoing echocardiograms and heart rate assessments without paced rhythms or atrial fibrillation. Outcomes (all-cause mortality or hospitalization and medical costs per day alive) were assessed using electronic medical records, hospital cost accounting data, and national death records. Patients were stratified by heart rate (<70 and ≥70 beats/min) and compared using generalized linear models specified with gamma error distributions and log links for costs and proportional hazard models for mortality/hospitalization. Of 722 eligible patients, 582 patients (81%) were treated with ß blockers. The median heart rate was 81 beats/min (25th and 75th percentiles 69 to 96) and 527 patients (73%) had a heart rate ≥70 beats/min. After multivariate adjustment, a heart rate ≥70 beats/min was associated with increased 1-year all-cause mortality or hospitalization, hazard ratio 1.37 (95% CI 1.07 to 1.75) and increased medical costs per day alive, cost ratio 2.03 (95% CI 1.53 to 2.69). In conclusion, at a large tertiary care center, despite broad use of ß blockers, a heart rate ≥70 beats/min was observed in 73% of patients with HFrEF and associated with worse 1-year outcomes and increased direct medical costs per day alive.

Effect of ivabradine on numbers needed to treat for the prevention of recurrent hospitalizations in heart failure patients.

BACKGROUND: Ivabradine, a specific heart rate lowering agent, was shown in the SHIFT study to reduce time to first hospitalization for worsening heart failure (HF) in chronic systolic HF patients and also to reduce recurrent/total hospitalizations over the study interval. We assessed the effects of adding ivabradine in patients with systolic HF on the number needed to treat (NNT) to reduce recurrent hospitalizations. METHODS: The SHIFT trial included 6505 patients with symptomatic HF (NYHA II-IV), left ventricular ejection fraction ≤35% and heart rate ≥70 bpm in sinus rhythm. Patients were randomized to either ivabradine or placebo in addition to guidelines-based drug therapy. The times to first hospitalization were analyzed using a univariate Cox proportional-hazards model; the associated NNT was calculated using Kaplan-Meier estimates of the time-to-event curves at 1 year in each treatment arm. Recurrent hospitalizations were analyzed using a negative binomial and the estimated annual event rates used to calculate the associated patient-time NNTs respectively. RESULTS: The estimated NNT (number needed to initiate treatment with ivabradine to prevent one first HF hospitalization within 1 year) was 27 (estimated hazard ratio: 0.75, P < 0.0001). For recurrent HF hospitalizations, one event would be prevented on average per 14 patient-years for any year of follow-up over the course of SHIFT (estimated rate ratio: 0.71, P < 0.0001). A key limitation of this analysis is that it did not account for a relationship between recurrent HF hospitalizations and subsequent mortality. CONCLUSION: In chronic systolic HF the effect of ivabradine on reducing recurrent HF hospitalizations results in a lower NNT compared to the effect on the time for first hospitalization. The effect of ivabradine on recurrent hospitalizations, in addition to first events, may be a more appropriate measure when considering the impact of a treatment with ivabradine on healthcare resource utilization.

Retrospective cost analysis of gemcitabine in combination with cisplatin in non-small cell lung cancer compared to other combination therapies in Europe.

In two recent randomised trials, gemcitabine plus cisplatin (Gem/Cis) was found to be at least as effective as vinorelbine plus cisplatin (Vin/Cis), paclitaxel plus cisplatin (Pac/Cis), paclitaxel plus carboplatin (Pac/Carbo), or docetaxel plus cisplatin (Doc/Cis) in patients with advanced non-small cell lung cancer (NSCLC). In cost-minimisation analyses of these studies from the perspectives of the national health services of five European countries (France, Germany, Italy, Spain, UK), Gem/Cis was associated with lower average treatment-related costs than Vin/Cis, Pac/Cis, and Pac/Carbo, and similar or lower costs than Doc/Cis. The incremental cost savings per patient of Gem/Cis compared to Vin/Cis ranged from 827 Euro to 2055 Euro per patient and from 1616 Euro to 5342 Euro compared to the paclitaxel-containing regimens. Overall, results were generally similar between countries, and were robust to univariate sensitivity analyses. Although differences in healthcare systems mean that the results may not be generalisable to all countries/settings, these results provide an economic rationale for the use of Gem/Cis as a first-line treatment option in Europe for patients with NSCLC.

Cost-effectiveness analysis of rituximab treatment in patients in Germany with rheumatoid arthritis after etanercept-failure.

OBJECTIVE: The present health economic analysis investigated the cost-effectiveness-ratios of either (1) rituximab or (2) an alternative TNF-alpha-inhibiting agent as second line biological treatment in patients with active rheumatoid arthritis (RA) and an inadequate response to etanercept therapy. METHODS: Incremental cost per quality-adjusted life-year (QALY) gained by rituximab treatment of RA is compared to TNF-inhibitor change (standard sequence) in a Markov-model (perspective: health care payer, full life-time approach). Direct cost components taken into account were treatment costs (medication-, administration- and monitoring costs) and resource utilisation (outpatient costs, inpatient costs). Indirect costs were estimated separately by the assessment of impaired work capacity due to RA (2008 Euro currency, discount rate 3.5%). Utility measures for the different treatment options were obtained from the ACR-response rates of published pivotal clinical trials. RESULTS: Direct costs amount to euro 178,373 (standard sequence) and euro 192,295 (rituximab sequence), respectively, rendering incremental direct costs of euro 13,922. Incremental utilities yield 0.57 QALYs and the incremental cost-effectiveness-ratio (ICER) of rituximab compared to the standard sequence amounts to euro 24,517. Inclusion of indirect costs leads to less incremental costs and a lower ICER of euro 15,565/QALY. Thus, ICERs stay beneath the accepted threshold of euro 50,000/QALY. CONCLUSION: Rituximab appears to be a cost-effective treatment alternative compared to the switch between TNF-inhibitors as second line biological treatment in patients with active RA having failed etanercept.

Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs.

OBJECTIVES: To compare the patterns of American College of Rheumatology (ACR) response between tocilizumab and other biologic agents in patients with rheumatoid arthritis who have inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). METHODS: Systematic literature review identified similarly designed double-blind, randomized, placebo-controlled trials over an 18-year period that investigated the effectiveness of abatacept (2), rituximab (2), and TNF-alpha inhibitors etanercept, infliximab, and adalimumab (11) in DMARD-IR patients; data from 3 placebo-controlled, phase 3 trials for tocilizumab, a newly developed IL-6 inhibitor, were included. The endpoint of interest was ACR20/50/70 response criteria at 24 to 30 weeks. Results were analyzed simultaneously using Bayesian mixed-treatment comparison techniques. Nonoverlapping ACR response rates (ACR70) for each agent were compared among treatments to identify differences in ACR response pattern. Separate analyses of overlapping ACR20/50/70 responses were conducted to identify the source of any differences. Results were expressed as relative risk of ACR20/50/70 response and associated 95% credible interval (CrI). RESULTS: Patterns across nonoverlapping ACR response levels varied significantly across treatments. In subsequent analyses, the effectiveness of tocilizumab appeared to be comparable to that of other biologic agents for ACR20 and ACR50 responses but greater for ACR70. Specifically, tocilizumab had greater ACR70 responses than both TNF-alpha inhibitors (relative risk = 1.8; CrI = 1.2, 2.6) and abatacept (relative risk = 2.0; CrI = 1.3, 3.1). CONCLUSIONS: Among DMARD-IR patients, tocilizumab shows a pattern of response that differs from that of other biologic agents. Post-hoc analyses suggest that the difference lies in a higher likelihood of ACR70 response with tocilizumab.