Burden of central nervous system complications in sickle cell disease: A systematic review and meta-analysis.

Sickle cell disease (SCD) patients are at high risk of central nervous system (CNS) complications and may experience significant morbidity. The study was conducted to describe the comprehensive burden of SCD-related CNS complications and to identify patient-reported outcome (PRO) instruments for future research. The review included 32 studies published from January 2000 to 2020, evaluating humanistic and economic outcomes. Twenty-three studies reported humanistic outcomes, 16 of which measured cognitive function using Wechsler Intelligence Scales. A meta-analysis was conducted, finding full-scale intelligence quotient (IQ) was significantly lower in: overt stroke versus controls: -12.6 (p < .001); silent cerebral infarct (SCI) versus controls: -5.7 (p < .001); overt stroke versus SCI: -9.4 (p = .008); and any event versus controls: -7.6 (p < .001). This review quantified the cognitive deficits associated with CNS complications in pediatric SCD populations and highlights the need for improved prevention/treatment. As PRO evidence was limited, we discussed areas for future research.

Increased risk for atypical fractures associated with bisphosphonate use.

BACKGROUND: Studies suggest an increasing occurrence of atypical femoral fractures with the use of bisphosphonates. OBJECTIVE: To examine whether the use of bisphosphonates increases the risk for atypical fractures. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Literature search of MEDLINE, Embase and Cochrane CENTRAL (1948-June 2013). SELECTION CRITERIA: (i) randomized controlled trial or an observational study, (ii) evaluated bisphosphonate therapy versus no treatment and (iii) reported an incidence of subtrochanteric or diaphyseal fracture individually, or a composite of both. Two independent investigators completed study selection, data extraction and validity assessment. The Cochrane Risk of Bias Tool was used to assess the quality of included studies. RESULTS: Ten (n = 658497) studies were included in the meta-analysis which demonstrated a statistically significant increased risk of subtrochanteric or diaphyseal fracture with bisphosphonate use [adjusted odds ratios (AOR) = 1.99, 95% confidence intervals (CI)= 1.28-3.10] with I (2) = 84.3% (95% CI = 73.5%-89.5%) and Egger P = 0.01. Subtrochanteric fractures showed an AOR = 2.71 (95% CI = 1.86-3.95) with I (2) = 83.6% (95% CI = 64.3%-90.3%) and Egger's P = 2.29. Diaphyseal fractures had an AOR = 2.06 (95% CI = 1.70-2.50), I (2) = 29.7% (95% CI = 0%-73.7%) and Egger's P = 1.22. CONCLUSION: Results suggest there is an increased risk for atypical fractures associated with bisphosphonates and raises awareness to the potential complications related with bisphosphonates. These findings warrant the comprehensive evaluation of patients before initiating bisphosphonate therapy and highlights the need for additional medical decision analyses in future studies to compare the benefit over potential harms of bisphosphonate therapy.

Treatment Patterns and Healthcare Resource Utilization of Patients With Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Claims Data Analysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder commonly treated with complement inhibitors such as eculizumab, ravulizumab, and pegcetacoplan. This study aims to describe treatment patterns, healthcare resource utilization, and cost for newly diagnosed PNH patients in 2 large, health insurance claims databases: MarketScan and Optum. Among the 271 patients meeting the inclusion criteria in MarketScan, 57.9% were female, and the average age was 46.6 years. Among these newly diagnosed patients, 25.1% (n = 68) of patients received a PNH-specific pharmacologic treatment, and the average time from diagnosis to treatment was 4.7 months. The medication possession ratio was 97.0%, but discontinuation was common (58.8%). The average per-patient-per-month costs were $18,978, driven by pharmacy and infusion ($11,182), outpatient ($4086), and inpatient ($3318) costs. Despite the availability of multiple treatments, 39.9% of patients had an inpatient stay, and 50.9% had an emergency department visit. Better care management and the introduction of new treatment options are needed to address delays between diagnosis and treatment, and high rates of hospitalization and emergency department use among patients with PNH.

Prolonged versus standard-duration venous thromboprophylaxis in major orthopedic surgery: a systematic review.

BACKGROUND: The optimal duration of thromboprophylaxis after major orthopedic surgery is unclear. PURPOSE: To compare the benefits and harms of prolonged versus standard-duration thromboprophylaxis after major orthopedic surgery in adults. DATA SOURCES: Cochrane Central Register of Controlled Trials and Scopus from 1980 to July 2011 and MEDLINE from 1980 through November 2011, without language restrictions. STUDY SELECTION: Randomized trials reporting thromboembolic or bleeding outcomes that compared prolonged (≥21 days) with standard-duration (7 to 10 days) thromboprophylaxis. DATA ABSTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Eight randomized, controlled trials (3 good-quality and 5 fair-quality) met the inclusion criteria. High-strength evidence showed that compared with standard-duration therapy, prolonged prophylaxis resulted in fewer cases of pulmonary embolism (PE) (5 trials; odds ratio [OR], 0.14 [95% CI, 0.04 to 0.47]; absolute risk reduction [ARR], 0.8%), asymptomatic deep venous thrombosis (DVT) (4 trials; relative risk [RR], 0.48 [CI, 0.31 to 0.75]; ARR, 5.8%), symptomatic DVT (4 trials; OR, 0.36 [CI, 0.16 to 0.81]; ARR, 1.5%), and proximal DVT (6 trials; RR, 0.29 [CI, 0.16 to 0.52]; ARR, 7.1%). Moderate-strength evidence showed fewer symptomatic objectively confirmed episodes of venous thromboembolism (4 trials; RR, 0.38 [CI, 0.19 to 0.77]; ARR, 5.7%), nonfatal PE (4 trials; OR, 0.13 [CI, 0.03 to 0.54]; ARR, 0.7%), and DVT (7 trials; RR, 0.37 [CI, 0.21 to 0.64]; ARR, 12.1%) with prolonged prophylaxis. High-strength evidence showed more minor bleeding events with prolonged prophylaxis (OR, 2.44 [CI, 1.41 to 4.20]; absolute risk increase, 6.3%), and insufficient evidence from 1 trial on hip fracture surgery suggested more surgical-site bleeding events (OR, 7.55 [CI, 1.51 to 37.64]) with prolonged prophylaxis. LIMITATIONS: Data relevant to knee replacement or hip fracture surgery were scant and insufficient. Most trials had few events; the strength of evidence ratings that were used may not adequately capture uncertainty in such situations. CONCLUSION: Prolonged prophylaxis decreases the risk for venous thromboembolism, PE, and DVT while increasing the risk for minor bleeding in patients undergoing total hip replacement.

Real-world characteristics of patients with sickle cell disease who initiated crizanlizumab therapy.

OBJECTIVE: To provide real-word evidence of patients with SCD initiating crizanlizumab, their use of other SCD treatments, and crizanlizumab treatment patterns. METHODS: Using IQVIA's US-based, Longitudinal Patient-Centric Pharmacy and Medical Claims Databases patients with a diagnosis of SCD between November 1, 2018, and April 30, 2021, and ≥1 claim for crizanlizumab (date of first claim = index date) between November 1, 2019, and January 31, 2021 who were ≥16 years of age, and had ≥12 months of pre-index data were selected for analysis. Two cohorts were identified based on available follow-up time (3- and 6-month cohorts). Patient characteristics were reported along with pre- and post-index SCD treatments and crizanlizumab treatment patterns (e.g. total doses received, gap-days between doses, days on therapy, discontinuation, and restarts). RESULTS: 540 patients met the base inclusion criteria (345 in the 3-month cohort and 262 in the 6-month cohort. Most patients (64%) were female with a mean (SD) age of 35 (12) years overall. Concomitant hydroxyurea use was observed in 19-39% of patients, while concomitant L-glutamine use was observed for 4-8% of patients. 85% of 3-month cohort patients received at least two doses of crizanlizumab, while 66% of the 6-month cohort received at least 4 doses of crizanlizumab. The median number of gap days between doses was 1 or 2. CONCLUSIONS: 66% of patients who receive crizanlizumab receive at least 4 doses within 6-months. The low median number of gap days suggests high adherence.

The Burden of Sickle Cell Disease on Children and Their Caregivers: Caregiver Reports of Children's Health-Related Quality of Life and School Experiences, Caregiver Burden, and Their Association with Frequency of Vaso-Occlusive Crises.

Background: Children with sickle cell disease (SCD) experience a multiplex of disease-related symptoms and complications, including vaso-occlusive crises (VOCs), episodes characterized by extreme pain. Methods: A cross-sectional observational survey examined the health-related quality of life (HRQoL) and school experiences of children with SCD 2 months-11 years, burden experienced by their caregivers, and associations between these outcomes and VOC frequency. Caregivers (N=167) of children with SCD in the US completed the Infant-Toddler Quality of Life-Short Form 47 (ITQoL-SF47) for children 2 months-4 years, the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) and PROMIS Pain Interference and Sleep Disturbance Parent Proxy short forms for children 5-11 years, and a study-specific survey of school experiences. Results: Children with SCD 2 months-4 years had lower ITQoL-SF47 scores (ie, worse HRQoL, p<0.001) than a normative sample of children; across domains, differences ranged from 18.73-45.03 points and exceeded minimal important difference (MID) thresholds. Except for the behavior domain, children with SCD 5-11 years had lower scores on all CHQ-PF50 domains than the normative sample (p<0.001); differences ranged from 6.78-36.37 points and exceeded MID thresholds. Children with more frequent VOCs had lower HRQoL and worse school experiences than children with less frequent VOCs (p<0.05, except for behavior domains). The largest differences based on VOC frequency were observed for overall health and bodily pain/discomfort among children 2 months-4 years (differences=40.88 and 32.50 points, respectively), and bodily pain and role/social limitations due to physical health among children 5-11 years (differences=38.99 and 37.80, respectively). Caregivers of children with more frequent VOCs experienced greater burden than caregivers of children with less frequent VOCs, though specific areas of impact (eg, caregiver emotions, time) differed across child age groups. Conclusion: VOC frequency is negatively associated with HRQoL, highlighting the burden experienced by children with SCD and their caregivers.

Treatment patterns and burden of complications associated with sickle cell disease: A US retrospective claims analysis.

Complications associated with sickle cell disease (SCD) that are highly impactful for patients but until recently have been less understood include priapism, nephropathy, and neurologic injury. We conducted a retrospective study using US administrative claims data from July 01, 2013 through March 31, 2020 to analyze incidence of these complications, SCD treatment patterns, and healthcare resource utilization (HCRU) and costs among 2524 pediatric and adult patients with SCD (mean [SD] age 43.4 [22.4] years). The most common treatments during follow-up were short-acting opioids (54.0% of patients), red blood cell transfusion (15.9%), and hydroxyurea (11.0%). SCD complications occurred frequently; in the overall population, the highest follow-up incidences per 1000 person-years were for acute kidney injury (53.1), chronic kidney disease (40.6), and stroke (39.0). Complications occurred across all age groups but increased in frequency with age; notably, acute kidney injury was 69.7 times more frequent among ages 65+ than ages 0-15 (p < 0.001). Follow-up per-patient-per-month HCRU also increased with age; however, all-cause healthcare costs were similarly high for all age groups and were driven primarily by inpatient stays. Patients with SCD across the age spectrum have a high burden of complications with the use of current treatments, suggesting unmet needs for treatment management.

Real-world healthcare resource utilization and costs associated with tisagenlecleucel and axicabtagene ciloleucel among patients with diffuse large B-cell lymphoma: an analysis of hospital data in the United States.

This study compared the real-world healthcare resource utilization (HRU), costs, adverse events (AEs), and AE treatments associated with the chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Adults with DLBCL who received tisa-cel or axi-cel were identified in the Premier Healthcare Database (2017-2020). Non-CAR-T costs, HRU, and AE rates during the infusion and follow-up periods were compared between the tisa-cel and axi-cel cohorts. Of 119 patients, 33 received tisa-cel (86% as inpatient infusion) and 86 received axi-cel (100% inpatient). Tisa-cel was associated with significantly shorter mean inpatient length of stay than axi-cel during infusion (11.3 vs. 18.3 days) and follow-up ([monthly] 3.9 vs. 6.9 days). Non-CAR-T costs were significantly lower for tisa-cel compared with axi-cel during infusion ($27594.8 vs. $51378.3) and follow-up ([monthly] $28777.3 vs. $46575.7; both p< .05). Rates of AEs and AE treatments were similar.

Systematic review: comparative effectiveness of adjunctive devices in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention of native vessels.

BACKGROUND: During percutaneous coronary intervention (PCI), dislodgement of atherothrombotic material from coronary lesions can result in distal embolization, and may lead to increased major adverse cardiovascular events (MACE) and mortality. We sought to systematically review the comparative effectiveness of adjunctive devices to remove thrombi or protect against distal embolization in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI of native vessels. METHODS: We conducted a systematic literature search of Medline, the Cochrane Database, and Web of Science (January 1996-March 2011), http://www.clinicaltrials.gov, abstracts from major cardiology meetings, TCTMD, and CardioSource Plus. Two investigators independently screened citations and extracted data from randomized controlled trials (RCTs) that compared the use of adjunctive devices plus PCI to PCI alone, evaluated patients with STEMI, enrolled a population with 95% of target lesion(s) in native vessels, and reported data on at least one pre-specified outcome. Quality was graded as good, fair or poor and the strength of evidence was rated as high, moderate, low or insufficient. Disagreement was resolved through consensus. RESULTS: 37 trials met inclusion criteria. At the maximal duration of follow-up, catheter aspiration devices plus PCI significantly decreased the risk of MACE by 27% compared to PCI alone. Catheter aspiration devices also significantly increased the achievement of ST-segment resolution by 49%, myocardial blush grade of 3 (MBG-3) by 39%, and thrombolysis in myocardial infarction (TIMI) 3 flow by 8%, while reducing the risk of distal embolization by 44%, no reflow by 48% and coronary dissection by 70% versus standard PCI alone. In a majority of trials, the use of catheter aspiration devices increased procedural time upon qualitative assessment.Distal filter embolic protection devices significantly increased the risk of target revascularization by 39% although the use of mechanical thrombectomy or embolic protection devices did not significantly impact other final health outcomes. Distal balloon or any embolic protection device increased the achievement of MBG-3 by 61% and 20% and TIMI3 flow by 11% and 6% but did not significantly impact other intermediate outcomes versus control. Upon qualitative analysis, all device categories, with exception of catheter aspiration devices, appear to significantly prolong procedure time compared to PCI alone while none appear to significantly impact ejection fraction. Many of the final health outcome and adverse event evaluations were underpowered and the safety of devices overall is unclear due to insufficient amounts of data. CONCLUSIONS: In patients with STEMI, for most devices, few RCTs evaluated final health outcomes over a long period of follow-up. Due to insufficient data, the safety of these devices is unclear.

A systematic literature review of frequency of vaso-occlusive crises in sickle cell disease.

BACKGROUND AND PURPOSE: Sickle cell disease (SCD) is a collection of rare inherited blood disorders affecting approximately 100,000 people in the U.S. and 20-25 million people globally. Individuals with SCD experience recurrent episodes of severe and unpredictable pain that are caused by vaso-occlusive crises (VOCs), a hallmark of the disease. VOCs are the primary cause of hospitalization in SCD, result in missed workdays and school days, and decrease quality of life (QoL). Although VOCs cause significant burden in the lives of individuals with SCD, there is no synthesis on the frequency of VOCs in the real world. This systematic literature review sought to identify literature describing the frequency of VOCs experienced by individuals with SCD in real-world settings. METHODS: MEDLINE and 6 congresses were searched (date range: January 1, 2000 to June 30, 2020). Studies were reviewed independently by two researchers. Studies assessing frequency or prevalence of VOCs or VOC-related outcomes were included. RESULTS: Of 1438 studies identified in the search, 52 met pre-specified inclusion and exclusion criteria. Reported frequency of VOCs varied widely ranging from a mean or median of 0 VOCs/year to 18.2 VOCs/year. The proportion of patients experiencing ≥ 3 VOCs/year ranged from 4 to 67% and the proportion of patients experiencing ≥ 5 VOCs/year ranged from 18 to 59%. Measures of VOC severity were limited, with 13 studies considering frequency of complicated VOCs and only 1 study reporting duration of VOC episodes. CONCLUSIONS: This is the first study to systematically assess published evidence pertaining to VOCs in real-world settings. Reported VOC frequency in real-world settings varied widely, with a majority of studies only considering VOCs managed in an inpatient or outpatient setting. Studies that considered VOCs managed at home reported a higher frequency of VOCs, suggesting that many studies may underestimate the frequency of VOCs. This systematic literature review (SLR) highlights the need for consistent reporting of (1) self-reported VOCs, including those managed at home, (2) definitions of VOCs, (3) complicated VOCs, and (4) duration of VOC episodes in literature.

Patient-Reported Outcomes and Economic Burden of Adults with Sickle Cell Disease in the United States: A Systematic Review.

PURPOSE: To systematically estimate the patient-reported outcomes (PROs) and economic burden of sickle cell disease (SCD) among adults in the United States (US). PATIENTS AND METHODS: Two systematic literature reviews (SLRs), one each for the PROs and economic topics, were performed using MEDLINE and Embase to identify observational studies of adults with SCD. Included studies were published between 2007 and 2018 and evaluated health-related quality of life (HRQL), function, healthcare resource utilization (HCRU), or costs. Given the high degree of clinical and methodological heterogeneity, findings were summarized qualitatively. RESULTS: The SLRs identified 7 studies evaluating the PROs and 15 studies evaluating the economic burden meeting the pre-specified selection criteria. The PRO evidence showed the prevalence of depression and anxiety to be 21-33% and 7-36%, respectively, in adults with SCD. The mean SF-36 physical summary scores ranged from 33.6 to 59.0 and from 46.3 to 61.5 for the mental summary scores. Overall HRQL for adults with SCD was poor and significantly worse in those with opioid use. Adult SCD patients were found to have varying rates of emergency department (ED) utilization (0.3-3.5 annual ED visits), hospitalizations (0.5-27.9 per patient per year), and/or readmission (12-41%). Key factors associated with significant HCRU were age, dental infection, and SCD-related complications. SCD specialized care settings and SCD intensive management strategy were reported to significantly decrease the number of hospitalizations. CONCLUSION: This systematic evidence synthesis found that disease burden measured by PROs and economic burden of SCD on adults in the US are substantial despite the availability of approved SCD treatments during 2007-2018. The use of hydroxyurea, optimal management with opioids, and employing intensive treatment strategies may help decrease the overall burden to patients and healthcare systems. Published data on costs associated with SCD are limited and highlight the need for more economic studies to characterize the full burden of the disease.

A meta-analysis of the placebo response in antimuscarinic drug trials for overactive bladder.

BACKGROUND: The purpose of this analysis was to characterize the placebo response in antimuscarinic drug trials for OAB, based on changes in commonly-used efficacy endpoints. METHODS: Placebo arm data for incontinence episodes, micturitions, voided volume and study characteristics were extracted from randomized placebo controlled antimuscarinic drug trials in OAB, from studies identified in a prior meta-analysis, and from a systematic review of more recently published studies. Relationships between variables were examined using linear regression, and changes in endpoints were analyzed by a meta-analysis approach. The effect of placebo arm size and magnitude of placebo response on probability of successful study outcome was analyzed using an ANOVA model. RESULTS: Changes in the placebo arms for all 3 endpoints were substantial and statistically significant, and highly heterogeneous. There were significant associations between baseline and change scores for some but not all of the endpoints. More recent studies tended to have more subjects than earlier studies, and there were positive associations between probability of achieving statistically significant results and size of the placebo arm. The magnitude of changes in placebo arms did not appear to influence the likelihood of the study to be statistically significant. CONCLUSION: This analysis confirms earlier observation that the placebo response in OAB trials is substantial and highly heterogeneous. There are multiple potential reasons for this; however, these could not be explored in this analysis of study-level data. Two approaches may be used in clinical trials to manage high placebo effect: recruitment of 1) greater numbers of patients and/or 2) more severely affected patients; however, only the former approach is associated with increased probability of successful study outcome.

Mapping the 12-item multiple sclerosis walking scale to the EuroQol 5-dimension index measure in North American multiple sclerosis patients.

OBJECTIVE: To map the 12-item Multiple Sclerosis Walking Scale (MSWS-12) onto the EuroQol 5-dimension (EQ-5D) health-utility index in multiple sclerosis (MS) patients participating in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry. DESIGN: Cross-sectional MSWS-12 to EQ-5D cross-walking analysis. SETTING: NARCOMS registry spring 2010 biannual update and supplemental survey. PARTICIPANTS: North American patients completing both the MSWS-12 and the EQ-5D randomly split into derivation and validation cohorts. OUTCOME MEASURES: Ordinary least squares regression was performed within the derivation cohort, with participants' EQ-5D as the dependent variable. Results of the MSWS-12 were input as independent variable(s) into six regression models. Model goodness-of-fit was subsequently assessed in the validation cohort using the mean absolute error (MAE), root mean square error (RMSE) and the adjusted R(2). The best performing model was refined in the entire cohort and utilised for additional analyses. RESULTS: A total of 3505 NARCOMS participants were included. Their mean±SD EQ-5D and MSWS-12 scores were 0.74±0.18 and 50.8±33.5, respectively, and these assessments were found to be moderately correlated (r=-0.553, p<0.001). The model using all individual MSWS-12 item scores as independent variables was found to have the best fit (MAE=0.109±0.096, RMSE=0.145, adjusted R(2)=0.329). The percentage of EQ-5D estimates within 0.05 and 0.10 of the actual value were 30% and 61%, respectively. This mapping equation was more precise in patients with moderate mobility impairment (MAE=0.087±0.061 at patient-determined disease step (PDDS) of 3-6) and less precise in patients with no (MAE=0.141±0.128 at PDDS of 0-2) or severe mobility impairment (MAE=0.121±0.049 at PDDS ≥7). CONCLUSIONS: The EQ-5D scores can be predicted using the MSWS-12 item scores with reasonable precision in North American patients with MS. Prediction estimates were more precise in patients with moderate mobility impairment.

Comparative effectiveness of combined pharmacologic and mechanical thromboprophylaxis versus either method alone in major orthopedic surgery: a systematic review and meta-analysis.

STUDY OBJECTIVE: To evaluate the comparative efficacy and safety of combination pharmacologic and mechanical venous thromboembolism (VTE) prophylaxis versus either method alone in major orthopedic surgery. DESIGN: Systematic review with meta-analysis of six randomized controlled trials. PATIENTS: Patients undergoing total hip replacement, total knee replacement, or hip fracture surgery who received VTE prophylaxis. MEASUREMENTS AND MAIN RESULTS: We conducted a systematic literature search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus databases (January 1980-July 2011) to identify trials that directly compared pharmacologic plus mechanical VTE prophylaxis to either strategy alone, evaluated United States Food and Drug Administration-approved agents, and reported rates of mortality, VTE, bleeding, and other adverse effects. Six trials were included, none of which were conducted in patients who had hip fracture surgery. The quality of each trial was evaluated, and the strength of evidence for each outcome was rated. No significant difference was found in the rate of pulmonary embolism or nonfatal pulmonary embolism when the combination of pharmacologic and mechanical prophylaxis was compared to pharmacologic prophylaxis alone, with low strength of evidence. The risk of deep vein thrombosis (DVT) was significantly decreased in the combination group (relative risk [RR] 0.48 [95% confidence interval (CI) 0.32-0.72]), with moderate strength of evidence, with benefits of combination therapy persisting in the total knee replacement subgroup (RR 0.41 [95% CI 0.25-0.68]). There was insufficient evidence to evaluate other final or intermediate outcomes or harms. In the comparison of combined pharmacologic and mechanical prophylaxis to mechanical prophylaxis alone, there was insufficient evidence to evaluate any final health outcomes or harms. There was no significant difference in the risk of proximal DVT when comparing combination prophylaxis to mechanical prophylaxis alone (RR 0.78 [95% CI 0.35-1.74]) based on low strength of evidence. CONCLUSIONS: The risk of DVT was decreased with the use of combination prophylaxis versus pharmacologic prophylaxis alone in patients undergoing total hip replacement or total knee replacement. However, due to primarily insufficient evidence for most outcomes evaluated, the balance of benefits to harms of combined pharmacologic and mechanical prophylaxis versus either strategy alone cannot be determined in patients undergoing major orthopedic surgery.

Cost-effectiveness of apixaban compared with warfarin for stroke prevention in atrial fibrillation.

BACKGROUND: Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention. METHODS: Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS(2) score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios. RESULTS: Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY. CONCLUSIONS: In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.

Cost-effectiveness of apixaban compared with aspirin for stroke prevention in atrial fibrillation among patients unsuitable for warfarin.

BACKGROUND: Compared with aspirin, apixaban reduces stroke risk in atrial fibrillation (AF) patients unsuitable for warfarin by 63% but does not increase major bleeding. We sought to determine the cost-effectiveness of apixaban versus aspirin. METHODS AND RESULTS: Using the Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin-K Antagonist Treatment (AVERROES) trial and other studies, we constructed a Markov model to evaluate the costs (2011US$), quality-adjusted life-years (QALYs), and incremental cost-effectiveness of apixaban versus aspirin from the Medicare perspective. Our base-case assumed a 70-year-old AF patient cohort with a CHADS(2) score=2 and a lower-risk of bleeding. We used a 1-month cycle-length and ran separate base-case analyses assuming a trial-length (1-year) and a longer-term (10-year) follow-up. Total costs/patient were $3454 and $1805 for apixaban and aspirin in the trial-length and $44 232 and $50 066 in the 10-year model. Corresponding QALYs were 0.96 and 0.96 in the trial-length and 6.87 and 6.51 in the 10-year model, making apixaban inferior in the first model but dominant in the latter. Conclusions were sensitive to baseline stroke rate in both models, and the monthly cost of major stroke, relative risk of stroke, and prior vitamin-K antagonist use in the life-time model. Probabilistic sensitivity analysis suggested apixaban would only be a cost-effective alternative (<$50 000/QALY) to aspirin 11% of the time in the trial-length model, but cost-effective or dominant 96.7% and 87.5% of iterations in the 10-year model. CONCLUSIONS: In our trial-length model, apixaban was more costly and no more effective than aspirin; however, as follow-up was extended, apixaban became cost-effective and eventually dominant.

Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation.

Rivaroxaban has been found to be noninferior to warfarin for preventing stroke or systemic embolism in patients with high-risk atrial fibrillation (AF) and is associated with a lower rate of intracranial hemorrhage. To assess the cost-effectiveness of rivaroxaban compared to adjusted-dose warfarin for the prevention of stroke in patients with AF, we built a Markov model using a United States payer/Medicare perspective and a lifetime time horizon. The base-case analysis assumed a cohort of patients with AF 65 years of age with a congestive heart failure, hypertension, age, diabetes, stroke (2 points) score of 3 and no contraindications to anticoagulation. Data sources included the Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and other studies of anticoagulation. Outcome measurements included costs in 2011 United States dollars, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Patients with AF treated with rivaroxaban lived an average of 10.03 QALYs at a lifetime treatment cost of $94,456. Those receiving warfarin lived an average of 9.81 QALYs and incurred costs of $88,544. The ICER for rivaroxaban was $27,498 per QALY. These results were most sensitive to changes in the hazard decrease of intracranial hemorrhage and stroke with rivaroxaban, cost of rivaroxaban, and time horizon. Monte Carlo simulation demonstrated rivaroxaban was cost-effective in 80% and 91% of 10,000 iterations at willingness-to-pay thresholds of $50,000 and $100,000 per QALY, respectively. In conclusion, this Markov model suggests that rivaroxaban therapy may be a cost-effective alternative to adjusted-dose warfarin for stroke prevention in AF.

Cost-effectiveness of fingolimod versus interferon beta-1a for relapsing remitting multiple sclerosis in the United States.

OBJECTIVE: Fingolimod has been shown to be more efficacious than interferon (IFN) beta-1a, but at a higher drug acquisition cost. The aim of this study was to assess the cost-effectiveness of fingolimod compared to IFN beta-1a in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) in the US. METHODS: A Markov model comparing fingolimod to intramuscular IFN beta-1a using a US societal perspective and a 10-year time horizon was developed. A cohort of 37-year-old patients with RRMS and a Kurtzke Expanded Disability Status Scale score of 0-2.5 were assumed. Data sources included the Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) and other published studies of MS. Outcomes included costs in 2011 US dollars, quality-adjusted life years (QALYs), number of relapses avoided, and incremental cost-effectiveness ratios (ICERs). RESULTS: Compared to IFN beta-1a, fingolimod was associated with fewer relapses (0.41 vs 0.73 per patient per year) and more QALYs gained (6.7663 vs 5.9503), but at a higher cost ($565,598 vs $505,234). This resulted in an ICER of $73,975 per QALY. Results were most sensitive to changes in drug costs and the disutility of receiving IFN beta-1a. Monte Carlo simulation demonstrated fingolimod was cost-effective in 35% and 70% of 10,000 iterations, assuming willingness-to-pay thresholds of $50,000 and $100,000 per QALY, respectively. LIMITATIONS: Event rates were primarily derived from a single randomized clinical trial with 1-year duration of follow-up and extrapolated to a 10-year time horizon. Comparison was made to only one disease-modifying drug-intramuscular IFN beta-1a. CONCLUSION: Fingolimod use is not likely to be cost-effective compared to IFN beta-1a unless fingolimod cost falls below $3476 per month or a higher than normal willingness-to-pay threshold is accepted by decision-makers.

Dosing frequency and medication adherence in chronic disease.

BACKGROUND: Prior research has shown a decrease in medication adherence as dosing frequency increases; however, meta-analyses have not been able to demonstrate a significant inverse relationship between dosing frequency and adherence when comparing twice-daily versus once-daily dosing. OBJECTIVE: To determine the effect of scheduled dosing frequency on medication adherence in patients with chronic diseases. METHODS: A systematic literature search of Medline and Embase from January 1986 to December 2011 and a hand search of references were performed to identify eligible studies. Randomized and observational studies were included if they utilized a prospective design, assessed adult patients with chronic diseases, evaluated scheduled oral medications taken 1 to 4 times daily, and measured medication adherence for at least 1 month using an electronic monitoring device. Manual searches of reference sections of identified studies and systematic reviews were also performed to find other potentially relevant articles. Standard definitions for medication taking, regimen, and timing adherence were used and evaluated. Studies were pooled using a multivariate linear mixed-model method to conduct meta-regression accounting for both random and fixed effects, weighted by the inverse of the variance of medication adherence. RESULTS: Fifty-one studies, comprising 65, 76, and 47 dosing frequency arms for the taking, regimen, and timing adherence endpoints were included. Unadjusted adherence estimates were highest when the least stringent definition, taking adherence, was used (range for dosing frequencies: 80.1%-93.0%) and lowest when the most stringent definition, timing adherence, was used (range for dosing frequencies: 18.8%-76.9%). In multivariate meta-regression analyses, the adjusted weighted mean percentage adherence rates for all regimens dosed more frequently than once per day were significantly lower compared with once-daily regimens (for 2-times, 3-times, and 4-times daily regimens, respectively: differences for taking adherence: -6.7%, -13.5%, and -19.2%; regimen adherence: -13.1%, -24.9%, and -23.1%; and timing adherence: -26.7%, -39.0%, and -54.2%). CONCLUSION: Patients with chronic diseases appear to be more adherent with once-daily compared with more frequently scheduled medication regimens. The use of more stringent definitions of adherence magnified these findings.