Estimating chronic hepatitis C prognosis using transient elastography-based liver stiffness: A systematic review and meta-analysis.

Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naïve CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta-analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to-cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates.

Long-term health care costs for prostate cancer patients on androgen deprivation therapy.

BACKGROUND: Comparing relative costs for androgen deprivation therapy (adt) protocols in prostate cancer (pca) requires an examination of all health care resources, not only those specific to pca. The objective of the present study was to use administrative data to estimate total health care costs in a population-based cohort of pca patients. METHODS: Patients in Ontario with pca who started 90 days or more of adt at age 66 years or older during 1995-2005 were selected from cancer registry and health care administrative databases. We classified patients (n = 21,818) by regimen (medical castration, orchiectomy, anti-androgen monotherapy, medical castration with anti-androgen, orchiectomy with anti-androgen) and indication (neoadjuvant, adjuvant, metastatic disease, biochemical recurrence, primary nonmetastatic). Using nonparametric regression methods, with inverse probability weighting to adjust for censoring, and bootstrapping, we computed mean 1-year, 5-year, and 10-year longitudinal total direct medical costs (2009 Canadian dollars). RESULTS: Mean first-year costs were highest for metastatic disease, ranging from $24,400 for orchiectomy to $32,120 for anti-androgen monotherapy. Mean first-year costs for all other indications were less than $20,000. Mean 5-year and 10-year costs were lowest for neoadjuvant treatment: approximately $43,000 and $81,000 respectively, with differences of less than $4,000 between regimens. Annual costs were highest in the first year of adt. Orchiectomy was the least costly regimen for most time periods, but was limited to primary and metastatic indications. Outpatient drugs, including pharmacologic adt, accounted for 17%-65% of total first-year costs. CONCLUSIONS: Compared with combined therapies, the adt monotherapies, particularly orchiectomy when clinically feasible, are more economical. Our methods exemplified the use of algorithms to elucidate clinical information from administrative data. Our approach can be adapted for other cancers to expand the range of studies using Canadian administrative data.

Population-based trends in systemic therapy use and cost for cancer patients in the last year of life.

BACKGROUND: The use of systemic therapy near the end of life can expose cancer patients to severe toxicity for minimal survival gain and comes with a high cost. Early palliative care is recommended, but there is evidence that aggressive care remains common. To better understand those patterns, the present study set out to describe trends in systemic therapy use and cost for cancer patients in the last year of life. METHODS: Using the BC Cancer Registry, a retrospective population-based cohort of cancer decedents (2002-2007) was identified and linked to systemic therapy records. The outcomes of interest were any systemic therapy use and total systemic therapy costs during the last year of life. Multiple logistic regression (systemic therapy use) and generalized linear regression (costs) were conducted, adjusting for age, sex, and survival. Subgroup analyses were performed for patients with primary colorectal, lung, prostate, or breast cancer. RESULTS: From 2002 to 2007, use of systemic therapy in the last 12-4 months of life increased by 21% (95% ci: 10% to 33%); no significant change in use in the last 3 months of life was observed. Costs for both periods increased over time, by 48% (95% ci: 36% to 63%) and by 33% (95% ci: 19% to 49%) respectively. The trends varied across cancer sites, with the greatest increases being observed for lung and colorectal cancer patients. CONCLUSIONS: The use and costs of systemic therapy have generally been increasing, putting pressure on health care providers and payers, but the quality-of-life implications for patients must be better understood.

Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis.

UNLABELLED: We completed a network meta-analysis of published papers to compare bisphosphonate gastrointestinal safety. We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events. Etidronate had the highest chance of discontinuation due to an adverse event. No difference was found for serious adverse events. INTRODUCTION: Bisphosphonates are first-line treatment for osteoporosis. Gastrointestinal (GI) adverse events (AE) are the primary reason for non-adherence. Little is known about the comparative GI safety of bisphosphonates. PURPOSE: Leverage published clinical trial data to examine the comparative GI safety of bisphosphonates. METHODS: We completed a systematic review of all English-language clinical trials that assessed bisphosphonate safety and/or efficacy in primary osteoporosis through to 2012. Randomized, blinded, and controlled studies were eligible. The primary outcome was any GI-related AE. Subanalyses were completed for upper GI symptoms, serious GI, nausea, esophageal-related events, and discontinuation due to AE. A Bayesian-based network meta-analysis was completed to allow for indirect comparisons. Results were reported as the probability that a specific drug had the highest number of events. RESULTS: We identified 50 studies: 32 alendronate, 12 risedronate, 5 etidronate, and 7 zoledronic acid. Zoledronic acid had the highest probability of having the highest number of any GI AE (91%) and nausea (70%). Etidronate (70%) and zoledronic acid (28%) had the highest probability of having the greatest attrition due to AE. Etidronate had the highest probability (56%) of having the greatest number of upper GI symptoms among oral bisphosphonates. CONCLUSION: Zoledronic acid had the highest probability of causing the greatest number of GI AE, possibly related to nausea. These results question the assumption that annual zoledronic acid will translate into better adherence. Little difference was found between alendronate and risedronate for serious AE. More research into real-world implications of the comparative safety of bisphosphonates is needed.

Health care costs for prostate cancer patients receiving androgen deprivation therapy: treatment and adverse events.

BACKGROUND: Serious adverse events have been associated with androgen deprivation therapy (adt) for prostate cancer (pca), but few studies address the costs of those events. METHODS: All pca patients (ICD-9-CM 185) in Ontario who started 90 days or more of adt or had orchiectomy at the age of 66 or older during 1995-2005 (n = 26,809) were identified using the Ontario Cancer Registry and drug and hospital data. Diagnosis dates of adverse events-myocardial infarction, acute coronary syndrome, congestive heart failure, stroke, deep vein thrombosis or pulmonary embolism, any diabetes, and fracture or osteoporosis-before and after adt initiation were determined from administrative data. We excluded patients with the same diagnosis before and after adt, and we allocated each patient's time from adt initiation to death or December 31, 2007, into health states: adt (no adverse event), adt-ae (specified single adverse event), Multiple (>1 event), and Final (≤180 days before death). We used methods for Canadian health administrative data to estimate annual total health care costs during each state, and we examined monthly trends. RESULTS: Approximately 50% of 21,811 patients with no pre-adt adverse event developed 1 or more events after adt. The costliest adverse event state was stroke ($26,432/year). Multiple was the most frequent (n = 2,336) and the second most costly health state ($24,374/year). Costs were highest in the first month after diagnosis (from $1,714 for diabetes to $14,068 for myocardial infarction). Costs declined within 18 months, ranging from $784 per 30 days (diabetes) to $1,852 per 30 days (stroke). Adverse events increased the costs of adt by 100% to 265%. CONCLUSIONS: The economic burden of adverse events is relevant to programs and policies from clinic to government, and that burden merits consideration in the risks and benefits of adt.

Direct health-care costs attributed to hip fractures among seniors: a matched cohort study.

SUMMARY: Using a matched cohort design, we estimated the mean direct attributable cost in the first year after hip fracture in Ontario to be $36,929 among women and $39,479 among men. These estimates translate into an annual $282 million in direct attributable health-care costs in Ontario and $1.1 billion in Canada. INTRODUCTION: Osteoporosis is a major public health concern that results in substantial fracture-related morbidity and mortality. It is well established that hip fractures are the most devastating consequence of osteoporosis, yet the health-care costs attributed to hip fractures in Canada have not been thoroughly evaluated. METHODS: We determined the 1- and 2-year direct attributable costs and cost drivers associated with hip fractures among seniors in comparison to a matched non-hip fracture cohort using health-care administrative data from Ontario (2004-2008). Entry into long-term care and deaths attributable to hip fracture were also determined. RESULTS: We successfully matched 22,418 female (mean age = 83.3 years) and 7,611 male (mean age = 81.3 years) hip fracture patients. The mean attributable cost in the first year after fracture was $36,929 (95 % CI $36,380-37,466) among women and $39,479 (95 % CI $38,311-$40,677) among men. These estimates translate into an annual $282 million in direct attributable health-care costs in Ontario and $1.1 billion in Canada. Primary cost drivers were acute and post-acute institutional care. Approximately 24 % of women and 19 % of men living in the community at the time of fracture entered a long-term care facility, and 22 % of women and 33 % of men died within the first year following hip fracture. Attributable costs remained elevated into the second year ($9,017 among women, $10,347 among men) for patients who survived the first year. CONCLUSIONS: We identified significant health-care costs, entry into long-term care, and mortality attributed to hip fractures. Results may inform health economic analyses and policy decision-making in Canada.

Changes in bone mineral density in men starting androgen deprivation therapy and the protective role of vitamin D.

SUMMARY: Androgen deprivation therapy in 80 men was associated with declines in bone mineral density (BMD), which were greatest in the first year, and in the lumbar spine compared to controls. Vitamin D use was associated with improved BMD in the lumbar spine and in the first year. INTRODUCTION: Decreased BMD is a common side effect of androgen deprivation therapy (ADT), leading to increased risk of fractures. Although loss of BMD appears to be greatest within the first year of starting ADT, there are few long-term studies of change in BMD, and risk factors for bone loss are not well-characterized. METHODS: Men aged 50+ with nonmetastatic prostate cancer starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual-energy x-ray absorptiometry at baseline and yearly for 3 years. Matched controls were men with prostate cancer not receiving ADT. Multivariable regression analysis examined predictors of BMD loss. RESULTS: Eighty ADT users and 80 controls were enrolled (mean age 69 years); 52.5 % had osteopenia and 8.1 % had osteoporosis at baseline. After 1 year, in adjusted models, ADT was associated with significant losses in lumbar spine BMD compared to controls (-2.57 %, p = 0.006), with a trend towards greater declines at the total hip (p = 0.09). BMD changes in years 2 and 3 were much smaller and not statistically different from controls. Use of vitamin D but not calcium was associated with improved BMD in the lumbar spine in year 1 (+6.19 %, p < 0.001) with smaller nonsignificant increases at other sites (+0.86 % femoral neck, +0.86 % total hip, p > 0.10) primarily in the first year. CONCLUSIONS: Loss of BMD associated with ADT is greatest at the lumbar spine and in the first year. Vitamin D but not calcium may be protective particularly in the first year of ADT use.

Prognosis of hepatitis C virus-infected Canadian post-transfusion compensation claimant cohort.

Accurate prognostic estimates were required to ensure the sufficiency of the $1.1 billion compensation fund established in 1998 to compensate Canadians who acquired hepatitis C virus (HCV) infection through blood transfusion between 1986 and 1990. This article reports the application of Markov modelling and epidemiological methods to estimate the prognosis of individuals who have claimed compensation. Clinical characteristics of the claimant cohort (n = 5004) were used to define the starting distribution. Annual stage-specific transition probabilities (F0-->F1, . . ., F3-->F4) were derived from the claimants, using the Markov maximum likelihood estimation method. HCV treatment efficacy was derived from the literature and practice patterns were estimated from a national survey. The estimated stage-specific transition probabilities of the cohort between F0-->F1, F1-->F2, F2-->F3 and F3-->F4 were 0.032, 0.137, 0.150 and 0.097 respectively. At 20 years after the index transfusion, approximately 10% of all living claimants (n = 3773) had cirrhosis and 0.5% developed hepatocellular carcinoma (HCC). For nonhaemophilic patients, the predicted 20-year (2030) risk of HCV-related cirrhosis was 23%, and the risk of HCC and liver-related death was 7% and 11% respectively. Haemophilic patients who are younger and are frequently co-infected with human immunodeficiency virus would have higher 20-year risks of cirrhosis (37%), HCC (12%) and liver-related death (19%). Our results indicate that rates of progression to advanced liver disease in post-transfusion cohorts may be lower than previously reported. The Canadian post-transfusion cohort offers new and relevant prognostic information for post-transfusion HCV patients in Canada and is an invaluable resource to study the natural history and resource utilization of HCV-infected individuals in future studies.

Economic evaluation of chemotherapy with mitoxantrone plus prednisone for symptomatic hormone-resistant prostate cancer: based on a Canadian randomized trial with palliative end points.

PURPOSE: To evaluate the economic consequences of the use of chemotherapy in patients with symptomatic hormone-resistant prostate cancer (HRPC) in the context of a previously published Canadian open-label, phase III, randomized trial with palliative end points. PATIENTS AND METHODS: The trial randomized 161 patients to initial treatment with mitoxantrone and prednisone (M + P) or to prednisone alone (P) and showed better palliation with M + P. There was no significant difference in survival. A detailed retrospective chart review was performed of resources used from randomization until death of 114 of 161 patients enrolled at the three largest centers: these included hospital admissions, outpatient visits, investigations, therapies (which included all chemotherapy and radiation), and palliative care. Cancer center and community hospital costs were calculated by using the hotel approximation method and case costing from the Ontario Case Cost Project, respectively. Cost-utility analysis was performed by transforming the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 global quality-of-life item measured every 3 weeks on trial to an estimate of utility, and extending the last known value through to death or last follow-up. RESULTS: The mean total cost until death or last follow-up by intention-to-treat was M + P CDN $27,300; P CDN $29,000. The 95% confidence intervals on the observed cost difference ranged from a saving of $9,200 for M + P (with palliative benefit) to an increased cost of $5,800 for M + P. The major proportion of cost (M + P 53% v P 66%; CDN $14,500 v $19,100) was for inpatient care. Initial M + P was consistently less expensive in whichever time period was used to compare costs. Cost-utility analysis showed M + P to be the preferred strategy with an upper 95% confidence interval for the incremental cost-utility ratio of CDN $19,700 per quality-adjusted life-year (QALY). CONCLUSION: A treatment that reduces symptoms and improves quality of life has the potential to reduce costs in other areas. Economic factors should not influence the clinical decision as to whether to use M + P in a symptomatic patient.

Primer on medical decision analysis: Part 3--Estimating probabilities and utilities.

This paper describes how to estimate probabilities and outcome values for decision trees. Probabilities are usually derived from published studies, but occasionally are derived from existing databases, primary data collection, or expert judgment. Outcome values represent quantitative estimates of the desirability of the outcome states, and are often expressed as utility values between 0 and 1. Utility values for different health states can be derived from the published literature, from direct measurement in appropriate subjects, or from expert opinion. Methods for assigning utilities to complex outcome states are described, and the concept of quality-adjusted life years is introduced.

Primer on medical decision analysis: Part 5--Working with Markov processes.

Clinical decisions often have long-term implications. Analysis encounter difficulties when employing conventional decision-analytic methods to model these scenarios. This occurs because probability and utility variables often change with time and conventional decision trees do not easily capture this dynamic quality. A Markov analysis performed with current computer software programs provides a flexible and convenient means of modeling long-term scenarios. However, novices should be aware of several potential pitfalls when attempting to use these programs. When deciding how to model a given clinical problem, the analyst must weigh the simplicity and clarity of a conventional tree against the fidelity of a Markov analysis. In direct comparisons, both approaches gave the same qualitative answers.

Primer on medical decision analysis: Part 1--Getting started.

This paper is Part 1 of a five-part series covering practical issues in the performance of decision analysis. The intended audience is individuals who are learning how to perform decision analyses, not just read them. The series assumes familiarity with the basic concepts of decision analysis. It imparts many of the recommendations the authors have learned in teaching a one-semester course in decision analysis to graduate students. Part 1 introduces the topic and covers questions such as choosing an appropriate question, determining the tradeoff between accuracy and simplicity, and deciding on a time frame.

Primer on medical decision analysis: Part 2--Building a tree.

This part of a five-part series covering practical issues in the performance of decision analysis outlines the basic strategies for building decision trees. The authors offer six recommendations for building and programming decision trees. Following these six recommendations will facilitate performance of the sensitivity analyses required to achieve two goals. The first is to find modeling or programming errors, a process known as "debugging" the tree. The second is to determine the robustness of the qualitative conclusions drawn from the analysis.

Primer on medical decision analysis: Part 4--Analyzing the model and interpreting the results.

This paper is the fourth of a five-part series that describes the principles of construction and evaluation of valid decision models. In this review, the authors describe the key principles of detecting and eliminating structural and programming errors in decision trees (debugging). In addition, they offer guidelines to facilitate the interpretation of analytic results of decision models.

Guidelines for verbal presentations of medical decision analyses.

Individuals new to decision analysis often have difficulty with oral presentations of original research projects. This article provides general guidelines on how to present effectively. Points include: 1) articulating the research issue, 2) reviewing current beliefs, 3) portraying the study question, 4) listing the main assumptions, 5) presenting the base-case analysis, 6) showing sensitivity analyses, and 7) discussing the implications. The guidelines comment on what to exclude from presentation and how best to handle audience questions. The guidelines do not replace general instruction in public speaking (or rigorous training in decision analysis), but may help students present research projects effectively.

Predicting utility scores for prostate cancer: mapping the Prostate Cancer Index to the Patient-Oriented Prostate Utility Scale (PORPUS).

BACKGROUND: The Prostate Cancer Index (PCI) is a health profile instrument that measures health-related quality of life with six subscales: urinary, sexual, and bowel function and bother. The Patient-Oriented Prostate Utility Scale (PORPUS-U) measures utility (0=dead and 1=full health). Utility is a preference-based approach to measure health-related quality of life, required for decision analyses and cost-effectiveness analyses. We developed a function to estimate PORPUS-U utilities from PCI scores. METHODS: The development data set included 676 community-dwelling prostate cancer (PC) survivors who completed the PCI and PORPUS-U by mail. We fit three linear regression models: one used original PORPUS-U scores and two used log-transformed PORPUS-U scores, one with a hierarchy constraint and one without. The model selection was performed using stepwise selection and fivefold cross validation. The validation data included 248 PC outpatients with three assessments on the PCI and PORPUS-U. Scores were retransformed for validation, with Duan's smearing estimator applied to correct potential bias. The predictive ability of the models was assessed with R(2), root mean square error (RMSE) and by comparing predicted and observed utilities. RESULTS: The best-fitting model used the log-transformed PORPUS-U with no hierarchy constraint. The R(2) was 0.72. The RMSE ranged from 0.040 to 0.061 for the three validation data sets. Differences between predicted and observed utilities ranged from 0.000 to 0.006 but predicted utilities overestimated the lowest 5% of observed PORPUS-U scores and underestimated the highest observed scores. CONCLUSIONS: Our algorithm can calculate PORPUS-U utility scores from PCI scores, thus supplementing descriptive quality of life measures with utility scores in PC patients. Utilities derived from mapping algorithms are useful for assigning utility to groups of patients but are less accurate at predicting utility of individual patients. We are exploring statistical methods to improve the mapping of utilities from descriptive instruments.

Utility and health-related quality of life in prostate cancer patients 12 months after radical prostatectomy or radiation therapy.

This study aims to examine and compare changes in quality of life after two common treatments for prostate cancer (PC), radical prostatectomy (RP) and radiation therapy (RT). Patients newly diagnosed with localized PC, scheduled to receive RP (n=68) or RT (n=66), completed three cancer/PC-specific psychometric instruments and three PC-specific utility instruments before treatment, and 2 and 12 months after treatment. We assessed the magnitude and time course of changes in psychometric and utility measures, and differences between treatments. The results showed that RP was associated with significant urinary and sexual dysfunction; RT caused bowel problems. Fatigue and pain were common to both. RP patients reported more problems with physical, role and social function. Utilities decreased significantly after both treatments. Effects were most severe 2 months post treatment, and then showed some recovery, but many endured for 1 year. After 1 year, 30-60% of patients had utility scores that were clinically significantly worse than at baseline. Secondary androgen deprivation therapy also significantly decreased psychometric and utility measures of quality of life. Many adverse symptoms reported 2 months after RP and RT endure for 1 year. Despite different symptom profiles, RP and RT result in similar utility decrements.

Cost-utility of universal hepatitis A vaccination in Canada.

Hepatitis A (HA) vaccination in Canada is currently targeted toward high-risk groups. The cost-effectiveness and expected health outcomes of universal vaccination relative to targeted vaccination in low-incidence countries such as Canada are currently unknown. Here, we conducted a cost-utility analysis for this situation, with Canada as the study population. We included vaccine costs, time costs, infection costs, and public health costs. We assessed a range of possible universal vaccination strategies over an 80-year time horizon using multiple cost perspectives. A dynamic model was used to account for herd immunity. Aggregate health gains from switching to universal vaccination are modest (10-30 QALYs per year). However, a "9+9" strategy that replaces two doses of monovalent hepatitis B (HB) vaccine at 9/10 years (universally administered in most provinces) with two doses of bivalent HA/HB vaccine is cost-saving from the societal perspective. At a willingness to pay threshold of $50,000/QALY, mean net benefit is +49.4 QALYs (S.D. 12.6) from the societal perspective and +3.8 QALYS (S.D. 3.0) from the payer perspective for the "9+9" strategy. Net benefit from the payer perspective is sensitive to the marginal cost of HA/HB vaccine relative to HB vaccine. Similar conclusions may apply in other countries with low incidence and a targeted vaccination policy.