Marcela Haasova

The acute effects of physical activity on cigarette cravings: systematic review and meta‐analysis with individual participant data

AIMS To conduct an updated systematic review and the first meta-analysis of experimental trials investigating the acute effects of short bouts of physical activity (PA) on strength of desire (SoD) and desire to smoke (DtS) using individual participant data (IPD). METHODS A systematic review of literature and IPD meta-analyses included trials assessing the acute effects of shorts bouts of PA on SoD and DtS among temporarily abstaining smokers not using pharmaceutical aids for smoking cessation. Authors of eligible studies were contacted and raw IPD were obtained. Two-stage and one-stage IPD random-effects meta-analyses were conducted. Participants engaging in PA were compared against control participants, using post-intervention SoD and DtS with baseline adjustments. RESULTS A two-stage IPD meta-analysis assessing effects of PA on SoD yielded an average standardized mean difference (SMD) between PA and control conditions (across 15 primary studies) of -1.91 [95% confidence interval (CI): -2.59 to -1.22]. A two-stage IPD meta-analysis assessing effects of PA on DtS yielded an average SMD between PA and control conditions (across 17 primary studies) of -2.03 (95% CI: -2.60 to -1.46). Additional meta-analyses, including those using a one-stage model, those including only parallel arm studies and meta-analyses comparing only moderate exercise against a control condition, showed significant craving reduction following PA. Despite a high degree of between-study heterogeneity, effects sizes of all primary studies were in the same direction, with PA showing a greater reduction in cravings compared with controls. CONCLUSIONS There is strong evidence that physical activity acutely reduces cigarette craving.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Associations electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Adjusting for unmeasured confounding in non-randomised longitudinal studies: a methodological review

Objectives Motivated by recent calls to use electronic health records for research, we reviewed the application and development of methods for addressing the bias from unmeasured confounding in longitudinal data. Study Design and Setting Methodological review of existing literature. We searched MEDLINE and EMBASE for articles addressing the threat to causal inference from unmeasured confounding in nonrandomized longitudinal health data through quasi-experimental analysis. Results Among the 121 studies included for review, 84 used instrumental variable analysis (IVA), of which 36 used lagged or historical instruments. Difference-in-differences (DiD) and fixed effects (FE) models were found in 29 studies. Five of these combined IVA with DiD or FE to try to mitigate for time-dependent confounding. Other less frequently used methods included prior event rate ratio adjustment, regression discontinuity nested within pre-post studies, propensity score calibration, perturbation analysis, and negative control outcomes. Conclusion Well-established econometric methods such as DiD and IVA are commonly used to address unmeasured confounding in nonrandomized longitudinal studies, but researchers often fail to take full advantage of available longitudinal information. A range of promising new methods have been developed, but further studies are needed to understand their relative performance in different contexts before they can be recommended for widespread use.

The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.

BACKGROUND Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). OBJECTIVE To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). DATA SOURCES The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. REVIEW METHODS The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed indication (based on start dose administered) were included in the review. None of the RCTs were completely aligned with current European Union licenses. The results suggest a clinical benefit from ESAs for anaemia-related outcomes and an improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain, although point estimates are lower, confidence intervals are wide and not statistically significant. Base-case incremental cost-effectiveness ratios (ICERs) for ESA treatment compared with no ESA treatment ranged from £ 19,429 to £ 35,018 per QALY gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost. LIMITATIONS The relative effectiveness of ESAs was not addressed; all ESAs were assumed to have equivalent efficacy. No studies were completely aligned with their European labelling beyond the starting dose evaluated. There is questionable generalisability given that the included trials were published >20 years ago and there have been many changes to chemotherapy as well as to the quality of supportive treatment. Trial quality was moderate or poor and there was considerable unexplained heterogeneity for a number of outcomes, particularly survival, and evidence of publication bias. Adjustments were not made to account for multiple testing. CONCLUSIONS ESAs could be cost-effective when used closer to licence, but there is considerable uncertainty, mainly because of unknown impacts on overall survival. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005812. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddys Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013544. FUNDING The National Institute for Health Research HTA programme.

Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation

Background Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support Englands National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. Methods A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used. Results Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used. Conclusions A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources.

The association between habitual physical activity and cigarette cravings, and influence of smokers’ characteristics in disadvantaged smokers not ready to quit

RationaleHabitual physical activity (PA) may have an important role in suppressing cigarette cravings. Systematic reviews show a strong acute effect of bouts of PA on reducing cigarette cravings, and it may be that these effects accumulate.ObjectivesThe aim was to investigate the relationship between habitual levels of PA and cigarette cravings in disadvantaged smokers not ready to quit by examining baseline cross-sectional data from the Exercise Assisted Reduction then Stop smoking study (EARS).MethodsA series of linear regression models were applied to investigate the relationship between habitual PA and cigarette cravings and to identify additional predictors of cigarette cravings. The analyses were extended by including interaction terms with PA to identify potential moderators of the relationship between PA and cravings.ResultsA higher level of moderate intensity PA was associated with lower cravings (p = 0.033). Additional predictors were the mood and physical symptoms scale (p = 0.007; higher scores were associated with higher cravings) and alcohol consumption (p = 0.002; higher consumption was associated with lower cravings). In addition, a moderation effect of alcohol consumption was found; at higher levels of alcohol consumption, higher PA was significantly associated with higher cravings (p = 0.023).ConclusionsOverall, participation in regular PA is associated with reduced cigarette cravings; among those with heavy alcohol consumption, this participation is associated with higher cravings. These exploratory analyses suggest that further research into the relationship between PA, alcohol consumption and cigarette cravings is needed.

Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses

BackgroundDecisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs. However, there are also costs associated with the surveillance of CHC to determine a subgroup of patients with significant impairment. The aim of this systematic review was to describe the modelling methods used and summarise results in cost-effectiveness analyses (CEAs) of both CHC treatment with DAAs and surveillance of liver disease.MethodsElectronic databases including Embase and Medline were searched from inception to May 2015. Eligible studies included models predicting costs and/or outcomes for interventions, surveillance, or management of people with CHC. Narrative and quantitative synthesis were conducted. Quality appraisal was conducted using validated checklists. The review was conducted following principles published by NHS Centre for Research and Dissemination.ResultsForty-one CEAs met the eligibility criteria for the review; 37 evaluated an intervention and four evaluated surveillance strategies for targeting DAA treatment to those likely to gain most benefit. Included studies were of variable quality mostly due to reporting omissions. Of the 37 CEAs, eight models that enabled comparative analysis were fully appraised and synthesized. These models provided non-unique cost-effectiveness estimates in a specific DAA comparison in a specific population defined in terms of genotype, prior treatment status, and presence or absence of cirrhosis. Marked heterogeneity in cost-effectiveness estimates was observed despite this stratification. Approximately half of the estimates suggested that DAAs were cost-effective considering a threshold of US

Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis

30,000 and 73% with threshold of US

1038PDA COST-EFFECTIVENESS ANALYSIS OF ERYTHROPOIESIS-STIMULATING AGENTS FOR TREATING CANCER-TREATMENT INDUCED ANAEMIA

50,000. Two models evaluating surveillance strategies suggested that treating all CHC patients regardless of the staging of liver disease could be cost-effective.ConclusionsCEAs of CHC treatments need to better account for variability in their estimates. This analysis suggested that there are still circumstances where DAAs are not cost-effective. Surveillance in place of a treat-all strategy may still need to be considered as an option for deploying DAAs, particularly where acquisition cost is at the limit of affordability for a given health system.