Sohan Deshpande

Cannabinoids for Medical Use: A Systematic Review and Meta-analysis

IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES Twenty-eight databases from inception to April 2015. STUDY SELECTION Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. DATA EXTRACTION AND SYNTHESIS Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. RESULTS A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. CONCLUSIONS AND RELEVANCE There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis.

BACKGROUND The principal diagnosis/indication for this assessment is chronic diarrhoea due to bile acid malabsorption (BAM). Diarrhoea can be defined as the abnormal passage of loose or liquid stools more than three times daily and/or a daily stool weight > 200 g per day and is considered to be chronic if it persists for more than 4 weeks. The cause of chronic diarrhoea in adults is often difficult to ascertain and patients may undergo several investigations without a definitive cause being identified. BAM is one of several causes of chronic diarrhoea and results from failure to absorb bile acids (which are required for the absorption of dietary fats and sterols in the intestine) in the distal ileum. OBJECTIVE For people with chronic diarrhoea with unknown cause and in people with Crohns disease and chronic diarrhoea with unknown cause (i.e. before resection): (1) What are the effects of selenium-75-homocholic acid taurine (SeHCAT) compared with no SeHCAT in terms of chronic diarrhoea, other health outcomes and costs? (2) What are the effects of bile acid sequestrants (BASs) compared with no BASs in people with a positive or negative SeHCAT test? (3) Does a positive or negative SeHCAT test predict improvement in terms of chronic diarrhoea, other health outcomes and costs? DATA SOURCES A systematic review was conducted to summarise the evidence on the clinical effectiveness of SeHCAT for the assessment of BAM and the measurement of bile acid pool loss. Search strategies were based on target condition and intervention, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. The following databases were searched up to April 2012: MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; the Cochrane Databases; Database of Abstracts of Reviews of Effects; Health Technology Assessment (HTA) Database; and Science Citation Index. Research registers and conference proceedings were also searched. REVIEW METHODS Systematic review methods followed the principles outlined in the CRD guidance for undertaking reviews in health care and the National Institute for Health and Care Excellence (NICE) Diagnostic Assessment Programme interim methods statement. In the health economic analysis, the cost-effectiveness of SeHCAT for the assessment of BAM, in patients with chronic diarrhoea, was estimated in two different populations. The first is the population of patients with chronic diarrhoea with unknown cause and symptoms suggestive of diarrhoea-predominant irritable bowel syndrome (IBS-D) and the second population concerns patients with Crohns disease without ileal resection with chronic diarrhoea. For each population, three models were combined: (1) a short-term decision tree that models the diagnostic pathway and initial response to treatment (first 6 months); (2) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving BAS; and (3) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving regular treatment (IBS-D treatment in the first population and Crohns treatment in the second population). Incremental cost-effectiveness ratios were estimated as additional cost per additional responder in the short term (first 6 months) and per additional quality-adjusted life-year (QALY) in the long term (lifetime). RESULTS We found three studies assessing the relationship between the SeHCAT test and response to treatment with cholestyramine. However, the studies had small numbers of patients with unknown cause chronic diarrhoea, and they used different cut-offs to define BAM. For the short term (first 6 months), when trial of treatment is not considered as a comparator, the optimal choice depends on the willingness to pay for an additional responder. For lower values (between £1500 and £4600) the choice will be no SeHCAT in all scenarios; for higher values either SeHCAT 10% or SeHCAT 15% becomes cost-effective. For the lifetime perspective, the various scenarios showed widely differing results: in the threshold range of £20,000-30,000 per QALY gained we found as optimal choice either no SeHCAT, SeHCAT 5% (only IBS-D) or SeHCAT 15%. When trial of treatment is considered a comparator, the analysis showed that for the short term, trial of treatment is the optimal choice across a range of scenarios. For the lifetime perspective with trial of treatment, again the various scenarios show widely differing results. Depending on the scenario, in the threshold range of £20,000-30,000 per QALY gained, we found as optimal choice either trial of treatment, no SeHCAT or SeHCAT 15%. CONCLUSIONS In conclusion, the various analyses show that for both populations considerable decision uncertainty exists and that no firm conclusions can be formulated about which strategy is optimal. Standardisation of the definition of a positive SeHCAT test should be the first step in assessing the usefulness of this test. As there is no reference standard for the diagnosis of BAM and SeHCAT testing provides a continuous measure of metabolic function, diagnostic test accuracy (DTA) studies are not the most appropriate study design. However, in studies where all patients are tested with SeHCAT and all patients are treated with BASs, response to treatment can provide a surrogate reference standard; further DTA studies of this type may provide information on the ability of SeHCAT to predict response to BASs. A potentially more informative option would be multivariate regression modelling of treatment response (dependent variable), with SeHCAT result and other candidate clinical predictors as covariates. Such a study design could also inform the definition of a positive SeHCAT result. STUDY REGISTRATION The study is registered as PROSPERO CRD42012001911. FUNDING The National Institute for Health Research Health Technology Assessment programme.

A systematic review to assess adherence and persistence with statins

Abstract Objective: To identify and assess studies published over a 10 year period up to February 2016 which measure adherence or persistence with statins, to summarize their methods, strengths and weaknesses and to summarize evidence linking statin adherence/persistence with risk of cardiovascular events. Methods: Electronic databases and abstracts from four major cardiovascular disease conferences were searched from January 2005 to February 2016. The study selection process was performed by two reviewers working independently. Studies were included if they reported data regarding patient adherence or persistence with statins in adults with primary hypercholesterolemia, using any type of study design or length of follow-up. One reviewer extracted the study data and assessed study quality, which was checked by a second reviewer independently. Given the heterogeneity between the included studies a narrative critique and summary is presented. Results: We report on 84 real world studies which aimed to assess adherence or persistence with statins. The majority of studies concluded that good adherence/persistence was associated with reduction in cardiovascular events and mortality. In two studies high intensity statin regimens were associated with poorer patient adherence when compared to low intensity statins. Adherence and persistence with statin therapy also has an impact on hospitalization costs and other cardiovascular disease (CVD) related costs. Conclusions: Adherence and persistence are associated with a reduction in CVD events and mortality. There was limited evidence to suggest that high intensity statin regimens are associated with poorer treatment adherence when compared to lower intensity regimens. Hence, more robust studies are required to establish this association. As recommended by the 2013 ACC/AHA, 2016 ESC and several other clinical guidelines, clinicians and pharmacy managers should regularly monitor statin therapy adherence.

The relationship between Lp(a) and CVD outcomes: a systematic review

Robust associations between lipoprotein(a) [Lp(a)] and CVD outcomes among general populations have been published in previous studies. However, associations in high risk primary prevention and secondary prevention populations are less well defined. In order to investigate this further, a systematic review was performed including prospective studies, which assessed the relationship between Lp(a) and CVD outcomes using multivariable analyses. Additional information was gathered on Lp(a) assays, multivariable modelling and population characteristics.Literature searches from inception up to December 2015 retrieved 2850 records. From these 60 studies were included. Across 39 primary prevention studies in the general population (hazard ratios ranged from 1.16 to 2.97) and seven high risk primary prevention studies (hazard ratios ranged from 1.01 to 3.7), there was evidence of a statistically significant relationship between increased Lp(a) and an increased risk of future CVD. Results in 14 studies of secondary prevention populations were also suggestive of a modest statistically significant relationship (hazard ratios ranged from 0.75 to 3.7).Therefore current evidence would suggest that increased Lp(a) levels are associated with modest increases in the risk of future CVD events in both general and higher risk populations. However, further studies are required to confirm these findings.

Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia

Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low‐density lipoprotein cholesterol (LDL‐C) when added to statin therapy in patients who need additional LDL‐C reduction. Methods and Results We conducted a systematic review and network meta‐analysis of randomized trials of lipid‐lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid‐lowering therapies that enrolled patients requiring further LDL‐C reduction while on maximally tolerated medium‐ or high‐intensity statin, of which 15 could be relevant for inclusion in LDL‐C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL‐C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (−74.1%; 95% credible interval −79.81% to −68.58%), alirocumab 75 mg (−20.03%; 95% credible interval −27.32% to −12.96%), and alirocumab 150 mg (−13.63%; 95% credible interval −22.43% to −5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe. Conclusions PCSK9 inhibitors added to medium‐ to high‐intensity statin therapy significantly reduce LDL‐C in patients requiring further LDL‐C reduction. The network meta‐analysis showed a significant treatment difference in LDL‐C reduction for evolocumab versus alirocumab.

A systematic literature review comparing methods for the measurement of patient persistence and adherence

Abstract Objectives: A systematic literature review was conducted comparing different approaches estimating persistence and adherence in chronic diseases with polypharmacy of oral and subcutaneous treatments. Methods: This work followed published guidance on performing systematic reviews. Twelve electronic databases and grey literature sources were used to identify studies and guidelines for persistence and adherence of oral and subcutaneous therapies in hypercholesterolemia, type 2 diabetes, hypertension, osteoporosis and rheumatoid arthritis. Outcomes of interest of each persistence and adherence data collection and calculation method included pros: accurate, easy to use, inexpensive; and cons: inaccurate, difficult to use, expensive. Results: A total of 4158 records were retrieved up to March 2017. We included 16 observational studies, 5 systematic reviews and 7 guidelines, in patients with hypercholesterolemia (n = 8), type 2 diabetes (n = 4), hypertension (n = 2), rheumatoid arthritis (n = 1) and mixed patient populations (n = 13). Pharmacy and medical records offer an accurate, easy and inexpensive data collection method. Pill count, medication event monitoring systems (MEMs), self-report questionnaires and observer report are easy to use. MEMS and biochemical monitoring tests can be expensive. Proportion of days covered (PDC) was recommended as a gold standard calculation method for long-term treatments. PDC avoids use of days’ supply in calculation, hence is more accurate compared to medication possession ratio (MPR) to assess adherence to treatments in chronic diseases. Conclusions: Decisions on what method to use should be based on considerations of the route of medication administration, the resources available, setting and aim of the assessment. Combining different methods may provide wider insights into adherence and persistence, including patient behavior.

Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review.

Abstract Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A systematic review was performed to evaluate the relationship between coronary atherosclerotic plaque burden changes measured by intravascular ultrasound (IVUS) and CVD outcomes. Research design and methods Rigorous systematic review methodology was used to identify prospective studies of any design assessing the relationship between atherosclerotic plaque volume (percentage or total atheroma volume [PAV or TAV]) changes and CVD outcomes, using multivariable analyses. Main outcome measures CVD outcomes including major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results Literature searches from inception to February 2015 retrieved 6958 records after de-duplication. From these four studies (14 papers) were included. One study reported a significantly lower rate of CVD outcomes associated with a greater reduction in PAV (hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.07–0.83). One study reported that large plaque volume was significantly associated with a greater risk of major adverse cardiac events (MACEs) (HR 1.73, 95% CI: 1.02–2.96). Similarly, a third study reported a significant increase in MACE with an increase in baseline PAV (HR 1.51, 95% CI: 1.06–2.51). Only one potentially inadequately powered Japanese study did not find a statistically significant relationship between PAV changes and MACE. Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes. However, this evidence comes from a limited number of studies which mainly focus on Japanese populations and populations after PCI. Further large prospective studies are required to confirm these findings.

Risk scores to guide referral decisions for people with suspected ovarian cancer in secondary care: a systematic review and cost-effectiveness analysis

BACKGROUND Ovarian cancer is the sixth most common cancer in UK women and can be difficult to diagnose, particularly in the early stages. Risk-scoring can help to guide referral to specialist centres. OBJECTIVES To assess the clinical and cost-effectiveness of risk scores to guide referral decisions for women with suspected ovarian cancer in secondary care. METHODS Twenty-one databases, including MEDLINE and EMBASE, were searched from inception to November 2016. Review methods followed published guidelines. The meta-analysis using weighted averages and random-effects modelling was used to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). The cost-effectiveness analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different risk-scoring methods, and subsequent care pathways. Modelling comprised a decision tree and a Markov model. The decision tree was used to model short-term outcomes and the Markov model was used to estimate the long-term costs and QALYs associated with treatment and progression. RESULTS Fifty-one diagnostic cohort studies were included in the systematic review. The Risk of Ovarian Malignancy Algorithm (ROMA) score did not offer any advantage over the Risk of Malignancy Index 1 (RMI 1). Patients with borderline tumours or non-ovarian primaries appeared to account for disproportionately high numbers of false-negative, low-risk ROMA scores. (Confidential information has been removed.) To achieve similar levels of sensitivity to the Assessment of Different NEoplasias in the adneXa (ADNEX) model and the International Ovarian Tumour Analysis (IOTA) groups simple ultrasound rules, a very low RMI 1 decision threshold (25) would be needed; the summary sensitivity and specificity estimates for the RMI 1 at this threshold were 94.9% (95% CI 91.5% to 97.2%) and 51.1% (95% CI 47.0% to 55.2%), respectively. In the base-case analysis, RMI 1 (threshold of 250) was the least effective [16.926 life-years (LYs), 13.820 QALYs] and the second cheapest (£5669). The IOTA groups simple ultrasound rules (inconclusive, assumed to be malignant) were the cheapest (£5667) and the second most effective [16.954 LYs, 13.841 QALYs], dominating RMI 1. The ADNEX model (threshold of 10%), costing £5699, was the most effective (16.957 LYs, 13.843 QALYs), and compared with the IOTA groups simple ultrasound rules, resulted in an incremental cost-effectiveness ratio of £15,304 per QALY gained. At thresholds of up to £15,304 per QALY gained, the IOTA groups simple ultrasound rules are cost-effective; the ADNEX model (threshold of 10%) is cost-effective for higher thresholds. LIMITATIONS Information on the downstream clinical consequences of risk-scoring was limited. CONCLUSIONS Both the ADNEX model and the IOTA groups simple ultrasound rules may offer increased sensitivity relative to current practice (RMI 1); that is, more women with malignant tumours would be referred to a specialist multidisciplinary team, although more women with benign tumours would also be referred. The cost-effectiveness model supports prioritisation of sensitivity over specificity. Further research is needed on the clinical consequences of risk-scoring. STUDY REGISTRATION This study is registered as PROSPERO CRD42016053326. FUNDING DETAILS The National Institute for Health Research Health Technology Assessment programme.

Clinically inappropriate post hoc exclusion of study participants from test accuracy calculations: the ROMA score, an example from a recent NICE diagnostic assessment:

Objective To explore how the definition of the target condition and post hoc exclusion of participants can limit the usefulness of diagnostic accuracy studies. Methods We used data from a systematic review, conducted for a NICE diagnostic assessment of risk scores to inform secondary care decisions about specialist referral for women with suspected ovarian cancer, to explore how the definition of the target condition and post hoc exclusion of participants can limit the usefulness of diagnostic accuracy studies to inform clinical practice. Results Fourteen of the studies evaluated the ROMA score, nine used Abbott ARCHITECT tumour marker assays, five used Roche Elecsys. The summary sensitivity estimate (Abbott ARCHITECT) was highest, 95.1% (95% CI: 92.4 to 97.1%), where analyses excluded participants with borderline tumours or malignancies other than epithelial ovarian cancer and lowest, 75.0% (95% CI: 60.4 to 86.4%), where all participants were included. Results were similar for Roche Elecsys tumour marker assays. Although the number of patients involved was small, data from studies that reported diagnostic accuracy for both the whole study population and with post hoc exclusion of those with borderline or non-epithelial malignancies suggested that patients with borderline or malignancies other than epithelial ovarian cancer accounts for between 50 and 85% of false-negative ROMA scores. Conclusions Our results illustrate the potential consequences of inappropriate population selection in diagnostic studies; women with non-epithelial ovarian cancers or non-ovarian primaries, and those borderline tumours may be disproportionately represented among those with false negative, ‘low risk’ ROMA scores. These observations highlight the importance of giving careful consideration to how the target condition has been defined when assessing whether the diagnostic accuracy estimates reported in clinical studies will translate into clinical utility in real-world settings.

Response to Letter to the Editor Regarding “Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal”

We very much appreciate the interest Reifsnider et al. [1] have taken in our perspective on the single technology appraisal (STA) of abiraterone acetate (tradename Zytiga) plus prednisolone (AAP) acetate for the treatment of chemotherapynai ¨ve metastatic castration-resistant prostate cancer (mCRPC) prepared for the UK National Institute for Health and Care Excellence (NICE) [2, 3]. Here, we respond to the aspects highlighted by Reifsnider et al. [1] and correct factual inaccuracies in their reasoning. The main issues are printed in italics [1]. These points relate to (1) the statistical significance of the COU-AA-302 survival results and (2) the justification of the discrete-event simulation (DES) approach utilised by the company. Reifsnider et al. also highlight aspects that are unrelated to these main points, and we discuss these separately.