Moira Cruickshank

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review

BACKGROUND Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. OBJECTIVES To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. DATA SOURCES We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. METHODS Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. RESULTS Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). LIMITATIONS Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. CONCLUSIONS Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. STUDY REGISTRATION This study is registered as PROSPERO CRD42014014101. FUNDING The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Is self-monitoring an effective option for people receiving long-term vitamin K antagonist therapy? A systematic review and economic evaluation.

Objectives To investigate the clinical and cost-effectiveness of self-monitoring of coagulation status in people receiving long-term vitamin K antagonist therapy compared with standard clinic care. Design Systematic review of current evidence and economic modelling. Data sources Major electronic databases were searched up to May 2013. The economic model parameters were derived from the clinical effectiveness review, routine sources of cost data and advice from clinical experts. Study eligibility criteria Randomised controlled trials (RCTs) comparing self-monitoring versus standard clinical care in people with different clinical conditions. Self-monitoring included both self-management (patients conducted the tests and adjusted their treatment according to an algorithm) and self-testing (patients conducted the tests, but received treatment recommendations from a clinician). Various point-of-care coagulometers were considered. Results 26 RCTs (8763 participants) were included. Both self-management and self-testing were as safe as standard care in terms of major bleeding events (RR 1.08, 95% CI 0.81 to 1.45, p=0.690, and RR 0.99, 95% CI 0.80 to 1.23, p=0.92, respectively). Self-management was associated with fewer thromboembolic events (RR 0.51, 95% CI 0.37 to 0.69, p≤0.001) and with a borderline significant reduction in all-cause mortality (RR 0.68, 95% CI 0.46 to 1.01, p=0.06) than standard care. Self-testing resulted in a modest increase in time in therapeutic range compared with standard care (weighted mean difference, WMD 4.4%, 95% CI 1.71 to 7.18, p=0.02). Total health and social care costs over 10 years were £7324 with standard care and £7326 with self-monitoring (estimated quality adjusted life year, QALY gain was 0.028). Self-monitoring was found to have ∼80% probability of being cost-effective compared with standard care applying a ceiling willingness-to-pay threshold of £20 000 per QALY gained. Within the base case model, applying the pooled relative effect of thromboembolic events, self-management alone was highly cost-effective while self-testing was not. Conclusions Self-monitoring appears to be a safe and cost-effective option. Trial registration number PROSPERO CRD42013004944.

Collagenase clostridium histolyticum for the treatment of Dupuytren’s contracture: systematic review and economic evaluation

BACKGROUND Dupuytrens disease is a slowly progressive condition of the hand, characterised by the formation of nodules in the palm that gradually develop into fibrotic cords. Contracture of the cords produces deformities of the fingers. Surgery is recommended for moderate and severe contractures, but complications and/or recurrences are frequent. Collagenase clostridium histolyticum (CCH) has been developed as a minimally invasive alternative to surgery for some patients. OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of collagenase as an alternative to surgery for adults with Dupuytrens contracture with a palpable cord. DATA SOURCES We searched all major electronic databases from 1990 to February 2014. REVIEW METHODS Randomised controlled trials (RCTs), non-randomised comparative studies and observational studies involving collagenase and/or surgical interventions were considered. Two reviewers independently extracted data and assessed risk of bias of included studies. A de novo Markov model was developed to assess cost-effectiveness of collagenase, percutaneous needle fasciotomy (PNF) and limited fasciectomy (LF). Results were reported as incremental cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. RESULTS Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants) were included. Meta-analyses of RCTs assessing CCH versus placebo were performed. Joints randomised to collagenase were more likely to achieve clinical success. Collagenase-treated participants experienced significant reduction in contracture and an increased range of motion compared with placebo-treated participants. Participants treated with collagenase also experienced significantly more adverse events, most of which were mild or moderate. Four serious adverse events were observed in the collagenase group: two tendon ruptures, one pulley rupture and one complex regional pain syndrome. Two tendon ruptures were also reported in two collagenase case series. Non-randomised studies comparing collagenase with surgery produced variable results and were at high risk of bias. Serious adverse events across surgery studies were low. Recurrence rates ranged from 0% (at 90 days) to 100% (at 8 years) for collagenase and from 0% (at 2.7 years for fasciectomy) to 85% (at 5 years for PNF) for surgery. The results of the de novo economic analysis show that PNF was the cheapest treatment option, whereas LF generated the greatest QALY gains. Collagenase was more costly and generated fewer QALYs compared with LF. LF was £1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was £10,871 per QALY gained. Two subgroup analyses were conducted for a population of patients with moderate and severe disease and up to two joints affected. In both subgroup analyses, collagenase remained dominated. LIMITATIONS The main limitation of the review was the lack of head-to-head RCTs comparing collagenase with surgery and the limited evidence base for estimating the effects of specific surgical procedures (fasciectomy and PNF). Substantial differences across studies further limited the comparability of available evidence. The economic model was derived from a naive indirect comparison and was hindered by a lack of suitable data. In addition, there was considerable uncertainty about the appropriateness of many assumptions and parameters used in the model. CONCLUSIONS Collagenase was significantly better than placebo. There was no evidence that collagenase was clinically better or worse than surgical treatments. LF was the most cost-effective choice to treat moderate to severe contractures, whereas collagenase was not. However, the results of the cost-utility analysis are based on a naive indirect comparison of clinical effectiveness, and a RCT is required to confirm or refute these findings. STUDY REGISTRATION This study is registered as PROSPERO CRD42013006248. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of cholecystectomy compared with observation/conservative management for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones or cholecystitis: a systematic review and economic evaluation

BACKGROUND Approximately 10-15% of the adult population suffer from gallstone disease, cholelithiasis, with more women than men being affected. Cholecystectomy is the treatment of choice for people who present with biliary pain or acute cholecystitis and evidence of gallstones. However, some people do not experience a recurrence after an initial episode of biliary pain or cholecystitis. As most of the current research focuses on the surgical management of the disease, less attention has been dedicated to the consequences of conservative management. OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of cholecystectomy compared with observation/conservative management in people presenting with uncomplicated symptomatic gallstones (biliary pain) or cholecystitis. DATA SOURCES We searched all major electronic databases (e.g. MEDLINE, EMBASE, Science Citation Index, Bioscience Information Service, Cochrane Central Register of Controlled Trials) from 1980 to September 2012 and we contacted experts in the field. REVIEW METHODS Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies that enrolled people with symptomatic gallstone disease (pain attacks only and/or acute cholecystitis). Two reviewers independently extracted data and assessed the risk of bias of included studies. Standard meta-analysis techniques were used to combine results from included studies. A de novo Markov model was developed to assess the cost-effectiveness of the interventions. RESULTS Two Norwegian RCTs involving 201 participants were included. Eighty-eight per cent of people randomised to surgery and 45% of people randomised to observation underwent cholecystectomy during the 14-year follow-up period. Participants randomised to observation were significantly more likely to experience gallstone-related complications [risk ratio = 6.69; 95% confidence interval (CI) 1.57 to 28.51; p = 0.01], in particular acute cholecystitis (risk ratio = 9.55; 95% CI 1.25 to 73.27; p = 0.03), and less likely to undergo surgery (risk ratio = 0.50; 95% CI 0.34 to 0.73; p = 0.0004), experience surgery-related complications (risk ratio = 0.36; 95% CI 0.16 to 0.81; p = 0.01) or, more specifically, minor surgery-related complications (risk ratio = 0.11; 95% CI 0.02 to 0.56; p = 0.008) than those randomised to surgery. Fifty-five per cent of people randomised to observation did not require an operation during the 14-year follow-up period and 12% of people randomised to cholecystectomy did not undergo the scheduled operation. The results of the economic evaluation suggest that, on average, the surgery strategy costs £1236 more per patient than the conservative management strategy but was, on average, more effective. An increase in the number of people requiring surgery while treated conservatively corresponded to a reduction in the cost-effectiveness of the conservative strategy. There was uncertainty around some of the parameters used in the economic model. CONCLUSIONS The results of this assessment indicate that cholecystectomy is still the treatment of choice for many symptomatic people. However, approximately half of the people in the observation group did not require surgery or suffer complications in the long term indicating that a conservative therapeutic approach may represent a valid alternative to surgery in this group of people. Owing to the dearth of current evidence in the UK setting a large, well-designed, multicentre trial is needed. STUDY REGISTRATION The study was registered as PROSPERO CRD42012002817. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of open mesh repairs in adults presenting with a clinically diagnosed primary unilateral inguinal hernia who are operated in an elective setting: systematic review and economic evaluation

BACKGROUNDS Current open mesh techniques for inguinal hernia repair have shown similar recurrence rates. However, chronic pain has been associated with Lichtenstein mesh repair, the most common surgical procedure for inguinal hernia in the UK. The position of the mesh is probably an important factor. The Lichtenstein method requires dissection of the inguinal wall and fixation of the mesh. In contrast, in the open preperitoneal approach the mesh is placed in the preperitoneal space and held in place with intra-abdominal pressure. Currently, there is no consensus regarding the best open approach for repair of inguinal hernia. OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of open preperitoneal mesh repair compared with Lichtenstein mesh repair in adults presenting with a clinically diagnosed primary unilateral inguinal hernia. DATA SOURCES We searched major electronic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed, EMBASE, Cochrane Controlled Trials Register) from inception to November 2014 and contacted experts in the field. REVIEW METHODS Evidence was considered from randomised controlled trials (RCTs) that compared open preperitoneal mesh repair with Lichtenstein mesh repair for the treatment of inguinal hernia. Two reviewers independently selected studies for inclusion. One reviewer completed data extraction and assessed risk of bias for included studies, and two reviewers independently cross-checked the details extracted. Meta-analyses techniques were used to combine results from included studies. A Markov model was developed to assess the cost-effectiveness of open mesh procedures from a NHS health services perspective over a 25-year time horizon. RESULTS Twelve RCTs involving 1568 participants were included. Participants who underwent open preperitoneal mesh repair returned to work and normal activities significantly earlier than those who underwent Lichtenstein mesh repair [mean difference -1.49 days, 95% confidence interval (CI) -2.78 to -0.20 days]. Although no significant differences were observed between the two open approaches for incidence of pain [risk ratio (RR) 0.50, 95% CI 0.20 to 1.27], numbness (RR 0.48, 95% CI 0.15 to 1.56), recurrences (Peto odds ratio 0.76, 95% CI 0.38 to 1.52) or postoperative complications, fewer events were generally reported after open preperitoneal mesh repair. The results of the economic evaluation indicate that the open preperitoneal mesh repair was £256 less costly and improved health outcomes by 0.041 quality-adjusted life-years (QALYs) compared with Lichtenstein mesh repair. The open preperitoneal procedure was the most efficient and dominant treatment strategy with a high (> 98%) probability of being cost-effectiveness for the NHS at a willingness to pay of £20,000 for a QALY. Results were robust to a range of sensitivity analyses. However, the magnitude of cost saving or QALY gain was sensitive to some model assumptions. LIMITATIONS Overall, the included trials were of small sample size (mean 130.7 participants) and at high or unclear risk of bias. Meta-analyses results demonstrated significant statistical heterogeneity for most of the assessed outcomes. CONCLUSIONS Open preperitoneal mesh repair appears to be a safe and efficacious alternative to Lichtenstein mesh repair. Further research is required to determine the long-term effects of these surgical procedures as well as the most effective open preperitoneal repair technique in terms of both clinical efficacy and costs. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013510. FUNDING The National Institute for Health Research Health Technology Assessment programme.