HIV drug resistance testing: is the evidence really there?

OBJECTIVES: To assess the strength of evidence supporting the routine use of HIV drug resistance testing. DESIGN: A critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials. RESULTS: Two cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3-11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies. CONCLUSIONS: The available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.     

Quantitative bedside testing of troponin T: is it equal to laboratory testing? The Cardiac Reader Troponin T (CARE T) study

The progressive evolution of cardiac marker testing in patients with acute coronary syndromes has extended their role into risk stratification and guidance of therapeutic regimen. To provide utilization of cardiac markers around the clock and facilitate the diagnostic work-up of patients with acute chest pain in the emergency room, a point-of-care system for quantitative troponin T and myoglobin testing in whole blood samples was developed. Aim of this multicenter study was to evaluate bedside quantitative determination of myoglobin and troponin T in chest pain patients in a clinical routine setting. Five hospitals in Germany were contributing to blood sampling and 741 patients were included four hours (median) after onset of cardiac pain. Comparison between the rapid test and the established laboratory-based method showed a sufficient agreement of results with a correlation of r = 0.89 (Y = 0.856x + 0.029) for troponin T and r = 0.912 (Y= +1.145x + 3.457) for myoglobin. Diagnostic sensitivity and prognostic power of the troponin T results obtained in the emergency unit were thoroughly equivalent to the laboratory-based method. The results show that the cardiac reader system represents a promising alternative to central laboratory testing with an accuracy sufficiently for rapid decision making in the emergency room. Myoglobin results in this study did not add supplementary information to the cardiac reader troponin result. However, point-of-care testing of troponin T is advantageous whenever marker results could positively effect initial triage decisions and interventional management choices.     

The use of the antioxidant tirilazad mesylate in human liver transplantation: is there a therapeutic benefit?

Objectives: To test the hypothesis whether in patients undergoing liver transplantation the antioxidant tirilazad mesylate can reduce hepatic ischaemia-reperfusion injury and improve postoperative outcome. Design: Prospective, randomised, placebo controlled trial. Setting: University hospital. Patients: 20 patients were randomised to receive either tirilazad mesylate or placebo (saline). Interventions: Patients in the tirilazad group (n = 10) received four intravenous infusions of tirilazad at 6-h intervals (men 3 mg/kg, women 3.75 mg/kg) after the induction of anaesthesia. The other patients (n = 10) served as controls. Measurements and results: Plasma levels of malonaldehyde (MDA) were determined after the induction of anaesthesia prior to the infusion of tirilazad (baseline), during the anhepatic period, and 5 min and 24 h after reperfusion. Postoperatively, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and serum cholinesterase were determined daily for 1 week. Compared to baseline, plasma MDA levels did not significantly change during the anhepatic period and after reperfusion and they did not differ between groups. Postoperative liver enzymes and prothrombin time did not differ between groups, but on the first (p = 0.03) and second (p = 0.01) postoperative day cholinesterase levels were significantly higher in tirilazad-treated patients than in control patients. For neither length of stay in the intensive care unit nor hospital stay were any differences observed between groups. Conclusions: In patients undergoing liver transplantation, tirilazad does not improve overall outcome. Whether the higher cholinesterase levels on the first 2 postoperative days in tirilazad treated patients indicates an earlier recovery of liver function remains to be tested. Received: 13 November 1998 Final revision received: 10 March 1999 Accepted: 6 April 1999     

Is there evidence to support the use of direct Factor Xa inhibitors in coronary artery disease?

As coronary artery disease (CAD) remains a leading cause of death in the world, the development of anti-coagulants to prevent CAD progressing to myocardial infarction and death is a high priority. A number of direct Factor Xa (FXa) inhibitors are being developed for use in CAD. Despite being developed to the stage of Phase II clinical trials, DX-9065a is no longer a priority with its developing company for further development, possibly because the Phase II trials did not show any major benefit of DX-9065a over heparin in subjects undergoing percutaneous coronary interventions (PCI) or with non-ST-elevation acute coronary syndromes (ACS). ZK-807834, otamixaban, apixaban, and rivaroxaban are all direct FXa inhibitors that have undergone preclinical and some clinical testing for use in CAD. In a large Phase II clinical trial of subjects with ACS, some doses of otamixaban had a better benefit/risk profile than the unfractionated heparin/eptifibatide combination. However, neither ZK-807834 nor otamixaban appear to be undergoing further clinical development at present. In ACS, placebo-controlled large Phase II clinical trials with apixaban and rivaroxaban have not shown clear cut benefits. Nevertheless, apixaban and rivaroxaban are presently in placebo-controlled Phase III clinical trials for ACS. Presently, there is no compelling evidence to support the use of direct FXa inhibitors in ACS.     

Microalbuminuria testing in diabetes: is a dipstick as effective as laboratory tests?

The National Service Framework (NSF) for Diabetes (Department of Health, 2002) aims to improve care for people with diabetes. Primary care trusts need to demonstrate the provision of cost-effective and evidence based care. The National Institute for Clinical Excellence guidelines (NICE, 2002) recommend that microalbuminuria is tested annually in people with diabetes, either by a dipstick method or by a laboratory method. A mini systematic review was undertaken to establish whether a dipstick method of detecting microalbuminuria is as effective as a laboratory method. Four databases were searched and studies comparing dipstick and laboratory methods were included. A hand search was also included. The review was further limited to the Micral test II compared to a reference laboratory standard. Four studies met the inclusion criteria and it was concluded that the Micral test II has a high sensitivity but not very high specificity with lower positive predictive value; it was therefore found to be adequate as a screening tool but not as a diagnostic tool. Therefore the Micral II test is not as effective as a laboratory comparator.     

Efficacy of Hoodia for weight loss: is there evidence to support the efficacy claims?

Increasing rates of adult obesity and its negative health consequences are likely to become an increasing burden to the Canadian health care system. Consumers are looking for treatment options and often try the natural health products that are heavily promoted as safe, fast and effective. In this case report, MH, a 57‐year‐old overweight female wanted advice regarding whether she should use the natural product Hoodia to help her attain her weight loss goals. A literature search was conducted using Medline, EMBASE, the Cochrane Library, Natural Medicines Comprehensive Database and IPA from inception to March 2009. The internet, files of the authors and bibliographies of articles were searched for additional references. No published, peer‐reviewed randomized controlled trials examining efficacy of Hoodia were found. Unpublished data from two small trials reported promising results with no adverse events. However, this leaves many unanswered questions regarding the use of Hoodia for weight loss such as the appropriate dose and duration, short and long term safety and use in patients with concomitant diseases. Literature suggests that some commercial products may not actually contain Hoodia at all. Additionally, Hoodia is not yet listed in the Canadian Licensed Natural Health Products Database meaning products sold in Canada may not meet Canadian regulatory standards. Upon discussing this information, MH decided not to use Hoodia, and other evidence‐based recommendations were discussed.     

The impact of critical care outreach: is there one?

An evaluation of critical care outreach services was published in the previous issue of Critical Care that fails to demonstrate any important outcome benefit associated with these services. It is now time to ask some difficult questions about the future of outreach, including whether the lack of evidence should lead to disinvest-ment in such services.     

Role of CYP2C19 genotype testing in clinical use of clopidogrel: is it really useful?

Introduction: P2Y12 inhibitors, including clopidogrel have become an integral part of treatment for patients receiving coronary stent placement as a result of stable coronary artery disease or acute coronary syndromes (ACS) and also for medically managed ACS patients.

Areas covered: Clopidogrel efficacy can be significantly modified by polymorphism of CYP2C19 genotype (more than 25 allelic variants) involved in its metabolism that can adversely affect its anti-platelet activity. As a result, a substantial number of patients (20–30%) with ACS show an inadequate response to clopidogrel despite a standardized dosing regimen.

Experts commentary: Currently, there is conflicting evidence in regards to the use of CYP2C19 genotyping to identify poor responders to clopidogrel in clinical practice. ACC/AHA guidelines do not recommend routine use of CYP2C19 in clinical practice, whereas Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend its use to identify poor/intermediate metabolizers of Clopidogrel and suggest alternative P2Y12 inhibitors among ACS patients undergoing percutaneous coronary intervention. This review article will look at the literature evidence for the use of CYP2C19 genotyping in clinical practice.