Impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on renal and mortality outcomes in people with Type 2 diabetes and proteinuria.

AIM: To assess the impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal and mortality outcomes in people with Type 2 diabetes and proteinuria. METHODS: A literature search up to 6 June 2019 was performed. We included randomized trials of ≥100 participants with Type 2 diabetes and micro- or macroalbuminuria comparing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with placebo ± background anti-hypertensives or non-angiotensin-converting enzyme inhibitor or angiotensin receptor blocker-containing anti-hypertensives, which included follow-up of ≥12 months. Endpoints included doubling of serum creatinine, end-stage renal disease, all-cause and cardiovascular mortality and progression and regression of proteinuria. A Hartung-Knapp random-effects model (between-study variance calculated using the Paule-Mandel estimator) producing a risk ratio with 95% confidence interval was employed. RESULTS: The use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was not associated with a significant reduction in the risk of a doubling in serum creatinine (n = 7 trials, RR = 0.77, 95% CI = 0.50-1.21). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduced the risk of progressing to end-stage renal disease (n = 8, RR = 0.79, 95% CI = 0.75-0.83). No difference in all-cause (n = 11, RR = 0.98, 95% CI = 0.89-1.08) or cardiovascular mortality (n = 6 trials, RR = 1.08, 95% CI = 0.92-1.28), nor the composite outcome of doubling in serum creatinine, end-stage renal disease or mortality (n = 3 trials, RR = 0.87, 95% CI = 0.72-1.06), was observed. Progression of proteinuria was decreased with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use vs. control (n = 10, RR = 0.49, 95% CI = 0.33-0.74). Regression of proteinuria was not improved with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (n = 11, RR = 1.55, 95% CI = 0.93-2.58). CONCLUSION: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of end-stage renal disease and slow the progression of nephropathy, but they do not appear to decrease all-cause or cardiovascular mortality in people with Type 2 diabetes and proteinuria.

Effectiveness and safety of rivaroxaban vs warfarin in people with non-valvular atrial fibrillation and diabetes: an administrative claims database analysis.

AIM: To assess the effectiveness and safety of rivaroxaban vs warfarin in people with non-valvular atrial fibrillation and diabetes treated in routine practice. METHODS: Using US MarketScan claims data for the period November 2011 to December 2016, we identified oral anticoagulation-naïve people with non-valvular atrial fibrillation and diabetes (Type 1 or Type 2) and ≥12 months of continuous insurance coverage prior to the qualifying oral anticoagulation dispensing time. Rivaroxaban users were 1:1 propensity score-matched to warfarin users. Participants were followed until an event, oral anticoagulation switch/discontinuation, insurance disenrolment or end of follow-up. Rates (events/100 person-years) of the composite of stroke or systemic embolism and major bleeding were compared using Cox regression and reported as hazard ratios and 95% CIs. RESULTS: We assessed 5517 rivaroxaban users (20% received the reduced dose) and 5517 warfarin users with non-valvular atrial fibrillation and diabetes (~97% with Type 2 diabetes) with a median (interquartile range) available follow-up of 1.5 (0.7, 2.7) years. Rivaroxaban was associated with nonsignificant reductions in stroke or systemic embolism (0.87 vs 1.35/100 person-years; hazard ratio 0.68, 95% CI 0.44-1.05) and ischaemic stroke (0.69 vs 0.93/100 person-years; hazard ratio 0.78, 95% CI 0.48-1.30) compared with warfarin. No differences in major bleeding (2.7 vs 3.0/100 person-years; hazard ratio 0.96, 95% CI 0.74-1.25) were observed. Similar results were seen when analysis was limited to standard-dose rivaroxaban. Reduced-dose rivaroxaban was associated with a significantly decreased hazard of stroke or systemic embolism and ischaemic stroke, without an increase in major bleeding risk. CONCLUSIONS: Rivaroxaban has effectiveness and safety at least as good as those of warfarin in people with diabetes and non-valvular atrial fibrillation treated in routine clinical practice.

Clinical prediction rules for mortality in patients with pulmonary embolism and cancer to guide outpatient management: a meta-analysis.

Essentials Clinical prediction rules (CPRs) can stratify patients with pulmonary embolism (PE) and cancer. A meta-analysis was done to assess prognostic accuracy in CPRs for mortality in these patients. Eight studies evaluating ten CPRs were included in this study. CPRs should continue to be used with other patient factors for mortality risk stratification. SUMMARY: Background Cancer treatment is commonly complicated by pulmonary embolism (PE), which remains a leading cause of morbidity and mortality in these patients. Some guidelines recommend the use of clinical prediction rules (CPRs) to help clinicians identify patients at low risk of mortality and therefore guide care. Objective To determine and compare the accuracy of available CPRs for identifying cancer patients with PE at low risk of mortality. Methods A literature search of Medline and Scopus (January 2000 to August 2017) was performed. Studies deriving/validating ≥ 1 CPR for early post-PE all-cause mortality were included. A bivariate, random-effects model was used to pool sensitivity and specificity estimates for each CPR. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk of early mortality, mortality in low risk patients and odds ratios for death compared with higher-risk patients. Results Eight studies evaluating 10 CPRs were included. The highest sensitivities were observed with Hestia (98.1%, 95% confidence interval [CI] = 75.6-99.9%) and the EPIPHANY index (97.4%, 95% CI = 93.2-99.0%); sensitivities of remaining rules ranged from 59.9 to 96.6%. Of the six CPRs with sensitivities ≥ 95%, none had specificities > 33%. Random-effects meta-analysis suggested that 6.6-51.6% of cancer patients with PE were at low risk of mortality, 0-14.3% of low-risk patients died and low-risk patients had a 43-94% lower odds of death compared with those at higher risk. Conclusions Because of the limited total body of evidence regarding CPRs, their results, in conjunction with other pertinent patient-specific clinical factors, should continue to be used in identifying appropriate management for PE in patients with cancer.

External validation of the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) multivariable prediction rule.

OBJECTIVE: To validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) multivariable prediction rule using admission claims data. STUDY DESIGN: Retrospective claims database analysis. METHODS: This analysis was performed using Humana admission claims data from January 2007 to March 2014. We included adult patients admitted for their first PE during this period (International Classification of Diseases, ninth edition, Clinical Modification code of 415.1x in in the primary position or secondary position when accompanied by a primary code for a PE complication). The IMPACT rule, consisting of age plus 11 comorbidities, was used to estimate patients' probability of in-hospital mortality and classify risk. Low risk was defined as in-hospital mortality ≤ 1.5%. IMPACT was evaluated by evaluating prognostic test characteristic values and 95% confidence intervals (CIs). RESULTS: A total of 23,858 patients admitted for PE were included, and 3.3% died in-hospital. The IMPACT prediction rule classified 2371 (9.9%) as low-risk; with a sensitivity of 97.6%, 95% CI: 96.1-98.5, specificity of 10.2%, 95% CI: 9.8-10.6, negative and positive predictive values of 99.2% (95% CI: 98.7-99.5) and 3.5% (95% CI: 3.3-3.8) and c-statistic of 0.70, 95% CI: 0.0.68-0.72, for in-hospital mortality. IMPACT classified 42.7% of patients < 65 years old as low-risk; with a sensitivity, specificity and c-statistic of 85.0%, 95% CI: 77.4-90.5, 43.3%, 95% CI: 42.0-44.7 and 0.74, 95% CI: 0.69-0.78, respectively. CONCLUSION: The IMPACT prediction rule was valid when implemented in a database consisting largely of Medicare claims. Following further external validation and direct comparison to commonly used clinical prediction rules, IMPACT may become a valuable tool for payers and hospitals wishing to retrospectively assess whether their PE patients are being kept hospitalized for the optimal period of time.

Comparative efficacy and safety of antidiabetic drug regimens added to stable and inadequate metformin and thiazolidinedione therapy in type 2 diabetes.

AIMS: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). METHODS: MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. RESULTS: Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. CONCLUSION: When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure.

Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis.

AIM: To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. METHODS: We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. RESULTS: A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. CONCLUSIONS: When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.

Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials.

BACKGROUND: Observational studies suggest index clinical manifestation of venous thromboembolism (VTE) predicts recurrence type. Data regarding the association between index manifestation and recurrence rates are conflicting. OBJECTIVES: To perform a meta-analysis of randomized controlled trials (RCTs) to determine the type and frequency of recurrent VTE (rVTE) in persons after an index deep vein thrombosis (DVT) or pulmonary embolism (PE). PATIENTS/METHODS: We searched bibliographic databases for RCTs of acute (early) treatment of rVTE in persons with an index DVT or PE (±DVT), enrolling ≥ 50 subjects anticoagulated ≥ 3-months and reporting types of rVTE. We pooled (random-effects) the proportion of rVTEs that were DVTs, PEs, and fatal PEs, the proportion of recurrent PEs that were fatal, and absolute rVTE rates. RESULTS: In nine RCTs (N = 13 640; 413 rVTEs) evaluating persons with an index PE; 66% (95% CI, 60-72%) of rVTEs were PE and 27% (95% CI, 22-33%) were fatal PE. Among 25 RCTs (N = 17 340; 692 rVTEs) evaluating persons with an index DVT, 36% (95% CI, 29-44%) experienced a recurrent PE and 10% (95% CI, 7-13%) a fatal PE. Recurrent PEs following an index PE had a higher fatality rate than after an index DVT (41%; 95% CI, 33-48% vs. 25%; 95% CI, 18-33%; P = 0.007). The rVTE rate was higher following an index DVT compared with a PE (2.6%; 95% CI, 1.6-3.8% vs. 4.9%; 95% CI, 4.0-6.0%; P = 0.002). CONCLUSIONS: Our meta-analysis suggests most rVTEs will be the same type as the index event. While index DVTs are associated with a higher rVTE rate than index PEs; recurrent PEs are associated with high fatality.

Factors associated with 'caregiver burden' for atrial fibrillation patients.

BACKGROUND: The burden on caregivers providing support to atrial fibrillation (AF) patients has not been evaluated. OBJECTIVE: To examine the interrelationship between unpaid caregiver, patient and thromboprophylaxis characteristics and caregiver burden in AF. METHODS: We conducted a cross-sectional survey study of AF patient-caregiver dyads recruited from cardiology clinics at an urban teaching hospital. Eligible patients had a diagnosis of AF, received thromboprophylaxis to prevent stroke, lived in the community and had an adult, unpaid, English-speaking caregiver. Hierarchical multivariate regression was used to evaluate the association between caregiver, patient and thromboprophylaxis characteristics and caregiver burden as measured by the 'Caregiver Reaction Assessment' (CRA). RESULTS: Eighty patient-caregiver dyads were surveyed. The mean ± standard deviation scores for each CRA domain were 'Disrupted schedule' (2.4 ± 1.0), 'Financial problems' (2.1 ± 0.8), 'Lack of family support' (1.9 ± 0.7), 'Health problems' (1.9 ± 0.7) and 'Self-esteem' (0.9 ± 0.5). Significantly greater caregiver burden due to 'Disrupted schedule' was seen in those spending > 4 h/week providing care and when caring for frail, sick or disabled patients, with higher CHADS2 scores and requiring help with their medications. 'Financial problems' burden scores were significantly associated with caring for frail patients and those requiring more frequent office follow-up. 'Lack of family support' scores were inversely associated with having somebody else to help provide care and increased as patients CHADS2 score increased. Lower 'Health problem' burden scores were associated with female gender and higher scores with the need to spend > 4 h/week providing care. CONCLUSION: The greatest burden to caregivers of AF patients occurs due to schedule disruption.

Systematic review of the cost-effectiveness of varenicline vs. bupropion for smoking cessation.

The purpose of this systematic review was to review the cost-effectiveness of first-line non-nicotine therapies (varenicline and bupropion SR) for smoking cessation, identify differences in the models used and their conclusions of cost-effectiveness, and to determine which variables, if any, impact conclusions of cost-effectiveness. A systematic literature search was conducted in MEDLINE, PsychINFO, the National Health Service Economic Evaluation Database, the Health Technology Database and the Tufts Cost-effectiveness Analysis Registry from the earliest possible date through May 2011. To be included, studies had to compare cost-effectiveness of varenicline to bupropion using either a Markov model or discrete event simulation and be published as a full text manuscript in English or Spanish. Study selection and data extraction were done in duplicate with disagreement resolved through discussion. Data regarding the model characteristics, results and conclusions were extracted as were details to assess the quality of the study. Model characteristics and cost-effectiveness results were compared across studies and summarised qualitatively. Ten unique studies were included, all of which were Markov models. Eight studies used the Benefits of Smoking Cessation on Outcomes (BENESCO) model and all found varenicline to dominate bupropion. The two non-BENESCO models found varenicline to be cost-effective. Conclusions regarding the cost-effectives were changed upon sensitivity analysis with the following variables: time horizon, cost of bupropion, efficacy of either drug, age and the incidence of smoking related disease. Varenicline dominated bupropion in most cost-effectiveness models. However, applicability of models to clinical practice and variables which changed conclusion of cost-effectiveness should be considered in the interpretation of results.

Effect of pharmacological therapies for stroke prevention on major gastrointestinal bleeding in patients with atrial fibrillation.

Various antiplatelet and anticoagulation options are available for stroke prevention in patients with atrial fibrillation (AF). Currently, it is unclear whether these agents differ in their propensity to cause major gastrointestinal bleeding (MGIB). To our knowledge, no systematic evaluation of MGIB rates from randomised controlled trials (RCTs) of pharmacological stroke prevention in patients with AF has been conducted. Two independent investigators conducted systematic literature searches in MEDLINE and CENTRAL from the earliest possible date through November 2010. To be included, RCTs had to evaluate an adult population with AF or flutter and report data on the incidence of MGIB. Peto's odds ratios (ORs) with associated 95% confidence intervals (CIs) were calculated for all possible pair-wise comparisons of pharmacological stroke prevention alternatives. A total of 16 unique trials (n = 42,983) met inclusion criteria. The reported incidence of MGIB in placebo or control arms of identified trials was as high as 1.5%. Upon pair-wise meta-analysis of different pharmacological strategies, adjusted-dose vitamin K antagonists (VKAs) were found to be associated with a higher odds of MGIB compared with placebo/control (OR 3.21, 95% CI 1.32-7.82) and aspirin (or triflusal or indobufen) (OR 1.92, 95% CI 1.08-3.41). The addition of aspirin (or triflusal) to an adjusted-dose VKA resulted in greater odds of MGIB compared with aspirin alone (OR 4.72, 95% CI 1.35-16.49) and adjusted-dose VKA alone (OR 2.66, 95% CI 1.05-6.74). While aspirin increased the odds of MBIG by 3.23-fold compared with placebo/control, this finding did not reach statistical significance. The combination of aspirin and clopidogrel increased patients' odds of MGIB compared with aspirin alone (OR 1.93, 95% CI 1.46-2.56). Dabigatran was associated with a 30% increased odds of MGIB compared with adjusted-dose VKA (OR 1.30, 95% CI 1.06-1.59); however, ximelagatran was not. Low-intensity VKA therapy, alone or in combination with aspirin, was not associated with increased odds of MGIB compared with any (active-) comparator. The MGIB is a concern for patients with AF receiving pharmacological stroke prevention. Current RCT data suggest that dabigatran and adjusted-dose VKA therapy are associated with the highest odds of MGIB. Aspirin was not found to increase patients' odds of MGIB; however, this finding may be the result of type 2 error. Dual therapy resulting from the addition of an antiplatelet agent was typically associated with further increased odds of MGIB compared with monotherapy.

Are the risk factors listed in warfarin prescribing information associated with anticoagulation-related bleeding? A systematic literature review.

Warfarin significantly reduces thromboembolic risk, but perceptions of associated bleeding risk limit its use. The evidence supporting the association between bleeding and individual patient risks factors is unclear. This systematic review aims to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information are prescribed the drug. A systematic literature search of MEDLINE and Cochrane CENTRAL was conducted to identify studies reporting multivariate relationships between prespecified covariates and the risk of bleeding in patients receiving warfarin. The prespecified covariates were identified based on patient characteristics for bleeding listed in the warfarin package insert. Each covariate was evaluated for its association with specific types of bleeding. The quality of individual evaluations was rated as 'good', 'fair' or 'poor' using methods consistent with those recommended by the Agency for Healthcare Research and Quality (AHRQ). Overall strength of evidence was determined using the Grading of Recommendations Assessment, Development (GRADE) criteria and categorised as 'insufficient', 'very low', 'low', 'moderate' or 'high'. Thirty-four studies, reporting 134 multivariate evaluations of the association between a covariate and bleeding risk were identified. The majority of evaluations had a low strength of evidence for the association between covariates and bleeding and none had a high strength of evidence. Malignancy and renal insufficiency were the only two covariates that had a moderate strength of evidence for their association with major and minor bleeding respectively. The associations between covariates listed in the warfarin prescribing information and increased bleeding risk are not well supported by the medical literature.

Oral anti-diabetic drugs for the prevention of Type 2 diabetes.

AIM: To determine the comparative efficacy of oral anti-diabetic drugs in preventing the development of Type 2 diabetes. METHODS: A systematic literature search of MEDLINE, EMBASE and Cochrane CENTRAL was conducted for randomized controlled trials evaluating oral anti-diabetic drugs in patients at high risk for developing Type 2 diabetes. Mixed-treatment comparison meta-analysis methods were used to evaluate the relative risks and risk differences of developing Type 2 diabetes, along with associated 95% credible intervals. RESULTS: Overall, 20 trials (n = 23 230 participants) were included. Upon mixed-treatment comparison meta-analysis, thiazolidinediones, alpha-glucosidase inhibitors and biguanides significantly reduced the relative risk of developing diabetes by 64, 40 and 27%, respectively, compared with control. Sulphonylureas and glinides showed no significant effect. Moreover, thiazolidinediones significantly reduced the relative risk of diabetes by 50% compared with biguanides and trended towards a 40% risk reduction vs. alpha-glucosidase inhibitors [relative risk 0.60 (95% credible intervals 0.34-1.02)]. None of the results were appreciably altered upon subgroup or sensitivity analyses. When evaluating risk differences compared with control, thiazolidinediones (-9%, number needed to treat = 11), alpha-glucosidase inhibitors (-7%, number needed to treat = 14) and biguanides (-7%, number needed to treat = 14) continued to show significant benefit. CONCLUSIONS: Of the oral anti-diabetic drugs evaluated to prevent Type 2 diabetes, thiazolidinediones were associated with the greatest risk reduction compared with control and associated with greater risk reduction than biguanides. Alpha-glucosidase inhibitors and biguanides performed similarly, and better than control, while sulphonylureas and glinides provided no significant benefit.

Statin use and the prevention of venous thromboembolism: a meta-analysis.

AIMS: Statins are thought to have antithrombotic properties and may attenuate patients' odds of developing venous thromboembolism (VTE), but clinical studies have yielded variable estimates of this effect. The aim was to conduct a meta-analysis to evaluate the effect of statin use on development of VTE. METHODS: Randomised controlled trials (RCTs) and observational studies evaluating the effects of statins on the incidence of VTE were selected from MEDLINE (1996 to August 2009), Cochrane CENTRAL (second quarter, 2009), Cochrane Database of Systematic Reviews (second quarter, 2009) and a manual review of references. While no further restrictions were placed on RCTs, observational studies were only included if they reported adjusted effect sizes using appropriate methods. Development of deep vein thrombosis (DVT), pulmonary embolism (PE) and any VTE from RCTs and observational studies were pooled using traditional meta analytic techniques with a random-effects model. RESULTS: Ten studies were identified and eligible for meta-analysis. Upon meta-analysis, statin use was associated with a statistically significant reduction in the odds of developing VTE (AOR 0.68, 95% CI 0.54-0.86), DVT (AOR 0.59, 95% CI 0.43-0.82) and PE (AOR 0.70, 95% CI 0.53-0.94). DISCUSSION: Statin use is associated with significantly reduced odds of developing VTE, DVT or PE by 32%, 41% and 30% respectively. Our meta-analysis included one RCT, JUPITER, which alone provided statistically significant reduction in the odds of developing VTE and DVT (43% and 55% respectively), and a nonsignificant reduction on PE. CONCLUSION: Currently available evidence suggests that statins can reduce patients' odds of developing VTE.

Lack of effect of statins on maintenance of normal sinus rhythm following electrical cardioversion of persistent atrial fibrillation.

Randomised controlled trials evaluating the effect of statin use on maintenance of normal sinus rhythm (NSR) after electrical cardioversion (ECV) of persistent atrial fibrillation (AF) have demonstrated conflicting results. However, many of these trials were of relatively small size and thus underpowered to adequately evaluate this end-point. The aim of this study was to conduct a meta analysis evaluating the effect of statin use on maintenance of NSR after ECV of persistent AF. Randomised controlled trials evaluating the use of statins to maintain NSR after ECV of AF were identified through a systematic search including Medline (1950 through December 2009), the Cochrane CENTRAL Register (4th quarter, 2009) and a manual review of references without any language restrictions. Pooled estimates of effect are reported as relative risks (RRs) with accompanying 95% confidence intervals (CIs) using a random-effects model. Four trials (n = 424; range: 48-212) were identified and subject to meta analysis. Evaluated statins included atorvastatin 10 and 80 mg and pravastatin 40 mg/day. Over a mean of 2.1 months (range: 1-3 months) statins did not increase the likelihood of maintaining NSR following ECV (RR, 1.12; 95%CI, 0.85-1.46) compared with control. Current evidence does not suggest that statins are associated with an increased probability of maintaining NSR following ECV of persistent AF.

Antiplatelet agents for the prevention of arteriovenous fistula and graft thrombosis: a meta analysis.

AIMS: The aim of this study was to evaluate the impact of antiplatelet agents on the thrombosis rates of arteriovenous fistulae and grafts used for haemodialysis access. METHODS: In this meta analysis, a systematic search of the literature was used to identify randomised controlled trials evaluating the effect of antiplatelet agents in graft or fistula thrombosis or bleeding. Two authors identified eligible trials and abstracted data on outcomes and study characteristics. The incidence of thrombosis was the primary outcome of interest and was calculated separately for studies evaluating grafts and those evaluating fistulae. A random-effects model was used for statistical pooling. RESULTS: Ten trials were included in the analysis, nine of which reported outcomes on graft or fistula thrombosis. Antiplatelet agents reduced the rate of arteriovenous fistulae thrombosis (OR 0.54, 95% CI 0.31-0.94) but not grafts (OR 0.50, 95% CI 0.16-1.53). Both analyses had a moderate degree of statistical heterogeneity, likely because of differences in study design, antiplatelet agent and dose, as well as other possible factors. Review of bleeding events did not reveal a concerning risk of bleeding, but could not be statistically evaluated. CONCLUSIONS: Antiplatelet agents reduce the rate of arteriovenous fistula thrombosis; however, at this time, research does not support the use of these agents for preventing arteriovenous graft thrombosis.

Understanding heterogeneity in meta-analysis: the role of meta-regression.

BACKGROUND: Meta-regression has grown in popularity in recent years, paralleling the increasing numbers of systematic reviews and meta-analysis published in the biomedical literature. However, many clinicians and decision-makers may be unfamiliar with the underlying principles and assumptions made within meta-regression leading to incorrect interpretation of their results. AIMS: This paper reviews the appropriate use and interpretation of meta-regression in the medical literature, including cautions and caveats to its use. MATERIALS & METHODS: A literature search of MEDLINE (OVID) from 1966-February 2009 was conducted to identify literature relevant to the topic of heterogeneity and/or meta-regression in systematic reviews and meta-analysis. RESULTS: Meta-analysis, a statistical method of pooling data from studies included in a systematic review, is often compromised by heterogeneity of its results. This could include clinical, methodological or statistical heterogeneity. Meta-regression, said to be a merging of meta-analytic and linear regression principles, is a more sophisticated tool for exploring heterogeneity. It aims to discern whether a linear relationship exists between an outcome measure and on or more covariates. The associations found in a meta-regression should be considered hypothesis generating and not regarded as proof of causality. CONCLUSIONS: The current review will enable clinicians and healthcare decision-makers to appropriately interpret the results of meta-regression when used within the constructs of a systematic review, and be able to extend it to their clinical practice.

Adding a dopamine agonist to preexisting levodopa therapy vs. levodopa therapy alone in advanced Parkinson's disease: a meta analysis.

BACKGROUND: To perform a meta analysis of randomised placebo-controlled trials evaluating the use of dopamine agonist (DA) or placebo to preexisting levodopa therapy for the treatment of advanced Parkinson's disease (PD). We focused on clinically important efficacy [Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores as well as change in 'off' time and levodopa dose] and safety outcomes (withdrawal because of adverse drug events (ADEs), dyskinesias, hallucinations and mortality). METHODS: A systematic literature search was performed between January 1990 and July 2007. The primary outcome measures assessed were the reduction in scores of Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores as well as reduction in 'off' time and reductions in levodopa dose from baseline. Safety end-points were also evaluated. RESULTS: A total of 15 trials (n = 4380 subjects) were included in the meta analysis. Adjunctive DA use resulted in greater improvement as measured by the UPDRS ADL [weighted mean difference (WMD) -2.20, 95% confidence interval (CI) -2.64 to -1.76; p < 0.0001] and motor score reduction (WMD -5.56, 95% CI -6.82 to -4.31; p < 0.0001) as well as reduction in 'off' time measured in hours/day (WMD -1.20, 95% CI -1.78 to -0.62; p < 0.0001) and reduction in levodopa dose (WMD -128.5 mg, 95% CI -175.0 to -82.1; p < 0.0001) vs. placebo. Incidence of dyskinesia and hallucinations was higher with DAs [odds ratio (OR) 3.27, 95% CI 2.65-4.03; p < 0.0001] and (OR 3.34, 95% CI 2.44-4.58; p < 0.0001). Non-ergot DAs were qualitatively better, although both ergot and non-ergot DAs showed statistically significant improvements in all UPDRS scores. CONCLUSION: Adjunctive DA use to levodopa is superior to levodopa alone in reducing PD symptoms in patients not controlled with monotherapy. DAs seem especially useful amongst PD patients with wearing-off phenomenon from levodopa therapy, but can cause some adverse events.

Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis.

AIMS: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevent the progression of diabetic nephropathy (DN). Studies suggest that combination renin-angiotensin-aldosterone system (RAAS)-inhibiting therapy provides additive benefit in DN. However, these studies are small in size. We performed a meta-analysis of studies investigating combination therapy for DN. METHODS: Studies were identified through a search of medline, embase, cinahl and the Cochrane Database. All trials involving combined ACEI and ARB for slowing progression of DN were included. The primary end point was 24-h urinary protein excretion. Blood pressure, serum potassium and glomerular filtration rate (GFR) were secondary end points. RESULTS: In the 10 included trials, 156 patients received ACEI + ARB and 159 received ACEI only. Most studies were 8-12 weeks in duration. Proteinuria was reduced with ACEI + ARB (P = 0.01). This was associated with significant statistical heterogeneity (P = 0.005). ACEI + ARB was associated with a reduction in GFR [3.87 ml/min (7.32-0.42); P = 0.03] and a trend towards an increase in serum creatinine (6.86 micromol/l 95% CI -0.76-13.73; P = 0.09). Potassium was increased by 0.2 (0.08-0.32) mmol/l (P < 0.01) with ACEI + ARB. Systolic and diastolic blood pressure were reduced by 5.2 (2.1-8.4) mmHg (P < 0.01) and 5.3 (2.2-8.4) mmHg (P < 0.01), respectively. CONCLUSIONS: This meta-analysis suggests that ACEI + ARB reduces 24-h proteinuria to a greater extent than ACEI alone. This benefit is associated with small effects on GFR, serum creatinine, potassium and blood pressure. These results should be interpreted cautiously as most of the included studies were of short duration and the few long-term studies (12 months) have not demonstrated benefit.

The impact of gender on survival amongst patients with implantable cardioverter defibrillators for primary prevention against sudden cardiac death.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are a life-saving therapy for many patients with cardiovascular disease at increased risk of fatal dysrhythmias. As men comprise the majority of the study population (67-92%) in clinical trials, the benefit to women is unknown. We performed a meta-analysis of primary prevention trials to evaluate the impact of ICDs in men and women on death from any cause. METHODS: Included trials met the following criteria: (i) randomized controlled trials versus standard of care, (ii) ICD used as primary prevention in a well-described protocol and (iii) data provided on risk of death from any cause for both male and female patients. RESULTS: Five clinical trials were included in this meta-analysis. The risk of death from any cause was significantly reduced by 26% in male patients who received ICD therapy compared to control, hazard ratio (HR) 0.74 (95% CI 0.60-0.91) but not amongst female patients, HR 0.81 (95% CI 0.60-1.09). As the COMPANION trial evaluated the combination of biventricular pacemaker with ICD therapy we conducted a separate analysis without the inclusion of this study. Male patients receiving ICD therapy demonstrated a similar 24% reduction in risk of death from any cause, HR 0.76 (95% CI 0.58-0.99) whilst female patients demonstrated a reduction of only 12%, HR 0.88 (95% CI 0.63-1.22). CONCLUSIONS: Unlike their male counterparts, females did not significantly benefit from ICD therapy and without concurrent biventricular pacing, appear only to achieve a nonsignificant 12% reduction in risk of death.

The effects of Panax ginseng on quality of life.

Panax ginseng is marketed and used to maintain natural energy, increase mental and physical abilities, improve mood and promote general health and well-being. Panax ginseng has been studied in a number of randomized clinical trials investigating its effect on physical and psychomotor performance, cognitive function, immunomodulation, diabetes mellitus and herpes simplex type-II infections. Equivocal results have been demonstrated for many of these indications. P. ginseng is also commonly used to promote quality of life (QoL). As a result, ginseng's effect on QoL has become an increasingly important endpoint in clinical trials. We reviewed all studies (n = 9) that determined the effect of P. ginseng on QoL. P. ginseng's has been evaluated at dosages of 80-400 mg. Study duration has spanned from 2 to 9 months. Several QoL measures have been used, ranging from widely accepted core instruments to unpublished investigator-derived questionnaires. In addition, many of the investigators utilized ginseng extracts that were supplemented with vitamins and minerals while others used only standardized ginseng extract. Populations evaluated also differed in terms of underlying morbidity. Nearly every study evaluated (n = 8) demonstrated some degree of QoL improvement. Beneficial effects were evident within instrument summary component scores but improvement in overall composite scores of QoL was rarely seen. However, findings were equivocal. While populations evaluated varied in terms of underlying morbidity, there did not appear to be a substantial difference in their response to ginseng with respect to QoL. Despite some positive results, improvement in overall health-related quality of life cannot, given the current research, be attributed to P. ginseng. However, the possibility that various facets of QoL may have improved and the potential of early transient effects cannot be discounted.