Hannah Ewald

Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis

Colchicine is an old anti-inflammatory drug that has shown substantial cardiovascular benefits in recent trials. We systematically reviewed cardiovascular benefits and harms of colchicine in any population and specifically in patients with high cardiovascular risk. We evaluated randomised controlled trials comparing colchicine over at least 6 months versus any control in any adult population. Primary outcomes were all-cause mortality, myocardial infarction and adverse events. Cardiovascular mortality was a secondary outcome. We included 39 trials with 4992 patients. The quality of evidence for mortality outcomes and myocardial infarction was moderate but lower for adverse events. Colchicine had no effect on all-cause mortality (RR 0.94, 95% CI 0.82 to 1.09; I2=27%; 30 trials). Cardiovascular mortality was reduced in some but not all meta-analytical models (random-effects RR 0.34, 0.09 to 1.21, I2=9%; Petos OR 0.24, 0.09 to 0.64, I2=15%; Mantel-Haenszel fixed-effect RR 0.20, 0.06 to 0.68, I2=0%; 7 trials). The risk for myocardial infarction was reduced (RR 0.20, 0.07 to 0.57; 2 trials). There was no effect on total adverse events (RR 1.52, 0.93 to 2.46, I2=45%; 11 trials) but gastrointestinal intolerance was increased (RR 1.83, 1.03 to 3.26, I2=74%; 11 trials). Reporting of serious adverse events was inconsistent; no event occurred over 824 patient-years (4 trials). Effects in high cardiovascular risk populations were similar (4 trials; 1230 patients). We found no evidence supporting colchicine doses above 1 mg/day. Colchicine may have substantial cardiovascular benefits; however, there is sufficient uncertainty about its benefit and harm to indicate the need for large-scale trials to further evaluate this inexpensive, promising treatment in cardiovascular disease.

Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and meta-analysis.

Abstract Introduction: Benefits and harms of tenofovir disoproxil fumarate (TDF) in HIV-infected, antiretroviral treatment (ART)-naïve patients of any age have not been systematically reviewed since recent milestone trials were published. Methods: We searched MEDLINE, EMBASE, CENTRAL, SCI, LILACS, WHO GHL, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing TDF-based treatments with any other ART-regimen (last search 01/2015). Trial characteristics and results were extracted, risks of bias systematically assessed, and treatment effects synthesized in meta-analyses using random-effects models. Results: We included 22 RCTs (8297 patients). We found no differences between groups for mortality, AIDS, fractures, CD4 cell count, and virological failure; and inconclusive information due to inadequate reporting for cardiovascular events, renal failure, proteinuria, rash, and quality of life. Tenofovir disoproxil fumarate-based regimens significantly reduced total cholesterol (mean difference − 18.42 mg/dl; 95% confidence interval [CI] − 22.80 to − 14.0), LDL-cholesterol ( − 9.53 mg/dl; − 12.16 to − 6.89), HDL-cholesterol ( − 2.97 mg/dl; − 4.41 to − 1.53), and triglycerides ( − 29.77 mg/dl; − 38.61 to − 20.92), bone mineral density (BMD) (hip: − 1.41%; − 1.87 to − 0.94), and glomerular filtration rate (eGFR) ( − 3.47 ml/minute; − 5.89 to − 1.06) over 48 weeks of follow-up. Effects were similar in trials comparing fixed-dose TDF/FTC-based regimens with ABC/3TC-based regimens. We found no influence of baseline viral load on virological failure. Discussion: Moderate-quality evidence suggests similar effects of TDF-based treatment regimens and other ART on virological failure. Tenofovir disoproxil fumarate-based regimens are associated with a more favorable lipid profile, but with increased risk of reduced BMD and eGFR. Improved reporting quality is vital to allow assessment of clinical outcomes in future trials.

The Clinical Effectiveness of Pneumococcal Conjugate Vaccines: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND Streptococcus pneumoniae is responsible for approximately 1.6 million yearly deaths worldwide. An up-to-date evidence base on the effects of pneumococcal conjugate vaccines (PCVs) on infectious diseases and mortality in any population or setting regardless of age or health status is currently lacking. METHODS We systematically searched MEDLINE and EMBASE for pertinent randomized controlled trials (RCTs). Two reviewers independently screened 9498 titles/abstracts and 430 full-text papers for eligible trials. The outcomes of our meta-analysis were pooled using relative risks (RRs) with a random effects model or Petos odds ratios (ORs) if event rates were :lt;1%. RESULTS 21 RCTs comprising 361 612 individuals were included. PCVs reduced the risk for invasive pneumococcal disease (odds ratio [OR]: 0.43, 95% confidence interval [CI]: [0.36; 0.51]), all-cause acute otitis media (AOM) (RR: 0.93, 95% CI: [0.86; 1.00]), pneumococcal AOM (RR: 0.57, 95% CI: [0.39; 0.83]), allcause pneumonia (RR: 0.93, 95% CI: [0.89; 0.97]), and pneumococcal pneumonia (RR: 0.78, 95% CI: [0.62; 0.97]). We found no significant effect of PCVs on all-cause mortality (RR: 0.95, 95% CI: [0.88; 1.03]) or recurrent AOM (RR: 0.87, 95% CI: [0.72; 1.05]). CONCLUSION PCVs are associated with large risk reductions for pneumococcal infectious diseases, smaller risk reductions for infectious diseases from any cause, and no significant effect on all-cause mortality.

Colchicine and Prevention of Cardiovascular Events

CLINICAL QUESTION Is continuous long-term treatment with colchicine associated with lower rates of all-cause mortality and myocardial infarction and higher rates of adverse events? BOTTOM LINE Continuous long-term treatment with colchicine may be associated with lower rates of myocardial infarction, but may be associated with higher rates of gastrointestinal adverse events.

How to use FDA drug approval documents for evidence syntheses

Evidence syntheses may benefit from using aggregated clinical trial information in approval documents published online by the US Food and Drug Administration (FDA). We provide practical guidance on how to access and use this source of information for evidence syntheses on treatment effects of drugs and therapeutic biologics.

Comparative effectiveness of tenofovir in HIV-infected treatment-experienced patients: systematic review and meta-analysis

Background: Antiretroviral therapy (ART) regimens for HIV infection are frequently changed. We conducted a systematic review of randomized trials (RCTs) on the benefits and harms of switching to tenofovir disoproxil fumarate (TDF)-based regimens in ART-experienced patients. Methods: We included RCTs in HIV-infected adults comparing switching to a TDF-containing regimen with maintaining or switching to another regimen. We searched MEDLINE, EMBASE, CENTRAL, LILACS, SCI, and the WHO Global Health Library. We assessed bias with the Cochrane tool and synthesized data using random-effects meta-analyses and Peto’s approach. For further analyses, we added data from a previous systematic review in treatment-naïve patients. Results: 17 RCTs with 2210 patients were included. All but one study had a high risk of bias. There was no significant association of switching to TDF-based regimens with mortality, fractures, CD4-cell count, body fat, virological failure, LDL-, and HDL-cholesterol. TDF-based regimens decreased total cholesterol (mean difference −12.05 mg/dL; 95% CI −20.76 to −3.34), trigylcerides (−14.33 mg/dL; −23.73 to −4.93), and bone mineral density (BMD; hip: −2.46%; −3.9 to −1.03; lumbar spine −1.52%; −2.69 to −0.34). Effects on estimated glomerular filtration (eGFR) were inconsistent and depended on the measurement. Adding 22 RCTs from 8297 treatment-naïve patients gave consistent results with then significant reductions of LDL (−7.57 mg/dL; −10.37 to −4.78), HDL (−2.38 mg/dL; −3.83 to −0.93), and eGFR (−3.49 ml/min; −5.56 to −1.43). Conclusions: Switching to TDF-based regimens is associated with reductions of BMD and lipid levels and possibly lowered kidney function. The evidence is limited by the high risk of bias.