Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial's duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial's duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan-Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9-19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1-18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0-16.3), 17.4 days (PI, 6.0-28.8), and 8.5 days (PI, 1.9-15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507] .

Cardiovascular drugs and erectile dysfunction - a symmetry analysis.

AIM: Erectile dysfunction is a common problem among patients with cardiovascular diseases and the influence of cardiovascular drugs is much debated. The aim of this study was to evaluate the short term potential for different cardiovascular drugs to affect the risk of being prescribed a drug against erectile dysfunction. METHODS: We employed a symmetry analysis design and included all Danish male individuals born before 1950 who filled their first ever prescription for a cardiovascular drug and a 5-phosphodiesterase inhibitor within a 6 month interval during 2002-2012. If the cardiovascular drug induces erectile dysfunction, this would manifest as a non-symmetrical distribution of subjects being prescribed the cardiovascular drug first vs. persons following the opposite pattern. Furthermore, we calculated the number of patients needed to treat for one additional patient to be treated for erectile dysfunction (NNTH). RESULTS: We identified 20 072 males with a median age of 64 years (IQR 60-70) who initiated a cardiovascular drug and a 5-phosphodiesterase inhibitor within a 6 month interval. Sequence ratios showed minor asymmetry in prescription orders after adjustment for trends in prescribing. This asymmetry was most profound for thiazides (1.28, 95% CI 1.20, 1.38), calcium channel blockers (1.29, 95% CI 1.21, 1.38) and ACE inhibitors (1.29, 95% CI 1.21, 1.37), suggesting a small liability of these drugs to provoke erectile dysfunction. NNTH values were generally large, in the range of 330-6400, corresponding to small absolute effects. CONCLUSION: Our study does not suggest that cardiovascular drugs strongly affect the risk of being prescribed a drug against erectile dysfunction on a short term basis.

Postponement of cardiovascular outcomes by statin use: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To estimate the average outcome postponement (gain in days to an event) for cardiovascular outcomes in a meta-analysis of randomized, controlled statin trials, including any myocardial infarction, any stroke and cardiovascular death. DESIGN: Systematic review of large randomized, placebo-controlled trials of statin use, including a random-effects meta-analysis of all included trials. DATA SOURCES: We searched MEDLINE (15 July 2019) and ClinicalTrials.gov (16 October 2019). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized, placebo-controlled trials of statin use that included at least 1000 participants. We identified 15 cardiovascular outcomes that were reported in more than 2 trials. RESULTS: We included 19 trials. The summary outcome postponements for the 15 cardiovascular outcomes varied between -1 and 38 days. For four major outcomes, the summary outcome postponement in days was as follows: cardiovascular mortality, 9.27 days (95% CI: 3.6 to 14.91; I2  = 72%; 9 trials) non-vascular and non-cardiovascular mortality, 1.5 days (95% CI: -2.2 to 5.3; I2  = 0%; 6 trials) any myocardial infarction 18.0 days (95% CI; 12.1 to 24.1; I2  = 92%; 15 trials); and any stroke, 6.1 days (95% CI; 2.86 to 9.39; I2  = 66%; 14 trials). CONCLUSION: Statin treatment provided a small, average postponement of cardiovascular outcomes during trial duration.

Interaction between warfarin and cannabis.

Delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug-drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27-year-old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9-mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.

Treatment Failure of TNF-α Inhibitors in Obese Patients With Inflammatory Bowel Disease-A Cohort Study.

Background: In treatment of inflammatory bowel disease (IBD) with anti-tumor necrosis factor-α agents (anti-TNF-α), obesity has been suspected as a cause of accelerated loss of response (LOR). We sought to determine whether overweight IBD patients have accelerated LOR when treated with anti-TNF-α agents, compared with normal weight IBD patients. Methods: We identified a cohort of adult IBD patients treated with anti-TNF-α agents at a Danish university hospital. Patients were grouped according to body mass index (BMI), and our main outcome was time to LOR. We performed survival analyses on LOR and calculated hazard ratios (HRs) with the normal weight group as the reference, while adjusting for confounders. Results: Of 210 eligible patients, 92 (44%) experienced LOR. One hundred eighty patients were treated with infliximab and 30 with adalimumab, 114 (54%) were normal weight, 51 (24%) were overweight, and 45 (21%) were obese. Regression analysis produced the following adjusted HRs, compared with the normal weight group: overweight 0.89 (95% confidence interval [CI], 0.51-1.56) and obese 1.31 (95% CI, 0.76-2.24), thus showing no statistically significant association between BMI and time to LOR. Subgroup analyses produced similar results, except for obese ulcerative colitis patients having an adjusted HR of 2.42 (95% CI, 1.03-5.70). Conclusions: In IBD patients treated with anti-TNF-α agents, we found no overall association between increased BMI and accelerated LOR.

Phenobarbital compared to benzodiazepines in alcohol withdrawal treatment: A register-based cohort study of subsequent benzodiazepine use, alcohol recidivism and mortality.

BACKGROUND: Long-acting benzodiazepines such as chlordiazepoxide are recommended as first-line treatment for alcohol withdrawal. These drugs are known for their abuse liability and might increase alcohol consumption among problem drinkers. Phenobarbital could be an alternative treatment option, possibly with the drawback of a more pronounced acute toxicity. We evaluated if phenobarbital compared to chlordiazepoxide decreased the risk of subsequent use of benzodiazepines, alcohol recidivism and mortality. METHODS: The study was a register-based cohort study of patients admitted for alcohol withdrawal 1998-2013 and treated with either phenobarbital or chlordiazepoxide. Patients were followed for one year. We calculated hazard ratios (HR) for benzodiazepine use, alcohol recidivism and mortality associated with alcohol withdrawal treatment, while adjusting for confounders. RESULTS: A total of 1063 patients treated with chlordiazepoxide and 1365 patients treated with phenobarbital were included. After one year, the outcome rates per 100 person-years in the phenobarbital versus the chlordiazepoxide cohort were 9.20 vs. 5.13 for use of benzodiazepine, 37.9 vs. 37.9 for alcohol recidivism and 29 vs. 59 for mortality. Comparing phenobarbital to chlordiazepoxide treated, the HR of subsequent use of benzodiazepines was 1.56 (95%CI 1.05-2.30). Similarly, the HR for alcohol recidivism was 0.99 (95%CI 0.84-1.16). Lastly, the HR for 30-days and 1 year mortality was 0.25 (95%CI 0.08-0.78) and 0.51 (95%CI 0.31-0.86). CONCLUSION: There was no decreased risk of subsequent benzodiazepine use or alcohol recidivism in patients treated with phenobarbital compared to chlordiazepoxide. Phenobarbital treatment was associated with decreased mortality, which might be confounded by somatic comorbidity among patients receiving chlordiazepoxide.