Madeleine Durand

Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UKs General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.

Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. Design Population based cohort. Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis

Importance The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial. Objective To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis. Design, Setting, and Participants A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014. Exposures Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs. Main Outcomes and Measures Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models. Results Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association. Conclusions and Relevance In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs.

Risk of Spontaneous Intracranial Hemorrhage in HIV-infected Individuals: A Population-based Cohort Study

BACKGROUND We studied the association between HIV infection, antiretroviral medications, and the risk of spontaneous intracranial hemorrhage. METHODS We performed a cohort and nested case control study in an administrative database. We selected all HIV-positive individuals presenting between 1985 and 2007. Each HIV-positive subject was matched with 4 HIV-negative individuals. We used a Poisson regression model to calculate rates of intracranial hemorrhage according to HIV status. We conducted a case -control study nested within the cohort of HIV-positive individuals to look at the effect of antiretroviral medications. Odds ratios for antiretroviral exposure were obtained using conditional logistic regression. RESULTS There were 7,053 HIV-positive and 27,681 HIV-negative subjects, representing 138,704 person-years. There were 49 incident intracranial hemorrhages, 29 in HIV-positive and 20 in HIV-negative individuals. The adjusted hazard ratio for intracranial hemorrhage in HIV-positive compared to HIV-negative patients was 3.28 (95% confidence interval [CI] 1.75-6.12). The effect was reduced to 1.99 (95% CI 0.92-4.31) in the absence of AIDS-defining conditions, and increased to 7.64 (95% CI 3.78-15.43) in subjects with AIDS-defining conditions. Hepatitis C infection, illicit drug or alcohol abuse, intracranial lesions, and coagulopathy were all strongly associated with intracranial hemorrhage (all P < .001). In the case control study, 29 cases of ICH in HIV-positive individuals were matched to 228 HIV-positive controls. None of the antiretroviral classes were associated with an increase in the odds ratio of intracranial hemorrhage. CONCLUSIONS The risk of intracranial hemorrhage in HIV-positive individuals seems to be mostly associated with AIDS-defining conditions, other comorbidities, or lifestyle factors. No association was found between use of antiretroviral medications and intracranial hemorrhage.

Hepatic rupture in hemolysis, elevated liver enzymes, low platelets syndrome.

OBJECTIVE: Rupture of hepatic hematoma associated with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is a catastrophic complication of pregnancy. Maternal and fetal mortality rates are still high despite advances in diagnosis and treatment. We aimed to present our experience at two referral centers for hepatic disease and to compare it with cases from the literature. METHODS: We reviewed nine cases that occurred over the past 6 years in our centers and made an extensive literature review covering the past 10 years. We reviewed and compared multiple outcomes for all these cases. RESULTS: The median maternal age of our patients was 29 years (interquartile range 27–32). Embolization treatment was used with seven of nine (78%) of our patients compared with 5 of 88 (6%) in the literature (P<.001). Our maternal and fetal mortality rates were 0% (95% confidence interval [CI] 0–34%) and 30% (95% CI 7–65%), respectively, compared with 17% (95% CI 10–26%) and 38% (95% CI 31–52%]) from our review of the literature from 2000 to 2010. CONCLUSION: The use of hepatic artery embolization to address hepatic rupture associated with HELLP syndrome may help minimize morbidity and maternal mortality. LEVEL OF EVIDENCE: III

The Effects of Ursodeoxycholic Acid Treatment for Intrahepatic Cholestasis of Pregnancy on Maternal and Fetal Outcomes: A Meta-Analysis Including Non-Randomized Studies

OBJECTIVE The benefits of ursodeoxycholic acid (UDCA) use for treating intra-hepatic cholestasis of pregnancy (ICP) remain uncertain. A 2010 Cochrane Review of randomized control trials was unable to recommend either for or against the use of UDCA in treating ICP. We conducted a meta-analysis of the literature, including both non-randomized studies (NRSs) and RCTs. The objective of the study was to determine if patients included in NRSs were comparable to those in RCTs, and to determine whether the inclusion of NRSs could strengthen the available evidence and guide clinical practice on UDCA use in women with ICP. DATA SOURCES We searched Medline (Ovid), Embase (Ovid), EMB Reviews, Cinahl (Ebsco), and Web of Knowledge (Thomson Reuters) for articles published from 1966 to June 2012. STUDY SELECTION We included all eligible RCTs of UDCA versus placebo or other treatments, and all NRSs comparing UDCA with any other treatment in women with ICP. DATA SYNTHESIS We included 11 RCTs (n = 625 pregnancies) and six NRSs (n = 211 pregnancies). The women included in RCTs and NRSs were comparable, but study quality was poorer for NRSs. Overall, women treated with UDCA had decreased pruritus in 73% of RCTs and in 100% of NRSs with available data. Liver function tests were improved in 82% of RCTs and in 100% of NRSs with available data. UDCA use did not affect the Caesarean section rate, but was associated with less prematurity, less use of neonatal intensive care units (data available in only 3/17 studies), and trends towards increased birth weight and decreased meconium staining. There were 0/356 stillbirths with UDCA and 3/399 stillbirths with comparator. CONCLUSION UDCA treatment should be recommended for women with ICP to reduce adverse maternal and fetal outcomes.

Extracorporeal Membrane Oxygenation in Diffuse Alveolar Hemorrhage Secondary to Systemic Lupus Erythematosus

Diffuse alveolar hemorrhage (DAH) is a rare and potentially deadly complication of systemic lupus erythematosus (SLE). We report two adult cases where extracorporeal membrane oxygenation (ECMO) was used as rescue therapy for severe respiratory failure in this setting. We discuss the risk related to coagulation disturbance and the need for the circuit anticoagulation in this particular setting. We also briefly discuss the clinical problem of lack of knowledge on the bioavailability of the immunosuppressive treatment with the use of ECMO. We think that ECMO should be used as rescue therapy in patients with DAH caused by SLE, but strategies for anticoagulation require further precision.

Cost effectiveness of 'on demand' HIV pre-exposure prophylaxis for non-injection drug-using men who have sex with men in Canada.

Pre-exposure prophylaxis for individuals who are at high risk for HIV infection has been shown to be effective at preventing infection. The authors of this article aimed to investigate whether ‘on-demand’ pre-exposure prophylaxis is also cost effective, specifically in Canada in a population of men who have sex with men, who are at higher risk for HIV infection. The authors used multiple methods to generate a thorough cost-effectiveness analysis that has implications for the use of this therapy in Canada.

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study

Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism. Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016. Setting Community based, using healthcare data from six jurisdictions in Canada and the United States. Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis. Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites. Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients. Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment. Trial registration Clinical trials NCT02833987.

Pregnancy-Related Venous Thromboembolism Risk in Asymptomatic Women With Antithrombin Deficiency: A Systematic Review.

OBJECTIVE: To evaluate the risk of pregnancy-associated venous thromboembolism in women with asymptomatic antithrombin deficiency. DATA SOURCES: The search was performed on MEDLINE (Ovid and PubMed databases) for the period 1966 to June 2012 and ClinicalTrials.gov as of December 15, 2015. METHODS OF STUDY SELECTION: A systematic review including randomized controlled trials, cohort studies, and case–control studies was conducted. Selection criteria included objectively diagnosed venous thromboembolism or venous thromboembolism treated with 3 months of anticoagulation before the availability of objective testing. The study population consisted of pregnant women with asymptomatic antithrombin deficiency. TABULATION, INTEGRATION, AND RESULTS: Seven publications were included in the review. No randomized controlled trials were identified. The best available data consist of three retrospective cohort studies and four case–control studies. Pooled results from case–control studies yielded an estimated odds ratio for venous thromboembolism of 6.09 (95% confidence interval 1.58–23.43). No pooled estimates could be obtained for cohort studies. Data on use of thromboprophylaxis were scarce. CONCLUSION: Despite the small number of patients included, and the variation in study designs, pooled results from case–control studies show a significant association between asymptomatic antithrombin deficiency and pregnancy-associated venous thromboembolism. Thromboprophylaxis during pregnancy and postpartum should be considered in these women.