Variation in bleeding risk estimates among online calculators: Cross-sectional study of apps used by and for patients with atrial fibrillation.

OBJECTIVE: To assess the variation in bleeding risk estimates and risk stratification among Web and mobile applications for patients with atrial fibrillation. DESIGN: Cross-sectional study. SETTING: Simulated patient population. PARTICIPANTS: Hypothetical patient cohorts that encompassed all possible binary risk factor combinations for each clinical prediction model. INTERVENTIONS: Twenty-five bleeding risk calculators (18 Web and 7 mobile apps), each of which used 1 of 4 clinical prediction models to predict an individual's 12-month bleed risk: ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), HAS-BLED (hypertension [systolic blood pressure >160 mm Hg], abnormal renal or liver function, stroke [caused by bleeding], bleeding, labile international normalized ratio, elderly [age >65 years], drugs [acetylsalicylic acid or nonsteroidal anti-inflammatory drugs] or alcohol [≥8 drinks per week]), HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older [age >75 years], reduced platelet count or function, rebleeding risk [history of past bleeding], hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, and stroke), and mOBRI (modified Outpatient Bleeding Risk Index). MAIN OUTCOME MEASURES: Four simulated cohorts were constructed. The coefficient of variation, relative difference (RD), and 95% CI for annual bleeding risk estimates were calculated for all hypothetical patient cohorts. Additionally, pairwise agreement between calculators across low- (<10%), moderate- (10% to 20%), and high-risk (>20%) categories of patients was determined. RESULTS: The risk estimates the calculators generated were imprecise, with coefficients of variation ranging from 14% for HEMORR2HAGES to 64% for mOBRI. Wide variation was observed in annual risk estimates for calculators using the mOBRI (maximum RD=4.3) and HAS-BLED (maximum RD=3.1) models. The 95% CI of mean annual bleeding risk varied among models; 1 calculator using the HAS-BLED model had a 95% CI of mean annual risk estimates of 5.4% to 6.2%, while another HAS-BLED calculator reported a 95% CI of 17.7% to 18.5%. Concordance for risk category stratification among calculators was high for those based on mOBRI and ATRIA (=1 for both). Poor agreement was observed in 1 calculator using HEMORR2HAGES (=0.54) and another using HAS-BLED ( range=-0.11 to 0.35). CONCLUSION: Inconsistencies and a lack of precision were observed in annual risk estimates and risk stratification produced by Web and mobile bleeding risk calculators for patients with atrial fibrillation. Clinicians should refer to annual bleeding risks observed in major randomized controlled trials to inform risk estimates communicated to patients.

Drug-Drug Interaction of the Sodium Glucose Co-Transporter 2 Inhibitors with Statins and Myopathy: A Disproportionality Analysis Using Adverse Events Reporting Data.

INTRODUCTION: An increased risk of myopathy due to a potential interaction between sodium glucose co-transporter-2 inhibitors (SGLT-2i) and HMG-CoA reductase inhibitors (statins) has been suggested by case reports. OBJECTIVE: We aimed to assess if the reporting of myopathy is disproportionally higher among people using both SGLT-2i and statins compared to using either SGLT-2i or statins alone. METHODS: We conducted a disproportionality analysis using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). We included reports with at least one antihyperglycemic agent. We compared the proportion of myopathy cases to non-cases between those not using SGLT-2i or statins, using SGLT-2i only, statins only, or both. We calculated the reporting odds ratio and 95% confidence interval. We further stratified by individual SGLT-2i and selected statins (rosuvastatin or atorvastatin). RESULTS: We included 688,388 reports with at least one antihyperglycemic agent recorded, of which 9.80% had at least one SGLT-2i agent. Among all included reports, there were a total of 2202 myopathy cases with the majority, 61.26%, occurring among those using statins alone and only 2.72% of myopathy cases were among those using both SGLT-2i and statins together. Reporting of myopathy was not disproportionally higher among those reporting the use of SGLT-2i with statins (reporting odds ratio 2.95, 95% confidence interval 2.27-3.85) compared to statins alone (reporting odds ratio 6.41, 95% confidence interval 5.86-7.02). CONCLUSIONS: Reports of myopathy were not disproportionally higher among those using SGLT-2i with statins compared to SGLT-2i or statins alone at the class level. Further observational studies may be needed to better assess this interaction at the agent level.

Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis: An Example of Complementary Evidence for Rare Adverse Events.

Evidence from observational studies may be considered complementary to that of randomized controlled trials (RCTs), particularly when assessing rare outcomes of drug therapies. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic agents that have been linked to an increased risk of diabetic ketoacidosis (DKA). We conducted a systematic review and separately meta-analyzed data from RCTs (n = 18; 2013-2019) and cohort studies (n = 7; 2017-2020) to assess the consistency of the magnitude of association between SGLT-2 inhibitors and DKA risk. We illustrate the strengths and weaknesses of the 2 designs. Results from RCTs and observational studies consistently showed almost a doubling in the risk of DKA among patients using an SGLT-2 inhibitor as compared with placebo or an active comparator. In a random-effects model, the pooled relative risk was 2.08 (95% confidence interval (CI): 1.28, 3.40) from placebo-controlled RCTs and 0.82 (95% CI: 0.25, 2.68) from active-comparator RCTs. The pooled adjusted hazard ratio from observational studies was 1.74 (95% CI: 1.28, 2.38). Notably, the 2 designs complement each other in several domains, including external and internal validity and power. This demonstrates a need for more comprehensive evidence when assessing rare adverse events for both sources.

Assessing the risk of venous thromboembolism (VTE) in ambulatory patients with cancer: Rationale and implementation of a pharmacist-led VTE risk assessment program in an ambulatory cancer centre.

OBJECTIVES: The objectives of this paper were to identify and compare clinical prediction models used to assess the risk of venous thromboembolism (VTE) in ambulatory patients with cancer, as well as review the rationale and implementation of a pharmacist-led VTE screening program using the Khorana Risk Score model in an ambulatory oncology centre in Sault Ste. Marie, Ontario, Canada. DATA SOURCES: PubMed was used to identify clinical practice guidelines and review articles discussing risk prediction models used to assess VTE risk in ambulatory patients with cancer. DATA SUMMARY: Three commonly used VTE risk prediction models in ambulatory patients with cancer: the Khorana Risk Score, Vienna Cancer and Thrombosis Study (CATS) and Protecht Score, were identified via literature review. After considering guideline recommendations, site-specific factors (i.e. laboratory costs, time pharmacists spent calculating VTE risk) and evidence from the CASSINI and AVERT trials, a novel pharmacist-led VTE risk assessment program using the Khorana Risk Score was developed during a fourth-year PharmD clinical rotation at the Algoma District Cancer Program (ADCP) [ambulatory cancer care centre]. ADCP patients with a Khorana Risk Score of ≥2 were referred to the hematologist for a full VTE workup. Considering limitations, inclusion and exclusion criteria of the CASSINI and AVERT trials, the hematologist and pharmacy team decided on appropriate initiation of thromboprophylaxis with a direct oral anticoagulant (DOAC). CONCLUSIONS: The Khorana Risk Score was the chosen model used for the pharmacist-led VTE risk assessment program due to its user-friendly scoring algorithm, evidence from validation studies and clinical trials, as well as ease of integration into pharmacy workflow. More research is needed to determine if pharmacist-led VTE risk assessment programs will impact patient outcomes, such as morbidity and mortality, secondary to cancer-associated thrombosis.

Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews.

BACKGROUND: Multiple published quantitative systematic reviews have reported on adverse events associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus. AIMS: To summarize and appraise the quality of evidence from quantitative systematic reviews assessing adverse events of SGLT-2 inhibitors. METHODS: We searched PubMed, EMBASE and the Cochrane Library for quantitative systematic reviews assessing SGLT-2 inhibitor safety. Two reviewers extracted data and assessed methodological quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool. Main outcomes included pooled and single study point estimaates (in the absence of pooled estimates) with corresponding 95% confidence intervals (CIs) of SGLT-2 inhibitors versus placebo or active comparators for genitourinary infections, volume depletion, acute kidney injury, bone fractures, diabetic ketoacidosis, lower limb amputations, cancers, and other notable adverse events. RESULTS: Out of 1289 citations screened, 47 reviews assessed SGLT-2 inhibitor safety, of which 35 were of low quality. Canagliflozin, dapagliflozin and empagliflozin were consistently associated with an increased risk of genital tract infections versus placebo (point estimates ranged from 2.5 to 9.8) and other antihyperglycemic agents (point estimates ranged from 2.7 to 12.0). Canagliflozin and dapagliflozin were associated with an increased risk of diabetic ketoacidosis. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a statistically significant increased risk of urinary tract infections. Empagliflozin was associated with a statistically significant increased risk of bladder cancer; however, this finding was susceptible to detection bias. None of the agents were associated with a statistically significant increased risk of acute kidney injury, or bone fractures compared to placebo or mixed (active or placebo) comparators. Upper 95% CI limits do not rule out clinically meaningful outcomes. CONCLUSION: The majority of quantitative systematic reviews reporting on adverse events of SGLT-2 inhibitors were of low methodological quality. Despite almost 50 quantitative systematic reviews published on the safety of SGLT-2 inhibitors, clinicians are still left uncertain of the risks of important adverse effects. PLAIN LANGUAGE SUMMARY: SGLT-2 iInhibitor side effects: overview of reviews Many published systematic reviews have reported on side effects associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes. We aimed to summarize and appraise the quality of evidence from quantitative systematic reviews assessing side effects of SGLT-2 inhibitors. Using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool, two authors extracted data and assessed the methods of included reviews. Main outcomes included reported pooled and single study point estimates for several SGLT-2 inhibitor side effects such as genital infections, bone fractures, lower limb amputations, increased blood acidity, among others. Of the reviews included in our study, 35 of the 47 reviews assessed were of low quality. Canagliflozin and dapagliflozin were associated with an increased risk of blood acidity in a 2020 review. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a significantly increased risk of urinary tract infections. Empagliflozin was associated with an increased risk of bladder cancer; however, this finding was susceptible to bias. None of the agents were associated with an increased risk of kidney injury or bone fractures.

The association of sodium-glucose cotransporter 2 inhibitors with cancer: An overview of quantitative systematic reviews.

AIMS: To summarize reported cancer events associated with SGLT-2 inhibitors used in patients with type 2 diabetes mellitus, as well as assess the quality of included reviews. MATERIALS AND METHODS: In May 2019, we searched PubMed, Embase and the Cochrane Library for quantitative systematic reviews assessing the safety of SGLT-2 inhibitors. Data were abstracted using a standardized form, and methodological quality was assessed using the AMSTAR 2 tool. Main outcome measures included total cancer events and specific cancers such as breast cancer, bladder cancer, gastrointestinal cancer, prostate cancer, respiratory cancer, renal cancer and skin cancer. Pooled treatment effects from included reviews were summarized for SGLT-2 inhibitors as a class and for individual SGLT-2 inhibitors commonly used worldwide (canagliflozin, dapagliflozin and empagliflozin). RESULTS: We screened 1248 unique citations, of which eight quantitative systematic reviews meta-analysed results from studies reporting the association between an SGLT-2 inhibitor and any cancer. Only one review was rated as high quality according to AMSTAR 2 assessment. In total, data from 170 cancer-related point estimates (PE) were reported. As a class, SGLT-2 inhibitors were not associated with an increased risk of any cancer event versus placebo and active comparators. Most point estimates (7/143) were nonsignificant for individual cancers except for two associations. Empagliflozin was associated with an increased risk of bladder cancer versus placebo and active comparators in two reviews, while canagliflozin appeared protective for gastrointestinal cancer versus placebo and active comparators in one review. CONCLUSIONS: It appears that SGLT-2 inhibitors are not associated with an increased risk of total cancer or specific cancers in patients with type 2 diabetes. However, higher quality evidence is needed to derive confident conclusions.