Zhong Yuan

Characterizing Major Bleeding in Patients With Nonvalvular Atrial Fibrillation: A Pharmacovigilance Study of 27 467 Patients Taking Rivaroxaban

In nonvalvular atrial fibrillation (NVAF), rivaroxaban is used to prevent stroke and systemic embolism.

Associations between atrial fibrillation and early outcomes of patients with heart failure and reduced or preserved ejection fraction

BACKGROUND The relative impact of atrial fibrillation on early outcomes of patients with heart failure with reduced or preserved ejection fraction (EF) is unknown. METHODS We conducted a retrospective cohort study of clinical registry data linked to Medicare claims for patients with heart failure with reduced or preserved EF stratified by presence of atrial fibrillation at admission. Outcomes of interest were all-cause mortality and readmission at 30days. We used Kaplan-Meier methods to estimate mortality and calculated cumulative incidence estimates of readmission. We used Cox proportional hazards models to examine associations between atrial fibrillation and 30-day outcomes. RESULTS Among 66,357 patients admitted to 283 hospitals between January 2001 and March 2006, 46% had atrial fibrillation (44% of patients with reduced EF and 48% of patients with preserved EF). After adjustment for other patient characteristics, atrial fibrillation was associated with a modestly higher risk of 30-day mortality (HR, 1.08; 95% CI, 1.03-1.14) and readmission (HR, 1.06; 95% CI, 1.02-1.11). In subgroup analyses, atrial fibrillation was associated with a higher risk of 30-day mortality (HR, 1.16; 95% CI, 1.08-1.25) among patients with preserved EF but not among patients with reduced EF. The association of atrial fibrillation with readmission did not differ by heart failure type (P=.37 for the interaction). CONCLUSIONS Atrial fibrillation was associated with higher 30-day mortality among patients with heart failure with preserved EF but not reduced EF. The association of atrial fibrillation with 30-day readmission was modest and did not differ by heart failure type.

Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)

Background: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns. Methods: We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed. Results: After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50–0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60–0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12–3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis. Conclusions: In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.Background : Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose co-transporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual endpoints or safety concerns. Methods : We performed a population-based cohort study among type 2 diabetes patients with established cardiovascular disease newly initiated on antihyperglycemic agents (AHAs) within the US Department of Defense Military Health System between 4/1/2013 and 12/31/2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite endpoint of all-cause mortality (ACM) and hospitalization for heart failure (HHF) event, major adverse cardiovascular events (MACE; defined as ACM, nonfatal myocardial infarction, and nonfatal stroke), and individual endpoints were evaluated using conditional Cox models comparing new SGLT2i users with other AHAs. Exploratory safety endpoint was below-knee lower extremity amputation (BKA). Intent-to-treat and on-treatment analyses were performed. Results : After propensity matching, 25,258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of ACM and HHF (1.73 vs. 3.01 events per 100 person-years; HR 0.57; 95% CI: 0.50-0.65) and MACE (2.31 vs. 3.45 events per 100 person-years; HR 0.67, 95% CI: 0.60-0.75). SGLT2i initiation was also associated with a ≈two-fold higher risk of BKA (0.17 vs. 0.09 events per 100 person-years; HR 1.99, 95% CI: 1.12-3.51). Due to the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis. Conclusions : In this high-risk cohort, initiation of SGLT2i was associated with lower ACM, HHF, and MACE and higher BKA risk. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the BKA risk extends across the class of medication as the study was not powered to make comparisons among individual treatments.

Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium‐glucose co‐transporter‐2 inhibitors in the USA: A retrospective cohort study

To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co‐transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, compared with non‐SGLT2 inhibitor antihyperglycaemic agents (AHAs).

Benefit–risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty

Purpose Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit–risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) randomized clinical studies of rivaroxaban versus enoxaparin after total hip (THA) or knee (TKA) arthroplasty generally used pooled THA and TKA results, counted fatal bleeding as both an efficacy and a safety event, and included the active and placebo-controlled portions of RECORD2, which might confound benefit–risk assessments. We conducted a post hoc analysis without these constraints to assess benefit–risk for rivaroxaban versus enoxaparin in the RECORD studies. Patients and methods Data from the safety population of the two THA and two TKA studies were pooled separately. The primary analysis compared the temporal course of event rates and rate differences between rivaroxaban and enoxaparin prophylaxis for symptomatic venous thromboembolism plus all-cause mortality (efficacy events) versus nonfatal major bleeding (safety events). Additionally, these rates were used to derive measures of net clinical benefit, number needed to treat (NNT), and number needed to harm (NNH) for these two end points. Results After THA or TKA, and compared with enoxaparin, rivaroxaban therapy resulted in more efficacy events prevented than safety events caused, with benefits exceeding harms early and throughout treatment and follow-up. Relative to enoxaparin, rivaroxaban treatment prevented six efficacy events per harm event caused for THA, with NNT =262/NNH =1,711. For TKA, rivaroxaban treatment prevented four to five efficacy events per harm event caused, with NNT =102/NNH =442. Sensitivity analysis that included surgical-site bleeding resulted in NNH =345 for THA and NNH =208 for TKA. Conclusion In the RECORD studies, considering death, symptomatic venous thromboembolism, and major bleeding, rivaroxaban resulted in greater benefits than harms compared with enoxaparin. When incorporating surgical-site bleeding, rivaroxaban also results in greater benefit than harm for TKA and is balanced with enoxaparin for THA.

Relative importance of benefits and risks associated with antithrombotic therapies for acute coronary syndrome: patient and physician perspectives

Abstract Background: In acute coronary syndrome (ACS), antithrombotic therapies prevent thrombotic events, but also increase bleeding risk. Knowledge is limited about how patients and physicians balance these benefits and risks. Objective: To quantify US patient and physician preferences for outcomes associated with antithrombotic therapies in ACS. Methods: Two independent web-based surveys were conducted using best–worst scaling in board-certified cardiologists and adult patients hospitalized within the last 5 years due to heart attack and who used aspirin or prescription antithrombotic therapies. Participants selected best and worst of three possible outcomes across a series of questions. Outcomes included death, various levels of stroke, myocardial infarction (MI), and bleeding. Data were analyzed using a maximum difference model employing random-parameters logit. Relative importance of each outcome was estimated relative to death. Findings: Patients (n = 206) and physicians (n = 273) who met face validity requirements, viewed death and nonfatal major disabling stroke as nearly equivalent and most important outcomes to avoid. Relative to death and disabling stroke, physicians considered nondisabling stroke, all nonfatal bleeding, and mild MI all as least important to avoid, while patients considered all bleeds, except major bleeding requiring transfusion, as least important to avoid. Physicians considered severe MI equivalent to 0.92 (0.02 SE) deaths. Patients (∼0.35 [0.04] deaths) and physicians (∼0.64 [0.05] deaths) had different views for nonfatal moderate stroke. Patients viewed nonfatal major bleeding requiring transfusion ∼0.13 (0.02) deaths, and nonfatal heart attack ∼0.09 (0.02) deaths. Conclusion: US patients and physicians agree on the relative importance of avoiding death, disabling stroke and bleeding without transfusions. Differing perspectives on bleeding requiring transfusions, MI, and moderately disabling stroke suggest that patients and physicians may have different benefit–risk preferences. Transparent discussion between physicians and patients in ACS treatment shared decision-making seems warranted, although limitations of survey methodology and cultural differences compared with US participants should be considered.

Incidence of diabetic ketoacidosis among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors and other antihyperglycemic agents

AIMS To estimate and compare incidence of diabetes ketoacidosis (DKA) among patients with type 2 diabetes who are newly treated with SGLT2 inhibitors (SGLT2i) versus non-SGLT2i antihyperglycemic agents (AHAs) in actual clinical practice. METHODS A new-user cohort study design using a large insurance claims database in the US. DKA incidence was compared between new users of SGLT2i and new users of non-SGLT2i AHAs pair-matched on exposure propensity scores (EPS) using Cox regression models. RESULTS Overall, crude incidence rates (95% CI) per 1000 patient-years for DKA were 1.69 (1.22-2.30) and 1.83 (1.58-2.10) among new users of SGLT2i (n=34,442) and non-SGLT2i AHAs (n=126,703). These rates more than doubled among patients with prior insulin prescriptions but decreased by more than half in analyses that excluded potential autoimmune diabetes (PAD). The hazard ratio (95% CI) for DKA comparing new users of SGLT2i to new users of non-SGLT2i AHAs was 1.91 (0.94-4.11) (p=0.09) among the 30,196 EPS-matched pairs overall, and 1.13 (0.43-3.00) (p=0.81) among the 27,515 EPS-matched pairs that excluded PAD. CONCLUSIONS This was the first observational study that compared DKA risk between new users of SGLT2i and non-SGLT2i AHAs among patients with type 2 diabetes, and overall no statistically significant difference was detected.

CHA2DS2-VASc Scores and Major Bleeding in Patients With Nonvalvular Atrial Fibrillation Who Are Receiving Rivaroxaban.

Study objective Assessing stroke risk associated with nonvalvular atrial fibrillation depends on the evaluation of patient characteristics and clinical features. Clinicians must determine that the net clinical benefit from anticoagulation therapy outweighs its risk, namely, bleeding. Risk assessment for stroke is commonly performed by calculating a CHA2DS2‐VASc (congestive heart failure/left ventricular dysfunction, hypertension, ≥75 years, diabetes mellitus, previous stroke or transient ischemic attack or thromboembolism, vascular disease, aged 65 to 74 years, sex female) score. It is possible that CHA2DS2‐VASc scores also have a relationship with the incidence of major bleeding. We examined the relationship between CHA2DS2‐VASc scores and major bleeding in rivaroxaban users with nonvalvular atrial fibrillation. Methods Electronic medical records of more than 10 million patients from the Department of Defense Military Health System were queried to identify patients with nonvalvular atrial fibrillation who received rivaroxaban from January 1, 2013, to June 30, 2015. Baseline characteristics of the study population were described by CHA2DS2‐VASc scores and major bleeding status; major bleeding incidence was evaluated by CHA2DS2‐VASc score category and for each CHA2DS2‐VASc component. Results Overall, 44,793 patients met the inclusion criteria for this analysis. The major bleeding incidence rate was 2.84 (95% confidence interval 2.69 to 3.00) per 100 person‐years. The incidence of major bleeding increased from 0.30 to 5.40 per 100 person‐years among patients with a CHA2DS2‐VASc score of 0 to 5 or higher, respectively. Fatal outcomes among patients with major bleeding were positively correlated with CHA2DS2‐VASc scores; patients with higher scores had higher mortality rates. The CHA2DS2‐VASc component with the highest major bleeding incidence was for vascular disease, 5.69 (95% confidence interval 5.18 to 6.24) per 100 person‐years. Conclusion Higher CHA2DS2‐VASc scores are associated with increased incidence of major bleeding in nonvalvular atrial fibrillation patients receiving rivaroxaban.

POST-MARKETING PHARMACOVIGILANCE STUDY FOR THE ACTIVE DETECTION AND EVALUATION OF MAJOR BLEEDING IN RIVAROXABAN USERS WITH NON-VALVULAR ATRIAL FIBRILLATION

Rivaroxaban is a novel direct factor Xa inhibitor approved for multiple indications. As part of an FDA post-marketing safety requirement, a five-year observational study was designed to evaluate major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban. Using a

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767.