Efficacy, safety, and cost-effectiveness analysis of Cerebrolysin in acute ischemic stroke: A rapid health technology assessment.

This study conducts a rapid health technology assessment to systematically evaluate the effectiveness, safety, and cost-effectiveness of Cerebrolysin as an adjunctive therapy for acute ischemic stroke to provide evidence-based medicine for clinical decisions of Cerebrolysin. All systematic reviews/meta-analyses, pharmacoeconomic studies, and health technology assessment reports of Cerebrolysin for the treatment of acute ischemic stroke before August 17, 2023, were retrieved from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang, Weipu, Sinomed database and the official website of health technology assessment. According to the inclusion and exclusion criteria, 2 researchers independently carried out screening, data extraction, and quality evaluation and descriptively analyzed the results of the included studies. A total of 14 pieces of literature were incorporated, comprising 8 systematic reviews/meta-analyses and 6 pharmacoeconomic studies. In terms of effectiveness, compared to control groups, the use of Cerebrolysin as a treatment for acute ischemic stroke demonstrates certain advantages, including enhancement in total efficacy rate, neurological function, upper limb motor dysfunction, and facilitation of the recovery of activities of daily living. Especially in patients with moderate to severe acute ischemic stroke, Cerebrolysin has demonstrated the ability to enhance neurological function recovery and ameliorate disabilities. Regarding safety, adverse reactions were mild or comparable to those in the control group. The primary findings of economic studies reveal that advocating for the use of Cerebrolysin offers certain cost-effectiveness advantages. Cerebrolysin contributes to improved clinical efficacy and evaluation indexes while demonstrating favorable safety and economic benefits.

Cost-Effectiveness of Increased Use of Dual Antiplatelet Therapy After High-Risk Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Rates of dual antiplatelet therapy (DAPT) after high-risk transient ischemic attack or minor ischemic stroke (TIAMIS) are suboptimal. We performed a cost-effectiveness analysis to characterize the parameters of a quality improvement (QI) intervention designed to increase DAPT use after TIAMIS. METHODS AND RESULTS: We constructed a decision tree model that compared current national rates of DAPT use after TIAMIS with rates after implementing a theoretical QI intervention designed to increase appropriate DAPT use. The base case assumed that a QI intervention increased the rate of DAPT use to 65% from 45%. Costs (payer and societal) and outcomes (stroke, myocardial infarction, major bleed, or death) were modeled using a lifetime horizon. An incremental cost-effectiveness ratio <$100 000 per quality-adjusted life year was considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed. From the payer perspective, a QI intervention was associated with $9657 in lifetime cost savings and 0.18 more quality-adjusted life years compared with current national treatment rates. A QI intervention was cost-effective in 73% of probabilistic sensitivity analysis iterations. Results were similar from the societal perspective. The maximum acceptable, initial, 1-time payer cost of a QI intervention was $28 032 per patient. A QI intervention that increased DAPT use to at least 51% was cost-effective in the base case. CONCLUSIONS: Increasing DAPT use after TIAMIS with a QI intervention is cost-effective over a wide range of costs and proportion of patients with TIAMIS treated with DAPT after implementation of a QI intervention. Our results support the development of future interventions focused on increasing DAPT use after TIAMIS.

Cost-effectiveness analysis of CYP2C19 genotype-guided antiplatelet therapy for patients with acute minor ischemic stroke and high-risk transient ischemic attack in China.

AIMS: The study aimed to estimate the cost-effectiveness of CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel, compared to conventional antiplatelet therapy with clopidogrel and aspirin. METHODS: A 90-day decision tree and 30-year Markov model were employed to assess the costs and quality-adjusted life years (QALYs) of personalized antiplatelet therapy for patients with minor ischemic stroke and high-risk transient ischemic attack, compared to conventional antiplatelet therapy in the Chinese healthcare system. The primary outcome was the incremental cost-effectiveness ratio (ICER). The data sources included clinical trials, published literature, official documents and local prices. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings. RESULTS: The base-case analysis indicated that the CYP2C19 genotype-guided antiplatelet strategy was cost-effective, and cilostazol group and ticagrelor group yielded an ICER of 3327.40 US dollars (USD)/QALY and 3426.92 USD/QALY, respectively, which were less than threshold. The one-way sensitivity analysis showed the results were robust, where the most sensitive parameter was the disability distribution in the modified Rankin scale 3-5. The probabilistic analysis showed that the CYP2C19 genotype-guided antiplatelet therapy with either cilostazol or ticagrelor was 100% cost-effective under the willingness-to-pay threshold. CONCLUSIONS: CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel appeared to be more cost-effective than conventional antiplatelet therapy for acute minor ischemic stroke and high-risk transient ischemic attack patients over 30 years in China.

In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome.

Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function. Because of the improved beta cell function the glycaemic control that occurs with pioglitazone is prolonged. Pioglitazone has positive effects not only on cardiac risk factors and surrogate measures of cardiovascular disease, it also lowers the incidence of cardiac events in patients with diabetes. The recurrence of transient ischaemic attack and ischaemic stroke is also reduced in non-diabetic, insulin-resistant subjects. Utilized at preclinical stages (but not later) of heart failure, pioglitazone improves diastolic function and avoids progression to heart failure. Pioglitazone, through suppression of atrial remodelling, also decreases the incidence of atrial fibrillation. The manifestations of diseases associated with insulin resistance (non-alcoholic steatohepatitis and polycystic ovary disease) are also improved with pioglitazone. Pioglitazone may possibly improve psoriasis and other dermopathies. Pioglitazone is therefore an inexpensive and efficacious drug for the insulin-resistant subject with diabetes that is underutilized because of biases that have evolved from the toxicities of other thiazolidinediones.

Arsenic, polycyclic aromatic hydrocarbons, and metal exposure and risk assessment of stroke.

Globally, stroke is one of the primary causes of morbidity and mortality. In the USA, stroke is a major cause of death and disability. Limited studies assessed the impact of polycyclic aromatic hydrocarbons, arsenic, and other metal exposure and their association with the risk of stroke. This study aimed to assess different arsenic species, including total arsenic; two types of organic arsenic, i.e., arsenobetaine and arsenocholine; four types of inorganic arsenic, i.e., arsenic acid, arsenous acid, dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA); six types of urinary polycyclic aromatic hydrocarbon (PAH) compounds, i.e., 1-hydroxynaphthalene, 1-hydroxyphenanthrene, 1-hydroxypyrene, 2-hydroxynaphthalene, 2-hydroxyfluorene, and 3-hydroxyfluorene; and fourteen types of metals from urine specimen, i.e., manganese, cadmium, lead, mercury, barium, cobalt, strontium, molybdenum, cesium, thallium, antimony, tin, tungsten, and uranium and their association with those who reported having been told they had had a stroke by a medical professional. The National Health and Nutrition Examination Survey (NHANES) data used in this study include three data cycles from 2011-2016. In this study, data from a total of 5537 males and females who are aged 20 years and older were analyzed using logistic modeling of the complex weighted survey design. R version 3.6.3 software was used to conduct the analyses. Four species of urinary PAHs, including the third quantiles of 1-hydroxynaphthalene [odds ratio (OR): 2.327, 95% confidence interval (CI): 0.961-5.632], 2-hydroxynaphthalene [OR: 2.449, 95% CI: 1.067-5.622], and 3-hydroxyfluorene [OR: 2.289, 95% CI: 1.077-4.861] and the second quantiles of 3-hydroxyfluorene [OR: 2.201, 95% CI: 1.115, 4.346] and 1-hydroxypyrene [OR: 2.066, 95% CI: 1.037, 4.114], showed a positive correlation with increased odds of stroke. Among metals, the third (3rd) [OR: 3.566, 95% CI: 1.370, 9.280] and fourth (4th) [OR: 2.844, 95% CI: 0.947, 8.543] quantiles of urinary manganese showed a positive correlation with increased odds of stroke.

Assessment of Anticoagulant Initiation in Patients With New-Onset Atrial Fibrillation During Emergency Department Visit-Point-by-Point Response.

Patients with atrial fibrillation (AF) have an increased risk of stroke and systemic thromboembolism. Diagnosis of AF is commonly encountered in the emergency department (ED). The purpose of this study was to assess the number of patients with new-onset AF appropriately initiated on oral anticoagulation (AC) during their ED encounter. This retrospective analysis included patients discharged from the ED from July 2016 to July 2021 with a new diagnosis of AF. Patients were excluded if they were on AC before admission. The major endpoint was to identify the percentage of patients discharged from the ED without initiating AC. Minor endpoints included the average CHA2DS2-VASc scores and the reason for not initiating AC. A total of 380 patients were included in the final analysis. Of the 245 patients found to be indicated for AC, only 131 patients (53.5%) were initiated on AC and 114 patients (46.5%) were discharged without initiating AC. Almost half of the patients who presented to the ED with a new diagnosis of AF and indicated for AC were discharged without AC.

Associations Between Long-Term Air Pollutant Exposure and 30-Day All-Cause Hospital Readmissions in US Patients With Stroke.

BACKGROUND: Long-term exposure to air pollutants is associated with increased stroke incidence, morbidity, and mortality; however, research on the association of pollutant exposure with poststroke hospital readmissions is lacking. METHODS: We assessed associations between average annual carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particulate matter 2.5, and sulfur dioxide (SO2) exposure and 30-day all-cause hospital readmission in US fee-for-service Medicare beneficiaries age ≥65 years hospitalized for ischemic stroke in 2014 to 2015. We fit Cox models to assess 30-day readmissions as a function of these pollutants, adjusted for patient and hospital characteristics and ambient temperature. Analyses were then stratified by treating hospital performance on the Centers for Medicare and Medicaid Services risk-standardized 30-day poststroke all-cause readmission measure to determine if the results were independent of performance: low (Centers for Medicare and Medicaid Services rate for hospital <25th percentile of national rate), high (>75th percentile), and intermediate (all others). RESULTS: Of 448 148 patients with stroke, 12.5% were readmitted within 30 days. Except for tropospheric NO2 (no national standard), average 2-year CO, O3, particulate matter 2.5, and SO2 values were below national limits. Each one SD increase in average annual CO, NO2, particulate matter 2.5, and SO2 exposure was associated with an adjusted 1.1% (95% CI, 0.4-1.9%), 3.6% (95% CI, 2.9%-4.4%), 1.2% (95% CI, 0.2%-2.3%), and 2.0% (95% CI, 1.1%-3.0%) increased risk of 30-day readmission, respectively, and O3 with a 0.7% (95% CI, 0.0%-1.5%) decrease. Associations between long-term air pollutant exposure and increased readmissions persisted across hospital performance categories. CONCLUSIONS: Long-term air pollutant exposure below national limits was associated with increased 30-day readmissions after stroke, regardless of hospital performance category. Whether air quality improvements lead to reductions in poststroke readmissions requires further research.

Comparative safety of sulfonylureas among U.S. nursing home residents.

BACKGROUND: The comparative safety of sulfonylureas (SUs) in nursing home (NH) residents remains understudied despite widespread use. We compared the effects of three SU medications and initial SU doses on adverse glycemic and cardiovascular events among NH residents. METHODS: This national retrospective cohort study linked Medicare claims with Minimum Data Set 2.0 assessments for long-stay NH residents aged ≥65 years between January 2008 and September 2010. Exposures were the SU medication initiated (glimepiride, glipizide, or glyburide) and doses (standard or reduced). One-year outcomes were hospitalizations or emergency department visits for severe hypoglycemia, heart failure (HF), stroke, and acute myocardial infarction (AMI). After the inverse probability of treatment and inverse probability of censoring by death weighting, we estimated hazard ratios (HR) using Cox regression models with robust 95% confidence intervals (CI). RESULTS: The cohort (N = 6821) included 3698 new glipizide, 1754 glimepiride, and 1369 glyburide users. Overall, the mean (standard deviation) age was 81.4 (8.2) years, 4816 (70.6%) were female, and 5164 (75.7%) were White non-Hispanic residents. The rates of severe hypoglycemia were 30.3 (95% CI 22.3-40.1), 49.0 (95% CI 34.5-67.5), and 35.9 (95% CI 22.2-54.9) events per 1000 person-years among new glipizide, glimepiride, and glyburide users, respectively (glimepiride versus glipizide HR 1.6, 95% CI 1.0-2.4, p = 0.04; glyburide versus glipizide HR 1.2, 95% CI 0.7-1.9, p = 0.59). The rates of severe hypoglycemia were 27.1 (95% CI 18.6-38.0) and 42.8 (95% CI 33.6-53.8) events per 1000 person-years among new users of reduced and standard SU doses, respectively (HR 2.2, 95% CI 1.4-3.5, p < 0.01). Rates of HF, stroke, and AMI were similar between medications and doses. CONCLUSIONS: Among long-stay NH residents, new use of glimepiride and standard SU doses resulted in higher rates of severe hypoglycemic events. Cardiovascular outcomes may not be affected by the choice of SU medication or dose.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

BACKGROUND: Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. OBJECTIVE: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. DESIGN: Population-based cohort study. SETTING: Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). PARTICIPANTS: Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. INTERVENTION: First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. MEASUREMENTS: Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. RESULTS: Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. LIMITATION: Treatment selection was not randomized. CONCLUSION: As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. PRIMARY FUNDING SOURCE: Brigham and Women's Hospital and Harvard Medical School.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Adverse Events and Economic Burden Among Patients Receiving Systemic Treatment for Mantle Cell Lymphoma: A Real-World Retrospective Cohort Study.

BACKGROUND/AIM: Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs. PATIENTS AND METHODS: Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy. RESULTS: Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month. CONCLUSION: Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.

Stroke Risk Among Elderly Users of Haloperidol and Typical Antipsychotics Versus Atypical Antipsychotics: A Real-World Study From a US Health Insurance Claims Database.

BACKGROUND: We estimated stroke risk associated with new exposure to haloperidol, or any typical antipsychotic, versus atypical antipsychotic among patients aged ≥65 years regardless of dementia status. METHODS: IBM MarketScan Medicare Supplemental Database data (January 1, 2001 to December 31, 2017) were used. Stroke risk for new users of typical antipsychotics (T1 cohort) or haloperidol (T2 cohort) was compared with new users of atypical antipsychotics (C1 cohort) aged ≥65 years. Crude incidence rate (IR) and incidence proportion of stroke were estimated within each cohort and gender subgroup. Three propensity score (PS) matching strategies were employed: Unadjusted (crude), Sentinel PS replication, and a large-scale regularized regression model (adapted PS). RESULTS: Overall, 36,734 (T1), 24,074 (T2), and 226,990 (C1) patients were included. Crude IRs for stroke per 1000 person-years were 17.67 (T1), 23.74 (T2), and 14.17 (C1). In preplanned analyses, PS-matched calibrated hazard ratio (cHR) for stroke T1 versus C1 cohort was 1.08 (95% calibrated confidence interval [cCI] = 0.75, 1.55) with Sentinel PS strategy and 1.31 (95% cCI = 1.07, 1.60) with adapted PS strategy. The cHR for stroke in patients of T2 versus C1 was 1.69 (95% cCI = 1.08, 2.75) with Sentinel PS strategy and 1.45 (95% cCI = 1.17, 1.80) with adapted PS strategy. CONCLUSION: Stroke risk in elderly new users of haloperidol was elevated compared to new users of atypical antipsychotics and was elevated for typical antipsychotics using the adapted PS strategy.

Perioperative Cardiovascular Risk Assessment and Management for Noncardiac Surgery: A Review.

Importance: Perioperative cardiovascular complications occur in 3% of hospitalizations for noncardiac surgery in the US. This review summarizes evidence regarding cardiovascular risk assessment prior to noncardiac surgery. Observations: Preoperative cardiovascular risk assessment requires a focused history and physical examination to identify signs and symptoms of ischemic heart disease, heart failure, and severe valvular disease. Risk calculators, such as the Revised Cardiac Risk Index, identify individuals with low risk (<1%) and higher risk (≥1%) for perioperative major adverse cardiovascular events during the surgical hospital admission or within 30 days of surgery. Cardiovascular testing is rarely indicated in patients at low risk for major adverse cardiovascular events. Stress testing may be considered in patients at higher risk (determined by the inability to climb ≥2 flights of stairs, which is <4 metabolic equivalent tasks) if the results from the testing would change the perioperative medical, anesthesia, or surgical approaches. Routine coronary revascularization does not reduce perioperative risk and should not be performed without specific indications independent of planned surgery. Routine perioperative use of low-dose aspirin (100 mg/d) does not decrease cardiovascular events but does increase surgical bleeding. Statins are associated with fewer postoperative cardiovascular complications and lower mortality (1.8% vs 2.3% without statin use; P < .001) in observational studies, and should be considered preoperatively in patients with atherosclerotic cardiovascular disease undergoing vascular surgery. High-dose ß-blockers (eg, 100 mg of metoprolol succinate) administered 2 to 4 hours prior to surgery are associated with a higher risk of stroke (1.0% vs 0.5% without ß-blocker use; P = .005) and mortality (3.1% vs 2.3% without ß-blocker use; P = .03) and should not be routinely used. There is a greater risk of perioperative myocardial infarction and major adverse cardiovascular events in adults aged 75 years or older (9.5% vs 4.8% for younger adults; P < .001) and in patients with coronary stents (8.9% vs 1.5% for those without stents; P < .001) and these patients warrant careful preoperative consideration. Conclusions and Relevance: Comprehensive history, physical examination, and assessment of functional capacity during daily life should be performed prior to noncardiac surgery to assess cardiovascular risk. Cardiovascular testing is rarely indicated in patients with a low risk of major adverse cardiovascular events, but may be useful in patients with poor functional capacity (<4 metabolic equivalent tasks) undergoing high-risk surgery if test results would change therapy independent of the planned surgery. Perioperative medical therapy should be prescribed based on patient-specific risk.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Direct-Acting Oral Anticoagulants Versus Warfarin in Medicare Patients With Chronic Kidney Disease and Atrial Fibrillation.

BACKGROUND AND PURPOSE: The comparative effectiveness of direct-acting oral anticoagulants, compared with warfarin, for risks of stroke/systemic embolism, major bleeding, or death have not been studied in Medicare beneficiaries with atrial fibrillation and nondialysis-dependent chronic kidney disease. METHODS: Medicare data from 2011 to 2017 were used to identify patients with stages 3, 4, or 5 chronic kidney disease and new atrial fibrillation who received a new prescription for warfarin, apixaban, rivaroxaban, or dabigatran. We estimated marginal hazard ratios with 95% CIs for the association of each direct-acting oral anticoagulant, compared with warfarin, for the outcomes of interest using inverse-probability-of-treatment weighted Cox proportional hazards models in as-treated and intention-to-treat analyses. RESULTS: A total of 22 739 individuals met criteria (46.3% warfarin, 29.6% apixaban, 17.2% rivaroxaban, 6.9% dabigatran). Across the groups of anticoagulant users, mean age was 78.4 to 79.0 years; 50.3% to 51.4% were women, and 80.3% to 82.8% had stage 3 chronic kidney disease. In the as-treated analysis, for stroke/systemic embolism, hazard ratios, all compared with warfarin, were 0.70 (0.51-0.96) for apixaban, 0.80 (0.54-1.17) for rivaroxaban, and 1.15 (0.69-1.94) for dabigatran. For major bleeding, analogous hazard ratios were 0.47 (0.37-0.59) for apixaban, 1.05 (0.85-1.30) for rivaroxaban, and 0.95 (0.70-1.31) for dabigatran. There was no difference in the risk of all-cause mortality between the direct-acting oral anticoagulants and warfarin. Results of the intention-to-treat analysis were similar. CONCLUSIONS: Apixaban, compared with warfarin, was associated with decreased risk of stroke/systemic embolism and major bleeding; risks for both outcomes with rivaroxaban and dabigatran did not differ from risks with warfarin.

Comparisons between Oral Anticoagulants among Older Nonvalvular Atrial Fibrillation Patients.

OBJECTIVES: Older adult patients are underrepresented in clinical trials comparing non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin. This subgroup analysis of the ARISTOPHANES study used multiple data sources to compare the risk of stroke/systemic embolism (SE) and major bleeding (MB) among very old patients with nonvalvular atrial fibrillation (NVAF) prescribed NOACs or warfarin. DESIGN: Retrospective observational study. SETTING: The Centers for Medicare & Medicaid Services and three US commercial claims databases. PARTICIPANTS: A total of 88 582 very old (aged ≥80 y) NVAF patients newly initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015. MEASUREMENTS: In each database, six 1:1 propensity score matched (PSM) cohorts were created for each drug comparison. Patient cohorts were pooled from all four databases after PSM. Cox proportional hazards models were used to estimate hazard ratios (HRs) of stroke/SE and MB. RESULTS: The patients in the six matched cohorts had a mean follow-up time of 7 to 9 months. Compared with warfarin, apixaban (HR = .58; 95% confidence interval [CI] = .49-.69), dabigatran (HR = .77; 95% CI = .60-.99), and rivaroxaban (HR = .74; 95% CI = .65-.85) were associated with lower risks of stroke/SE. For MB, apixaban (HR = .60; 95% CI = .54-.67) was associated with a lower risk; dabigatran (HR = .92; 95% CI = .78-1.07) was associated with a similar risk, and rivaroxaban (HR = 1.16; 95% CI = 1.07-1.24) was associated with a higher risk compared with warfarin. Apixaban was associated with a lower risk of stroke/SE and MB compared with dabigatran (stroke/SE: HR = .65; 95% CI = .47-.89; MB: HR = .60; 95% CI = .49-.73) and rivaroxaban (stroke/SE: HR = .72; 95% CI = .59-.86; MB: HR = .50; 95% CI = .45-.55). Dabigatran was associated with a lower risk of MB (HR = .77; 95% CI = .67-.90) compared with rivaroxaban. CONCLUSION: Among very old NVAF patients, NOACs were associated with lower rates of stroke/SE and varying rates of MB compared with warfarin. J Am Geriatr Soc 67:1662-1671, 2019.

Comparison of Incident Cardiovascular Event Rates Between Generic and Brand l-Thyroxine for the Treatment of Hypothyroidism.

OBJECTIVE: To determine whether levothyroxine (L-T4) preparation (generic vs brand) affected hospitalization for cardiovascular events. PATIENTS AND METHODS: We performed a retrospective analysis using a large administrative claims database, OptumLabs Data Warehouse, creating two 1-to-1 propensity score-matched cohorts initiating generic or brand L-T4. Patients were followed for a mean of 1.0±1.2 years (range, 0-9.3 years). We included 87,902 propensity score-matched patients (43,951 patients per cohort) initiating generic or brand L-T4. Variables included in matching were age, sex, race/ethnicity, residence region, selected comorbidities, and Charlson-Deyo comorbidity score. Patients with previous use of any thyroid preparation, amiodarone, or lithium were excluded. Primary outcomes were the event rates for hospitalizations for incident atrial fibrillation, myocardial infarction, congestive heart failure, or stroke. RESULTS: In the generic L-T4 cohort, 35,242 (80.2%) were women and 7327 (16.7%) were 65 years of age or older; in the brand L-T4 cohort, 34,633 (78.8%) were women and 8092 (18.4%) were 65 years of age or older. We found no differences in event rates (events per 1000 person-years) for 4 outcomes comparing generic and brand L-T4 therapy: (1) atrial fibrillation (1.82 vs 2.19; hazard ratio [HR], 1.22; 95% CI, 0.90-1.65; P=.19); (2) myocardial infarction (2.12 vs 1.83; HR, 0.86; 95% CI, 0.64-1.17; P=.35); (3) congestive heart failure (2.27 vs 2.00; HR, 0.88; 95% CI, 0.66-1.18; P=.41); and (4) stroke (3.10 vs 2.38; HR, 0.77; 95% CI, 0.59-1.00; P=.05). Stratification by age group revealed no differences. CONCLUSION: In patients with newly treated hypothyroidism, cardiovascular event rates were similar for generic and brand L-T4.