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Background: Whether the cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are comparable between White and Asian populations remains unclear.Purpose: To compare the cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between White and Asian populations and to compare the cardiorenal benefits between the two agents in Asian patients.Data Sources: Electronic databases were searched up to 28 March 2021.Study Selection: We included the cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors and GLP-1RAs where investigators reported major adverse CV events (MACE), CV death/hospitalization for heart failure (HHF), or composite renal outcomes with stratification by race.Data Extraction: We extracted the hazard ratio of each outcome stratified by race (Asian vs. White populations).Data Synthesis: In 10 SGLT2 inhibitor trials, there was no significant difference between Asian and White populations for MACE (P = 0.55), CV death/HHF (P = 0.87), or composite renal outcomes (P = 0.97). In seven GLP-1RA trials, we observed a similar MACE benefit between Asian and White populations (P = 0.10). In our networkmeta-analysis we found a comparable benefit for MACE between SGLT2 inhibitors and GLP-1RAs in Asian patients.Limitations: The data were from stratified analyses.Conclusions: There appear to be comparable cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between Asian and White participants enrolled in CV and renal outcome trials; the two therapies seem to have similar CV benefits for Asian participants. [ABSTRACT FROM AUTHOR]

Importantly, our trial sequential analysis suggests that the sample size available provided inadequate statistical power to detect a significant treatment effect for CV outcomes in Black participants. CONCLUSIONS Although Black participants account for 11.7% of the diabetes population in the United States,8 participation of Black patients in clinical trials that evaluated novel glucose-lowering agents from 2013 to 2021 was less than 5% of trial enrollees. The composite endpoint of CV death/HHF was available in six trials (five trials for Black participants and six trials for White participants) (Figure 1). A meta-trial sequential analysis to address disparities in cardiovascular and renal outcome trials enrolment. [Extracted from the article]

The article discusses various reports published within the issue which includes elements of palliative care, importance of deactivating implantable cardioverter defibrillators and palliative care needs of individuals of all ages, independent of diagnosis and living circumstances.

The article offers information on research that tested the clinical utility of genotype-guided or pharmacologically based dosing of warfarin in small clinical trials or observational studies. The trial involved 1015 patients who were assigned to the use of either a genotype-guided algorithm or a clinically guided algorithm for warfarin dosing during the first 5 days. No significant difference in the percentage of time in the therapeutical international normalized ratio range was found.

This commentary posits the need for rapid evaluation of COVID-19 therapies as an inflection point spurring a much-needed rethinking of our research enterprise. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Depression is associated with an increased risk of cardiovascular disease. Some studies, but not all, have identified an association between use of selective serotonin re-uptake inhibitors (SSRIs) and reduced risk of myocardial infarction (MI). There may be a difference among SSRIs based on their affinity for the serotonin receptor. WHAT THIS STUDY ADDS • Current use of SSRIs by patients with depression may be associated with a reduced risk of MI. However, the risk seemed to be reduced only with longer term use of SSRIs. In addition, we did not observe a relationship between the affinity of SSRIs for the serotonin transporter and risk of MI. AIM To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression. METHODS This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR). RESULTS SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05). CONCLUSIONS Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk. [ABSTRACT FROM AUTHOR]

Patients receiving hemodialysis have high rates of cardiovascular morbidity and mortality that may be related to the hemodynamic effects of rapid ultrafiltration. Here we tested whether higher dialytic ultrafiltration rates are associated with greater all-cause and cardiovascular mortality, and hospitalization for cardiovascular disease. We used data from the Hemodialysis Study, an almost-7-year randomized clinical trial of 1846 patients receiving thrice-weekly chronic dialysis. The ultrafiltration rates were divided into three categories: up to 10 ml/h/kg, 10-13 ml/h/kg, and over 13 ml/h/kg. Compared to ultrafiltration rates in the lowest group, rates in the highest were significantly associated with increased all-cause and cardiovascular-related mortality with adjusted hazard ratios of 1.59 and 1.71, respectively. Overall, ultrafiltration rates between 10-13 ml/h/kg were not associated with all-cause or cardiovascular mortality; however, they were significantly associated among participants with congestive heart failure. Cubic spline interpolation suggested that the risk of all-cause and cardiovascular mortality began to increase at ultrafiltration rates over 10 ml/h/kg regardless of the status of congestive heart failure. Hence, higher ultrafiltration rates in hemodialysis patients are associated with a greater risk of all-cause and cardiovascular death. [ABSTRACT FROM AUTHOR]

The article reports on the influence of patient adherence on anticoagulation control with warfarin sodium. The authors of a cohort study said that participating patients have substantial difficulties maintaining adequate adherence with warfarin regimens and such poor adherence has a significant effect on anticoagulation control.

Background: Studies have postulated that cyclooxygenase-2 (COX-2) selective inhibitors affect cardiovascular risk through various mechanisms. Some of these mechanisms could increase risk (for example, inhibition of prostacyclin production), and some could decrease risk (for example, inhibition of inflammation). Objective: To determine the effect of COX-2 inhibitors on risk for nonfatal myocardial infarction (MI). Design: Case-control study. Setting: 36 hospitals in a 5-county area. Participants: 1718 case-patients with a first, nonfatal MI admitted to these hospitals and 6800 controls randomly selected from the same counties. Measurements: Self-reported medication use assessed through telephone interviews. Results: The adjusted odds ratio for MI among celecoxib users, relative to persons who did not use nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), was 0.43 (95% CI, 0.23 to 0.79) compared with 1.16 (CI, 0.70 to 1.93) among rofecoxib users. The use of rofecoxib was associated with a statistically significant higher odds of MI compared with the use of celecoxib (adjusted odds ratio for rofecoxib vs. celecoxib, 2.72 [CI, 1.24 to 5.95]; P= 0.01). Nonselective NSAIDs were associated with a reduced odds of nonfatal MI relative to nonusers. Comparisons of COX-2 inhibitors with nonselective NSAIDs were the following: rofecoxib versus naproxen (odds ratio, 3.39 [CI, 1.37 to 8.40]) and celecoxib versus ibuprofen or diclofenac (odds ratio, 0.77 [CI, 0.40 to 1.48]). Limitations: The possibility of recall bias and uncontrolled confounding in this observational study limit the ability to make definitive conclusions. The association of celecoxib with a lower odds of MI could have occurred by chance. Only about 50% of eligible participants completed telephone interviews. Conclusion: Celecoxib and rofecoxib were associated with different odds of MI. Cardiovascular effects among the COX-2 inhibitors seem different, but further studies, preferably randomized trials, are needed to fully understand the spectrum of effects of COX-2 inhibitors and potential differences among them. [ABSTRACT FROM AUTHOR]

: ObjectivesThis study was designed to determine if non-aspirin non-steroidal anti-inflammatory drugs (NANSAIDs) are associated with lower odds of myocardial infarction (MI) and if NANSAIDs, particularly ibuprofen, interfere with aspirin''s cardioprotective effect.: BackgroundThe NANSAIDs may reduce the risk of MI but may also interfere with aspirin''s cardioprotective effect.: MethodsA case-control study was conducted, with cases of first, nonfatal MI identified prospectively and controls identified randomly from the community.: ResultsThe use of NANSAIDs was associated with a significant reduction in MI among those not using aspirin (adjusted odds ratio [OR] 0.53; 95% confidence interval [CI]: 0.42 to 0.67). This was true for both ibuprofen (adjusted OR 0.52; 95% CI: 0.39 to 0.69) and naproxen (adjusted OR 0.48; 95% CI: 0.28 to 0.82). Although aspirin itself was associated with decreased odds of MI in those not also using NANSAIDs (adjusted OR relative to no aspirin use 0.79; 95% CI: 0.63 to 0.98), it was not associated with decreased odds of MI among those who were using NANSAIDs (OR 1.28; 95% CI: 0.85 to 1.94; p value for interaction = 0.026). The association of aspirin and reduced odds of MI diminished with increasing frequency of NANSAID use (test for interaction p = 0.006), particularly for ibuprofen (p = 0.018). Among frequent (4 times/week) NANSAID users, the OR for aspirin versus no aspirin was 2.04 (95% CI: 1.06 to 3.94). Users of prophylactic aspirin plus frequent ibuprofen had an OR relative to aspirin-only users of 2.03 (95% CI: 0.60 to 6.84).: ConclusionsIn the absence of aspirin use, NANSAIDs are associated with reduced odds of MI. In those using aspirin, NANSAIDs do not provide additional protection. Additional study is needed to determine the clinical impact of using NANSAIDs along with aspirin for cardioprotection. [Copyright &y& Elsevier]

We sought to test the validity and clinical utility of the Thrombolysis In Myocardial Infarction (TIMI) risk score for patients who have non–Q-wave myocardial infarction. A post hoc analysis of the Veterans Affairs Non–Q-Wave Infarction Strategies In-Hospital (VANQWISH) Trial was performed, wherein patients were assigned a TIMI risk score from which both 30-day and 12-month outcomes (death, nonfatal myocardial infarction, or urgent revascularization) were assessed. At 30 days, the TIMI risk score showed a close match between observed and predicted probabilities of events after adjustment for overall event rates. The event rate at 30 days was 6% for a score of 0 to 2, 10% for a score of 3, 13% for a score of 4, and 14% for a score of 5 to 7 (p = 0.003 and c statistic 0.59). Discriminative ability of the score was greater in the conservative group at 30 days (p = 0.0004, c statistic 0.67). The score remained modestly predictive of events at 1 year (c statistic 0.60). Conservative strategy patients had better 30-day outcomes than the invasive strategy patients if their score was 0 to 2 (odds ratio 0.24, 95% confidence interval 0.08 to 0.76). No significant difference in outcomes between strategies was detected for a score ≥3. The TIMI risk score provides moderate incremental prognostic information in high-risk patients, during both short- and long-term follow-up. [Copyright &y& Elsevier]

Reevaluates the function of calcium channel blocker (CCB) drugs in patients with uncomplicated and diabetic hypertension. Adverse coronary events related to the use of CCB; Effect of CCB in patients with acute coronary syndromes; Comparison of CCB versus beta blockers in coronary artery disease-stable angina; Effect of CCB in left ventricular dysfunction.

Examines the effects of coronary stenting in broad-based practice on six-moth revascularization and non-revascularization cardiac outcomes. Decrease in the need for repeated percutaneous coronary intervention in broad-based clinical practice.

Describes the relations between sexual activity and acute myocardial infarction (MI) with respect to the complex interplay among relative, attributable and absolute risk. Background risk of MI in the population; Relative risk of MI after sex; Absolute increase in risk and attributable risk.

Although several studies have reported on valve abnormalities among users of fenfluramine or dexfenfluramine, detailed information on these subjects has not been provided, limiting the ability to understand who may be at risk for valve abnormalities and to generate hypotheses about the etiology and pathogenesis of these abnormalities. This study was a detailed medical record review of 18 previously reported users of fenfluramine and phentermine, all with valve abnormalities on echocardiogram and 2 with surgical pathology. Both clinical characteristics and medication use were recorded by trained abstracters using a standardized data collection form. Two subjects (11%) had other possible etiologies of valve disease: a history of rheumatic fever and prescribed ergotamine. Three subjects (17%) had a history of migraine headaches and 4 (22%) had murmurs noted before using fenfluramine. Use of medications that may affect serotonin receptors was common: ergotamine (1 subject, 5%), selective serotonin reuptake inhibitors (6, 33%), sumatriptan (2, 11%), and mirtazapine (1, 5%). Prior medication and nonmedication allergies were recorded in 6 (33%) and 3 (17%) subjects, respectively. All subjects had symptoms possibly due to fenfluramine or phentermine side effects. This study raises the hypotheses that valvular heart disease among fenfluramine users may be less common than previously estimated, that serotonin excess may play a role in valve pathology, and that a patient's response to anorexigens and other medications may serve as a marker for increased risk. Further study is needed to test these hypotheses. [ABSTRACT FROM AUTHOR]

Assesses the relationship between the volume of percutaneous transluminal coronary angioplasty procedures performed in a cardiac catheterization laboratory and major complications. Evaluation of the applicability of current guidelines for minimum laboratory volume; Decrease in the rates of in-hospital mortality, emergency bypass surgery and complications.

Compares the risk for acute renal failure associated with ketorolac to that associated with opioids. Definition of renal failure; Incidence of failure after therapy; Rate ratios for ketorolac; Increase in rate of acute renal failure.

Deals with the importance of angiotensin-converting enzyme (ACE) inhibitors to the survival of patients with heart disease. Information on the scheme of evidence levels of extrapolating drug effects proposed by McAlister and colleagues; Result of a study by Pilote and colleagues on comparing the effectiveness of different ACE inhibitors in reducing mortality in elderly survivors of myocardial infarction; Source of potential bias in the findings on ACE.

A response by Teri E. Klein, Stephen E. Kimmel and Julie A. Johnson to letters to the editor about their article "Estimation of the warfarin dose with clinical and pharmacogenetic data," published in the February 19, 2009 issue, is presented.

Comments on research in the use of aspirin and ibuprofen after myocardial infarction. Mention of the challanges in designing a pharmacodynamic study questioning whether ibuprofen can inhibit aspirin's antiplatelet effect; Three studies that measure the clinical effects of combining ibuprofen and aspirin, Macdonald and Wei, Kurth et al, and Curtis et al; View that there is not enough evidence to make a recommendation for or against the concomitant use of ibuprofen and aspirin.

Prediction modeling for clinical decision making is of great importance and needed to be updated frequently with the changes of patient population and clinical practice. Existing methods are either done in an ad hoc fashion, such as model recalibration or focus on studying the relationship between predictors and outcome and less so for the purpose of prediction. In this article, we propose a dynamic logistic state space model to continuously update the parameters whenever new information becomes available. The proposed model allows for both time‐varying and time‐invariant coefficients. The varying coefficients are modeled using smoothing splines to account for their smooth trends over time. The smoothing parameters are objectively chosen by maximum likelihood. The model is updated using batch data accumulated at prespecified time intervals, which allows for better approximation of the underlying binomial density function. In the simulation, we show that the new model has significantly higher prediction accuracy compared to existing methods. We apply the method to predict 1 year survival after lung transplantation using the United Network for Organ Sharing data. [ABSTRACT FROM AUTHOR]

The Brier score has been a popular measure of prediction accuracy for binary outcomes. However, it is not straightforward to interpret the Brier score for a prediction model since its value depends on the outcome prevalence. We decompose the Brier score into two components, the mean squares between the estimated and true underlying binary probabilities, and the variance of the binary outcome that is not reflective of the model performance. We then propose to modify the Brier score by removing the variance of the binary outcome, estimated via a general sliding window approach. We show that the new proposed measure is more sensitive for comparing different models through simulation. A standardized performance improvement measure is also proposed based on the new criterion to quantify the improvement of prediction performance. We apply the new measures to the data from the Breast Cancer Surveillance Consortium and compare the performance of predicting breast cancer risk using the models with and without its most important predictor. [ABSTRACT FROM AUTHOR]

The Lung Allocation Score (LAS) is used in the U.S. to prioritize lung transplant candidates. Selection bias, induced by dependent censoring of waitlisted candidates and prediction of posttransplant survival among surviving, transplanted patients only, is only partially addressed by the LAS. Recently, a modified LAS (mLAS) was designed to mitigate such bias. Here, we estimate the clinical impact of replacing the LAS with the mLAS. We considered lung transplant candidates waitlisted during 2016 and 2017. LAS and mLAS scores were computed for each registrant at each observed organ offer date; individuals were ranked accordingly. Patient characteristics associated with better priority under the mLAS were investigated via logistic regression and generalized linear mixed models. We also determined whether differences in rank were explained more by changes in predicted pre- or posttransplant survival. Simulations examined how 1-year waitlist, posttransplant, and overall survival might change under the mLAS. Diagnosis group, 6-minute walk distance, continuous mechanical ventilation, functional status, and age demonstrated the highest impact on differential allocation. Differences in rank were explained more by changes in predicted pretransplant survival than changes in predicted posttransplant survival, suggesting that selection bias has more impact on estimates of waitlist urgency. Simulations suggest that for every 1000 waitlisted individuals, 12.8 (interquartile range: 5.2-24.3) fewer waitlist deaths per year would occur under the mLAS, without compromising posttransplant and overall survival. Implementing a mLAS that mitigates selection bias into clinical practice can lead to important differences in allocation and possibly modest improvement in waitlist survival. [ABSTRACT FROM AUTHOR]

Main Objective: To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users. Methods:This was a retrospective cohort study of new amphetamines (n = 38,586) or atomoxetine (n = 20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n = 238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator. Results: The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction. Conclusions: Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia. [ABSTRACT FROM AUTHOR]

Worsening renal function (RF) and improved RF during the treatment of decompensated heart failure have traditionally been thought of as hemodynamically distinct events. We hypothesized that if the pulmonary artery catheter-derived measures are relevant in the evaluation of cardiorenal interactions, the comparison of patients with improved versus worsening RF should highlight any important hemodynamic differences. All subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with admission and discharge creatinine values available were included (n = 401). No differences were found in the baseline, final, or change in pulmonary artery catheter-derived hemodynamic variables, inotrope and intravenous vasodilator use, or survival between patients with improved versus worsening RF (p = NS for all). Both groups were equally likely to be in the bottom quartile of cardiac index (p = 0.32), have a 25% improvement in cardiac index (p = 0.97), or have any worsening in cardiac index (p = 0.90). When patients with any significant change in renal function (positive or negative) were compared to those with stable renal function, strong associations between variables such as a reduced cardiac index (odds ratio 2.2, p = 0.02), increased intravenous inotrope and vasodilator use (odds ratio 2.9, p <0.001), and worsened all-cause mortality (hazard ratio 1.8, p = 0.01) became apparent. In contrast to traditionally held views, the patients with improved RF and those with worsening RF had similar hemodynamic parameters and outcomes. Combining these groups identified a hemodynamically compromised population with significantly worse survival than patients with stable renal function. In conclusion, the changes in renal function, regardless of the direction, likely identify a population with an advanced disease state and a poor prognosis. [ABSTRACT FROM AUTHOR]

Cardiac troponin is more accurate than creatine kinase (CK) testing for detecting myocardial injury in patients with acute coronary syndromes (ACS), but its effects on clinical care compared with CK testing alone is open to question. To test the effects of troponin I on medical decisions for patients undergoing cardiac enzyme testing. Randomized, controlled trial. Urban academic Veterans Affairs medical center. Three hundred ninety-two patients presenting to the emergency department (ED) and outpatient settings with symptoms and/or electrocardiograms suggestive but not diagnostic of ACS. Random assignment to linked CK-troponin I (CKTnI) testing or CK testing alone. ED discharge and cardiac catheterization incidence (primary); ED medication use, inpatient noninvasive testing, revascularization procedures, discharge medications, and 8-week ED visits, hospitalizations, and procedures (secondary). Groups were similar in all variables except history of heart failure (CK 26.8% vs CKTnI 17.0%). ACS comprised 12.2% of the cohort. ED discharge incidence was greater in the CKTnI arm (18% vs 9.6%; relative risk [RR], 1.83; 95% CI, 1.08 to 3.31; P=.02; number needed to test=12.6; 95% CI, 4.5 to 130). Troponin testing had no significant effect on catheterization incidence (18.2% vs 14.5%; RR, 1.19; 95% CI, 0.72 to 1.92; P>.20) or other outcomes except follow-up echocardiography (13.4% vs 7.4%; RR, 2.24; 95% CI, 1.11 to 4.69; P=.02). In a veterans population undergoing cardiac enzyme testing, CKTnI testing led to more ED discharges than CK testing alone but had no effect on inpatient care and was associated with more echocardiograms in a follow-up period. [ABSTRACT FROM AUTHOR]

Study objectives: Primary graft failure (PGF) is a severe acute lung injury syndrome that occurs following lung transplantation. We compared the clinical outcomes of patients who developed PGF with those who did not. Methods: We conducted a retrospective cohort study including 255 consecutive lung transplant procedures. PGF was defined as (1) diffuse alveolar opacities developing within 72 h of transplantation, (2) an arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FIO2) ratio of < 200 beyond 48 h postoperatively, and (3) no other secondary cause of graft dysfunction. PGF was tested for acceptance with 30-day and all-cause hospital mortality rates, overall survival, hospital length of stay (HLOS), duration of mechanical ventilation, and best 6-min walk test (6MWT) distance achieved within 12 months. Setting: Academic medical center. Results: The overall incidence of PGF was 11.8% (95% confidence interval [CI], 7.9 to 15.9%). The all-cause mortality rate at 30 days was 63.3% in patients with PGF and 8.8% in patients without PGF (relative risk [RR], 7.15; 95% CI, 4.34 to 11.80%; p < 0.001). A total of 73.3% of patients with PGF died during hospitalization vs 14.2% of patients without PGF (RR, 5.18%; 95% CI, 3.51 to 7.63; p < 0.001). The median HLOS in 30-day survivors was 47 days in patients with PGF vs 15 days in those without PGF (p < 0.001), and the mean duration of mechanical ventilation was 15 days in patients with PGF vs 1 day in those without PGF (p < 0.001). By 12 months, a total of 28.5% of survivors with PGF achieved a normal age-appropriate 6MWT distance vs 71.4% of survivors without PGF at 12 months (p = 0.014). The median best 6MWT distance achieved within the first 12 months was 1,196 feet in patients with PGF vs 1,546 feet in those without PGF (p = 0.009). Conclusions: PGF has a significant impact on mortality, HLOS, and duration of mechanical ventilation following lung transplantation. Survivors of PGF have a protracted recovery with impaired physical function up to 1 year following transplantation. [ABSTRACT FROM AUTHOR]

Background: The lung allocation system in the U.S. prioritizes lung transplant candidates based on estimated pre- and post-transplant survival via the Lung Allocation Scores (LAS). However, these models do not account for selection bias, which results from individuals being removed from the waitlist due to receipt of transplant, as well as transplanted individuals necessarily having survived long enough to receive a transplant. Such selection biases lead to inaccurate predictions.Methods: We used a weighted estimation strategy to account for selection bias in the pre- and post-transplant models used to calculate the LAS. We then created a modified LAS using these weights, and compared its performance to that of the existing LAS via time-dependent receiver operating characteristic (ROC) curves, calibration curves, and Bland-Altman plots.Results: The modified LAS exhibited better discrimination and calibration than the existing LAS, and led to changes in patient prioritization.Conclusions: Our approach to addressing selection bias is intuitive and can be applied to any organ allocation system that prioritizes patients based on estimated pre- and post-transplant survival. This work is especially relevant to current efforts to ensure more equitable distribution of organs. [ABSTRACT FROM AUTHOR]

Little is known about the distribution of cardiac sources of embolism among African-Americans with cryptogenic cerebrovascular events. We compared the prevalence of potential cardiac sources of embolism between black and white patients referred to our laboratory for transesophageal echocardiographic (TEE) evaluation of unexplained stroke or transient ischemic attack. Records were reviewed to exclude subjects with high-risk cardiac or vascular disorders likely to explain the index event. Of 297 patients satisfying the inclusion criteria, 196 were white and 87 black. Potential cardioembolic sources were significantly less common in blacks than in whites (adjusted odds ratio [OR], 0.44; 95% confidence interval [CI] 0.26 to 0.75), and related largely to the difference in prevalence of interatrial communication (OR 0.40; 95% CI 0.21 to 0.74). In contrast, African-Americans had a higher prevalence of left ventricular (LV) hypertrophy (OR 3.50; 95% CI 1.97 to 6.22), and particularly, moderate or severe hypertrophy (OR 4.03; 95% CI 1.88 to 9.65) compared with whites. In conclusion, in African-Americans with unexplained cerebrovascular events, the yield of TEE for potential cardioembolic sources, and especially interatrial communication, is lower than in their white counterparts. African-Americans exhibit a substantially higher prevalence of LV hypertrophy, which may be a marker for a higher burden of subclinical cerebrovascular disease involved in the pathogenesis of cryptogenic cerebral ischemia in this population. [Copyright &y& Elsevier]

Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta‐analyses. The most well‐known reasons for small study effects include publication bias, outcome reporting bias, and clinical heterogeneity. Methods to account for small study effects in univariate meta‐analysis have been extensively studied. However, detecting small study effects in a multivariate meta‐analysis setting remains an untouched research area. One of the complications is that different types of selection processes can be involved in the reporting of multivariate outcomes. For example, some studies may be completely unpublished while others may selectively report multiple outcomes. In this paper, we propose a score test as an overall test of small study effects in multivariate meta‐analysis. Two detailed case studies are given to demonstrate the advantage of the proposed test over various naive applications of univariate tests in practice. Through simulation studies, the proposed test is found to retain nominal Type I error rates with considerable power in moderate sample size settings. Finally, we also evaluate the concordance between the proposed tests with the naive application of univariate tests by evaluating 44 systematic reviews with multiple outcomes from the Cochrane Database. [ABSTRACT FROM AUTHOR]

Funnel plots have been widely used to detect small-study effects in the results of univariate meta-analyses. However, there is no existing visualization tool that is the counterpart of the funnel plot in the multivariate setting. We propose a new visualization method, the galaxy plot, which can simultaneously present the effect sizes of bivariate outcomes and their standard errors in a 2-dimensional space. We illustrate the use of the galaxy plot with 2 case studies, including a meta-analysis of hypertension trials with studies from 1979–1991 (Hypertension. 2005;45(5):907–913) and a meta-analysis of structured telephone support or noninvasive telemonitoring with studies from 1966–2015 (Heart. 2017;103(4):255–257). The galaxy plot is an intuitive visualization tool that can aid in interpreting results of multivariate meta-analysis. It preserves all of the information presented by separate funnel plots for each outcome while elucidating more complex features that may only be revealed by examining the joint distribution of the bivariate outcomes. [ABSTRACT FROM AUTHOR]

Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999–2012) and a commercial health insurance plan (Optum Clinformatics | 2000–2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75–1.10) in Medicaid and 0.88 (0.61–1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54–0.93] and 1.16 [0.89–1.52] in men and women respectively, interaction term p-value = 0.01). Conclusions: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA. [ABSTRACT FROM AUTHOR]

Background: Heart failure patients have high 30-day hospital readmission rates. Interventions designed to prevent readmissions have had mixed success. Understanding heart failure home management through the patient's experience may reframe the readmission "problem" and, ultimately, inform alternative strategies.Objective: To understand patient and caregiver challenges to heart failure home management and perceived reasons for readmission.Design: Observational qualitative study.Participants: Heart failure patients were recruited from two hospitals and included those who were hospitalized for heart failure at least twice within 30 days and those who had been recently discharged after their first heart failure admission.Approach: Open-ended, semi-structured interviews. Conclusions vetted using focus groups.Key Results: Semi-structured interviews with 31 patients revealed a combination of physical and socio-emotional influences on patients' home heart failure management. Major themes identified were home management as a struggle between adherence and adaptation, and hospital readmission as a rational choice in response to distressing symptoms. Patients identified uncertainty regarding recommendations, caused by unclear instructions and temporal incongruence between behavior and symptom onset. This uncertainty impaired their competence in making routine management decisions, resulting in a cycle of limit testing and decreasing adherence. Patients reported experiencing hopelessness and frustration in response to perceiving a deteriorating functional status. This led some to a cycle of despair characterized by worsening adherence and negative emotions. As these cycles progressed and distressing symptoms worsened, patients viewed the hospital as the safest place for recovery and not a "negative" outcome.Conclusion: Cycles of limit testing and despair represent important patient-centered struggles in managing heart failure. The resulting distress and fear make readmission a rational choice for patients rather than a negative outcome. Interventions (e.g., palliative care) that focus on methods to address these patient-centered factors should be further studied rather than methods to reduce hospital readmissions. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) and their families experience stress and suffering from a variety of sources over the course of the HF experience. Palliative care is an interdisciplinary service and an overall approach to care that improves quality of life and alleviates suffering for those living with serious illness, regardless of prognosis. In this review, we synthesize the evidence from randomized clinical trials of palliative care interventions in HF. While the evidence base for palliative care in HF is promising, it is still in its infancy and requires additional high-quality, methodologically sound studies to clearly elucidate the role of palliative care for patients and families living with the burdens of HF. Yet, an increase in attention to primary palliative care (e.g., basic physical and emotional symptom management, advance care planning), provided by primary care and cardiology clinicians, may be a vehicle to address unmet palliative needs earlier and throughout the illness course. [ABSTRACT FROM AUTHOR]

Background Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics. Methods The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999–2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30 days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180 days of concomitant use. Results Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100 person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin + gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR = 1.8, 1.4 to 2.4). Warfarin + fenofibrate was associated with a similar increased risk (aHR = 1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use. Conclusions Among warfarin-treated persons, the use of fibrates―but not statins―increases the risk of hospital presentation for GIB/ICH. [ABSTRACT FROM AUTHOR]

A letter is presented from readers discussing an analysis they performed on data from 1998 to 2004 on the use of percutaneous closure of patent foramen ovale and atrial septal defect in adults.

Background: Dosing algorithms for warfarin incorporate clinical and genetic factors, but human intervention to overrule algorithm-based dosing may occasionally be required. The frequency and reasons for varying from algorithmic warfarin management have not been well studied.Methods: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics trial who were randomized to either pharmacogenetic- or clinically-guided warfarin dosing algorithms. Clinicians and participants were blinded to dose but not international normalized ratio (INR) during the first 28 days. If an issue arose that raised concern for clinicians but might not be adequately accounted for by the protocol, then clinicians contacted the unblinded medical monitor who could approve exceptions if clinically justified. All granted exceptions were logged and categorized. We analyzed the relationships between dosing exceptions and both baseline characteristics and the outcome of percentage of time in the therapeutic INR range during the first 4 weeks.Results: Sixteen percent of participants required at least one exception to the protocol-defined warfarin dose (15% in the genotype arm and 17% in the clinical arm). Ninety percent of dose exceptions occurred after the first 5 days of dosing. The only baseline characteristic associated with dose exceptions was congestive heart failure (odds ratio 2.12, 95% confidence interval, 1.49-3.02, P <.001). Neither study arm nor genotype was associated with dose exceptions.Conclusion: Despite rigorous algorithms, human intervention is frequently employed in the early management of warfarin dosing. Congestive heart failure at baseline appears to predict early exceptions to standardized protocol management. [ABSTRACT FROM AUTHOR]

Several letters to the editor is presented in response to an article about pharmacogenetics and dosing of coumarin anticoagulants published in the December 12, 2014 issue.

Objective: The authors sought to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers. Method: This was a cohort study of new users of methylphenidate based on administrative data from a five-state Medicaid database and a 14-state commercial insurance database. All new methylphenidate users with at least 180 days of prior enrollment were identified. Users were matched on data source, state, sex, and age to as many as four comparison subjects who did not use methylphenidate, amphetamines, or atomoxetine. A total of 43,999 new methylphenidate users were identified and matched to 175,955 nonusers. Events of primary interest were 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, and 4) a composite endpoint of stroke or myocardial infarction. Results: The age-standardized incidence rate per 1,000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI=1.63-2.83) in methylphenidate users and 0.98 (95% CI=0.89-1.08) in nonusers, for an adjusted hazard ratio of 1.84 (95% CI=1.33-2.55). Dosage was inversely associated with risk. Adjusted hazard ratios for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from 1. Conclusions: Although initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one. [ABSTRACT FROM AUTHOR]

Increasing epidemiological evidence suggests independent associations between psoriasis and cardiovascular and metabolic disease. Our objective was to test the hypothesis that directly assessed psoriasis severity relates to the prevalence of metabolic syndrome and its components. A population-based, cross-sectional study was undertaken using computerized medical records from the Health Improvement Network Study population including individuals in the age group of 45-65 years with psoriasis and practice-matched controls. The diagnosis and extent of psoriasis were determined using provider-based questionnaires. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A total of 44,715 individuals were included: 4,065 with psoriasis and 40,650 controls. In all, 2,044 participants had mild psoriasis (2% body surface area (BSA)), 1,377 had moderate psoriasis (3-10% BSA), and 475 had severe psoriasis (>10% BSA). Psoriasis was associated with metabolic syndrome, adjusted odds ratio (adj. OR 1.41, 95% confidence interval (CI) 1.31-1.51), varying in a 'dose-response' manner, from mild (adj. OR 1.22, 95% CI 1.11-1.35) to severe psoriasis (adj. OR 1.98, 95% CI 1.62-2.43). Psoriasis is associated with metabolic syndrome and the association increases with increasing disease severity. Furthermore, associations with obesity, hypertriglyceridemia, and hyperglycemia increase with increasing disease severity independently of other metabolic syndrome components. These findings suggest that screening for metabolic disease should be considered for psoriasis, especially when it is severe. [ABSTRACT FROM AUTHOR]

Aims Renal neurohormonal activation leading to a reduction in glomerular filtration rate (GFR) has been suggested as a mechanism for renal insufficiency (RI) in the setting of heart failure. We hypothesized that RI occurring in the presence of renal neurohormonal activation may be prognostically more important than RI in the absence of renal neurohormonal activation. Methods and results Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial (n = 429), Beta-Blocker Evaluation of Survival Trial (BEST) (n = 2691), and Studies Of Left Ventricular Dysfunction (SOLVD) trial (n = 6782) limited datasets were studied. The blood urea nitrogen to creatinine ratio (BUN/Creatinine) was employed as a surrogate for renal neurohormonal activation and the primary outcome was the interaction between BUN/Creatinine and RI associated mortality. Baseline RI (GFR < 60 mL/min/1.73 m²) was associated with mortality in all study populations (P < 0.001). In patients with higher BUN/Creatinine, the risk of mortality was consistently greater in patients with RI [adjusted hazard ratio (HR) ESCAPE = 2.8, 95% confidence interval (CI) 1.3–14.3, P = 0.019; BEST = 1.6, 95% CI 1.2–2.2, P = 0.002; SOLVD = 1.6, 95% CI 1.3–2.0, P = 0.001]. However, in patients with lower BUN/Creatinine, the risk of mortality was not elevated in patients with RI (adjusted HR ESCAPE = 0.94, 95% CI 0.35–2.4, P = 0.90, P interaction = 0.005; BEST = 0.97, 95% CI 0.64–1.4, P = 0.90, P interaction = 0.02; SOLVD = 1.0, 95% CI 0.8–1.3, P = 0.71, P interaction = 0.005). Conclusion The association between RI and poor survival observed in heart failure populations appears to be contingent not simply on the presence of a reduced GFR, but possibly on the mechanism by which GFR is reduced. [ABSTRACT FROM AUTHOR]

Aims: One of the primary determinants of blood flow in regional vascular beds is perfusion pressure. Our aim was to investigate if reduction in blood pressure during the treatment of decompensated heart failure would be associated with worsening renal function (WRF). Our secondary aim was to evaluate the prognostic significance of this potentially treatment-induced form of WRF.Methods and Results: Subjects included in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial limited data were studied (386 patients). Reduction in systolic blood pressure (SBP) was greater in patients experiencing WRF (-10.3 ± 18.5 vs. -2.8 ± 16.0 mmHg, P < 0.001) with larger reductions associated with greater odds for WRF (odds ratio = 1.3 per 10 mmHg reduction, P < 0.001). Systolic blood pressure reduction (relative change > median) was associated with greater doses of in-hospital oral vasodilators (P ≤ 0.017), thiazide diuretic use (P = 0.035), and greater weight reduction (P = 0.023). In patients with SBP-reduction, WRF was not associated with worsened survival [adjusted hazard ratio (HR) = 0.76, P = 0.58]. However, in patients without SBP-reduction, WRF was strongly associated with increased mortality (adjusted HR = 5.3, P < 0.001, P interaction = 0.001).Conclusion: During the treatment of decompensated heart failure, significant blood pressure reduction is strongly associated with WRF. However, WRF that occurs in the setting of SBP-reduction is not associated with an adverse prognosis, whereas WRF in the absence of this provocation is strongly associated with increased mortality. These data suggest that WRF may represent the final common pathway of several mechanistically distinct processes, each with potentially different prognostic implications. [ABSTRACT FROM AUTHOR]

Aims One of the primary determinants of blood flow in regional vascular beds is perfusion pressure. Our aim was to investigate if reduction in blood pressure during the treatment of decompensated heart failure would be associated with worsening renal function (WRF). Our secondary aim was to evaluate the prognostic significance of this potentially treatment-induced form of WRF. Methods and results Subjects included in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial limited data were studied (386 patients). Reduction in systolic blood pressure (SBP) was greater in patients experiencing WRF (−10.3 ± 18.5 vs. −2.8 ± 16.0 mmHg, P < 0.001) with larger reductions associated with greater odds for WRF (odds ratio = 1.3 per 10 mmHg reduction, P < 0.001). Systolic blood pressure reduction (relative change > median) was associated with greater doses of in-hospital oral vasodilators (P ≤ 0.017), thiazide diuretic use (P = 0.035), and greater weight reduction (P = 0.023). In patients with SBP-reduction, WRF was not associated with worsened survival [adjusted hazard ratio (HR) = 0.76, P = 0.58]. However, in patients without SBP-reduction, WRF was strongly associated with increased mortality (adjusted HR = 5.3, P < 0.001, P interaction = 0.001). Conclusion During the treatment of decompensated heart failure, significant blood pressure reduction is strongly associated with WRF. However, WRF that occurs in the setting of SBP-reduction is not associated with an adverse prognosis, whereas WRF in the absence of this provocation is strongly associated with increased mortality. These data suggest that WRF may represent the final common pathway of several mechanistically distinct processes, each with potentially different prognostic implications. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD). Background: Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival. Methods: Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality. Results: In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018). Conclusions: The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic–associated mortality. [Copyright &y& Elsevier]

OBJECTIVE: The objective of this study was to compare the rate of severe cardiovascular events and death in children who use attention-deficit/hyperactivity disorder (ADHD) medications versus nonusers. PATIENTS AND METHODS: We performed a large cohort study using data from 2 administrative databases. All children aged 3 to 17 years with a prescription for an amphetamine, atomoxetine, or methylphenidate were included and matched with up to 4 nonusers on the basis of data source, gender, state, and age. Cardiovascular events were validated using medical records. Proportional hazards regression was used to calculated hazard ratios. RESULTS: We identified 241 417 incident users (primary cohort). No statistically significant difference between incident users and nonusers was observed in the rate of validated sudden death or ventricular arrhythmia (hazard ratio: 1.60 [95% confidence interval (CD: 0.19-13.60]) or all-cause death (hazard ratio: 0.76 [95% CI: 0.52-1.12]). None of the strokes identified during exposed time to ADHD medications were validated. No myocardial infarctions were identified in ADHD medication users. No statistically significant difference between prevalent users and nonusers (secondary cohort) was observed (hazard ratios for validated sudden death or ventricular arrhythmia: 1.43 [95% CI: 0.31-6.61]; stroke: 0.89 [95% CI: 0.11-7.11]; stroke/myocardial infarction: 0.72 [95% CI: 0.09-5.57]; and all-cause death: 0.77 [95% CI: 0.56- 1.07). CONCLUSIONS: The rate of cardiovascular events in exposed children was very low and in general no higher than that in unexposed control subjects. Because of the low number of events, we have limited ability to rule out relative increases in rate. [ABSTRACT FROM AUTHOR]