Publications

BACKGROUND: Risk-benefit tradeoffs between restrictive versus liberal red blood cell transfusion strategies may vary across individuals. This exploratory analysis aimed to derive and evaluate individualized treatment effects of defined transfusion strategies in patients with acute MI and anemia with the goal of minimizing adverse cardiovascular outcomes.

METHODS: This study analyzed 3,447 (98.4%) patients randomized in the MINT (Myocardial Ischemia and Transfusion) trial between April 2017 to April 2023. Outcomes for this analysis included 30-day death or recurrent MI, death, and major adverse cardiovascular events (MACE, a composite of death, MI, stroke, and ischemia-driven unscheduled revascularization). Machine learning methods were used to identify baseline patient characteristics that informed the individualized treatment effect of a restrictive versus liberal transfusion strategy for each patient. The expected population risk of an outcome under a scenario in which patients received their optimal treatment, as indicated by the individualized treatment effect, was contrasted with expected risks for universally applying a restrictive strategy or a liberal strategy to all patients.

RESULTS: Baseline characteristics did not inform individualized treatment effects on 30-day death and death or MI, suggesting minimal heterogeneity in treatment effect on these outcomes. An algorithm for estimating the individualized treatment effect on 30-day MACE included 12 baseline factors. If all patients received the optimal treatment as indicated by their estimated individualized treatment effect, the predicted risk of 30-day MACE in the sample population was 15.2% (95% CI 14.2%-16.2%). This corresponded to 4.0 (difference: -4.0%, 95% CI -5.8, -2.1) and 2.3 (difference: -2.3%, 95% CI -3.7, -0.9) percentage point risk reductions compared to applying a restrictive or liberal strategy to everyone respectively.

CONCLUSIONS: The MINT trial average treatment effect, favoring a liberal strategy, may be optimal to minimize risk of 30-day death and death or MI for acute MI patients with anemia represented in the MINT sample as no individualized treatment effects were estimated on these outcomes. However, individualized transfusion strategy decisions have potential to reduce risk of 30-day MACE. External validation of the MACE algorithm is required before clinical use.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02981407, https://clinicaltrials.gov/study/NCT02981407.

BACKGROUND: Blood transfusion may precipitate adverse outcomes, including heart failure (HF), among patients with acute myocardial infarction (MI). This study characterizes the effects of a restrictive or liberal transfusion strategy on outcomes in patients with MI and anemia with and without baseline HF.

METHODS: In the MINT trial (Myocardial Ischemia and Transfusion), 3504 patients with MI and anemia (hemoglobin <10 g/dL) were randomized to a restrictive (hemoglobin <8 g/dL) or liberal (hemoglobin <10 g/dL) transfusion strategy. We compared the effects of transfusion strategy on outcomes among patients with and without baseline HF. The primary outcome was death or HF at 30 days.

RESULTS: Compared with patients without baseline HF (n=1633), those with baseline HF (n=1871) had higher rates of death or HF (18.0% versus 10.0%) at 30 days. Restrictive transfusion resulted in numerically higher rates of death or HF (rate ratio, 1.20 [95% CI, 0.99-1.45] versus 0.94 [95% CI, 0.70-1.26]; Pinteraction=0.18) in patients with than in those without baseline HF. Among secondary outcomes, death or recurrent MI and death were more frequent among those with baseline HF. Restrictive transfusion resulted in numerically higher rates of death or MI and death in patients with than in those without baseline HF. Rates of HF were similar between restrictive and liberal transfusion in patients with baseline HF but lower with restrictive transfusion (rate ratio, 0.51 [95% CI, 0.29-0.92]; Pinteraction=0.02) in patients without baseline HF.

CONCLUSIONS: A liberal transfusion strategy is safe for patients with MI and anemia, including those with baseline HF. Restrictive transfusion tended to result in worse outcomes, particularly in patients with baseline HF.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407.

BACKGROUND: Ultrasound enhancing agents (UEAs) are an important diagnostic tool for transthoracic or stress echocardiography (TTE/SE) but recent concerns have been raised about their safety in reports from individual health systems. As such, we aimed to identify if UEAs for TTE/SE are associated with serious adverse events within 2 days of administration.

METHODS AND RESULTS: All-payor nationwide claims from 11.4 million insured individuals across the United States, 2018 to 2022 were used to evaluate rates of death, anaphylaxis, myocardial infarction, ventricular tachycardia, or cardiac arrest within 2 days of TTE/SE among adults receiving and not receiving UEAs. Of the 11 421 463 individuals included (mean age 57.5±16.2, 54.0% female, 46.2% White), a total of 500 073 (4.4%) received TTE/SE with UEAs. After propensity score matching, the odds of death were lower in those receiving UEAs (receipt versus nonreceipt, 0.02% versus 0.14%, odds ratio [OR], 0.23 [95% CI, 0.19-0.28], P<0.001) and were not different across agents (Definity: 0.02%, OR, 0.22 [95% CI, 0.18-0.28]; Lumason: 0.03%, OR, 0.33 [95% CI, 0.20-0.57]; Optison: 0.01%, OR, 0.17 [95% CI, 0.08-0.38]; all P < 0.001). Rates of nondeath outcomes were similar to those observed in individuals not receiving UEAs, overall, and across specific agents. Rates of all outcomes were stable across years, including considering pre- and post-COVID periods.

CONCLUSIONS: In this large nationwide claims analysis from 2018 to 2022, serious adverse events associated with UEAs for TTE/SE were uncommon and overall consistent across agents and years of study. Compared with nonreceipt, receipt of UEAs was associated with a lower odds of death within 2 days of TTE/SE.

BACKGROUND: Orthostatic hypotension (OH) is associated with cardiovascular disease, particularly among older adults. While a standing transthoracic echocardiogram (TTE) could theoretically identify changes in cardiac output to diagnose cardiogenic OH, there are no established protocols for orthostatic TTEs and their feasibility is unknown.

METHODS AND RESULTS: We recruited 115 patients scheduled for elective outpatient TTE. Consenting participants, who were able to stand safely, underwent their scheduled recumbent TTE, followed by a standing TTE, performed within 1-2 minutes of standing. The focused TTE used the apical window to measure velocity time integral across the aortic valve to assess cardiac output. Blood pressure (BP) was measured in the supine and standing positions and patients were asked about symptoms of dizziness and lightheadedness. OH was defined as a change in standing minus supine systolic BP ≤-20 mm Hg or in diastolic BP of ≤-10 mm Hg. Of the 115 enrolled participants, 102 (89%) completed the standing echocardiogram protocol. Among those completing, mean age was 63.4 (SD, 14.8) years (38% were ≥ 70 years), 48% women, and 34% had a BMI ≥ 30 kg/m2. There were 21% with OH. Upon standing, systolic BP changed by -5.9 mm Hg (95% CI: -9.5, -2.2), diastolic BP by 2.4 mm Hg (-0.1, 4.8), and cardiac output by -0.4 L/min (95% CI: -0.7, -0.1). Change in cardiac output (per 1 L/min) was associated with a higher odds of systolic OH (OR: 1.60; 95% CI: 1.05, 2.42), but not diastolic OH (OR: 1.21; 95% CI: 0.63, 2.32).

CONCLUSIONS: Standing TTE is safe, well-tolerated, and feasible in the ambulatory setting. Moreover, TTE changes in cardiac output are associated with systolic OH. This clinical assessment shows promise for distinguishing OH etiologies and could inform further research on treatments to prevent OH.

KEY POINTS: This Myocardial Ischemia and Transfusion (MINT) trial analysis evaluated the optimal transfusion strategy for patients with CKD and anemia experiencing acute myocardial infarction. In patients with CKD, a liberal transfusion strategy overall did not demonstrate benefit over a restrictive strategy.

BACKGROUND: CKD is associated with higher risk of myocardial infarction and anemia. Among patients with anemia and CKD who experience myocardial infarction, it remains uncertain whether a liberal red blood cell transfusion threshold strategy (hemoglobin cutoff <10 g/dl) is superior to a restrictive transfusion threshold (hemoglobin, 7–8 g/dl) strategy.

METHODS: Among the 3504 patients enrolled in the Myocardial Ischemia and Transfusion (MINT) trial with nonmissing serum creatinine, we compared baseline characteristics and 30-day and 6-month outcomes of patients without CKD (N=1279), CKD with eGFR 30–60 ml/min per 1.73 m2 (N=999), CKD with eGFR <30 ml/min per 1.73 m2 (N=802), and CKD requiring dialysis (N=415) by assigned transfusion strategy.

RESULTS: No statistically significant interactions were observed between CKD stage and assigned transfusion strategy. Among non–dialysis-dependent patients with an eGFR <30 ml/min per 1.73 m2, a restrictive transfusion strategy was associated with a higher risk of 30-day death or recurrent myocardial infarction (risk difference [RD], 5.8%; 95% confidence interval [CI], 0.4% to 11.2%) compared with a liberal transfusion strategy. Among patients with an eGFR 30–60 ml/min per 1.73 m2, a restrictive strategy was associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, 3.7%; 95% CI, −0.9% to 8.2%) compared with a liberal transfusion strategy. Among patients with CKD requiring dialysis, a restrictive strategy was also associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, −2.6%; 95% CI, −10.0% to 4.8%) compared with a liberal transfusion strategy.

CONCLUSIONS: In patients with CKD included in this MINT subgroup analysis, a liberal transfusion strategy was not worse than a restrictive transfusion strategy and was associated with less harm in subgroups not receiving dialysis.

CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: Myocardial Ischemia and Transfusion (MINT), NCT02981407.

BACKGROUND: Patients with cardiovascular (CV) diseases are increasingly frail but rarely represented in trials. Understanding effect modification by frailty on CV trials is critical as it could help define treatment strategies in frail patients.

OBJECTIVES: This meta-analysis aims to assess the implications of frailty on CV outcomes in clinical trials.

METHODS: Randomized controlled trials examining the effects of frailty in the context of CV trials were included (CRD42024528279). Outcomes included a composite of major adverse cardiac events (MACE), all-cause mortality, CV mortality, hospitalizations, and frailty-specific outcomes (physical, quality of life, and frailty scores). HRs and 95% CIs were pooled for clinical endpoints, and standardized mean differences (SMDs) were calculated for frailty-specific outcomes.

RESULTS: Thirty unique randomized controlled trials were included with a pooled total of 87,711 participants. Frail patients had a significantly increased risk of MACE (HR: 2.33 [95% CI: 1.87-2.91], P < 0.001, I2 = 83%), all-cause mortality (HR: 2.34 [95% CI: 1.80-3.05], P < 0.01, I2 = 75%), CV mortality (HR: 1.76 [95% CI: 1.60-1.93], P < 0.001, I2 = 0%), and hospitalizations (HR: 2.38 [95% CI: 1.65-3.43], P < 0.001, I2 = 92%) compared to nonfrail patients. In the frailest group, trial interventions decreased MACE (HR: 0.81 [95% CI: 0.74-0.88], P < 0.001, I2 = 0%) and hospitalization (HR: 0.81 [95% CI: 0.72-0.90], P < 0.001, I2 = 0%) risks with no significant difference in mortality risk (P > 0.05) compared with the control group. Trial interventions significantly improved physical (SMD: 0.15, 0.04-0.26) and quality of life (SMD: 0.15, 0.09-0.21) but not frailty scores (P > 0.05).

CONCLUSIONS: While frailty prognosticated a higher risk of CV events and mortality, frailty did not reduce treatment efficacy. CV trial interventions appear beneficial even in the frailest group.

BACKGROUND: Aortic valve calcium (AVC) is associated with increased risk of mortality, cardiovascular disease (CVD), non-CVD such as dementia. Traditional atherosclerotic CVD risk factors are associated with both AVC and chronic kidney disease (CKD), but whether there is an association between AVC and CKD is unknown.

OBJECTIVES: To ascertain whether AVC quantified by cardiac CT scanning is independently associated with the long-term risk of incident CKD among individuals without a previous history of CVD.

METHODS: We examined 6346 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac CT scanning at Visit 1 (2000-02) and had an eGFR of ≥ 60 mL/min/1.73 m2. AVC was quantified using the Agatston method and categorized as 0, 1-99, and ≥100. Incident CKD was defined as an eGFR < 60 mL/min/1.73 m2 accompanied with an at least 40 % decline in eGFR from baseline, and/or a diagnosis of CKD and indicators of end stage renal disease extracted from hospital records using the International Classification of Disease (ICD) codes. We performed Kaplan-Meier survival curve analyses along with multivariable adjusted Cox proportional hazard regression models to examine the association between AVC (categorical and log-transformed) and incident CKD.

RESULTS: Participants had a mean age 62.2 ± 10.1 years, 53 % were women, and AVC >0 was present in 795 (12 %) participants. During a median follow-up time of 16.9 years, 982 (15 %) participants developed incident CKD. AVC examined as a continuous variable was associated with a significantly increased risk of developing CKD (per log-unit [AVC+1] HR 1.06 [95 % CI: 1.02-1.10]; p = 0.005). Kaplan-Meier models showed a higher cumulative incidence for CKD with higher AVC levels. In the multivariable adjusted Cox models, participants with AVC ≥100 had a higher risk of incident CKD, compared with the AVC=0 group (HR 1.48 [95 % CI: 1.15-1.89]; p = 0.002). The observed associations remained after further adjusting for CAC score (p = 0.024), Lp(a) (p = 0.004), and the APOE-ε4 genotype (p = 0.004).

CONCLUSIONS: In a multi-ethnic cohort of participants free of CKD at baseline, AVC was independently associated with a higher risk of incident CKD. Further work is needed to understand the multidirectional relationship between AVC, CKD, and atherosclerosis.