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Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in CYP2C19 may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function CYP2C19 alleles and thus have reduced active clopidogrel metabolites, high on-treatment platelet reactivity, and increased ischemic risk. Prospective studies have examined the utility of CYP2C19 genetic testing to guide antiplatelet therapy, and more recently published meta-analyses suggest that pharmacogenetics represents a key treatment strategy to individualize antiplatelet therapy. Rapid genetic tests, including bedside genotyping platforms that are validated and have high reproducibility, are available to guide selection of P2Y12 inhibitors in clinical practice. The aim of this review is to provide an overview of the background and rationale for the role of a guided antiplatelet approach to enhance patient care.

AbstractIntroduction/AimsIn this study we investigated COVID‐19 vaccination–related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs).MethodsSeven‐day vaccine ADEs were collected in an international patient self‐reported e‐survey. Descriptive statistics were obtained and multivariable regression was performed.ResultsTen thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs]; median age, 42 [interquartile range, 30‐455] years; 74% female; 45% Caucasian; 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7; interquartile range [IQR], 1.04‐7.3) and minor (OR, 1.5; IQR, 1.1‐2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3; IQR, 1.2‐4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9; IQR, 1.1‐3.3; and OR, 2.2; IQR, 1.1‐4.3, respectively). Overall, ADEs were less frequent in inclusion‐body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients.DiscussionSeven‐day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID‐19 through vaccination likely outweighs the risk of vaccine‐related ADEs. Our results may inform future guidelines regarding COVID‐19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long‐term outcomes and disease flares are needed to shed more light on developing future COVID‐19 vaccination guidelines.

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

Introduction: Prior studies have shown 30-35% of patients with an abnormal stress test had non-obstructive coronary artery disease. The characteristics and outcomes of this patient population have not been well studied. We tested the hypothesis that there is a distinct group of individuals who have an exercise-induced cardiomyopathy not related to the presence of obstructive coronary artery disease or pre-existing structural heart disease. Methods: Our cohort included adults 18 years and older who underwent stress echocardiography at the Mayo Clinic. Patients were included if their resting left ventricular ejection fraction (LVEF) was greater than 50% and decreased by more than 5% to under 50% with exercise. We excluded patients who did not have coronary angiography in the 90 days following stress echocardiography and those with prior diagnosis of coronary artery disease or structural/valvular heart disease. Results: A total of 205627 stress echocardiograms were performed between 2003 and 2019, of which 127 patients were analyzed in our cohort. The median age was 68 years, and 76% were female. The median LVEF was 55% at rest and 45% with stress. Left bundle branch block was present in 9% of patients. Median peak systolic blood pressure was 174 mm Hg. Stress electrocardiogram was positive in 14% of patients. Median functional aerobic capacity [interquartile range] as a percentage of age/sex predicted capacity was 101% [73%, 117%]. Conclusion: We describe a cohort of patients with exercise-induced left ventricular systolic dysfunction not explained by obstructive coronary artery disease or structural heart disease. Forthcoming analyses of long term outcomes will be important to understand how these patients compare to patients without exercise-induced cardiac dysfunction.

Abstract Despite much of the past 2 years being engulfed by the devastating consequences of the SAR‐CoV‐2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show‐cased at the 15th Post‐American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th‐10th December 2020 and 7th‐10th October 2021, respectively. The inaugural Post‐ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Background: Ischemic event rates are low after percutaneous coronary intervention (PCI), conversely second generation P2Y12 inhibitors increase bleeding therefore identifying patients at risk to enable precision in prescribing dual anti-platelet therapy (DAPT) is of clinical interest. Prior machine-learning predictive analyses have been limited by use of older generation stents and lack of genetic data. We utilized clinical and genetic data of patients with new generation stents enrolled in TAILOR-PCI, a 40-center international trial to predict ischemic events after PCI. Methods: There were 4398 eligible post PCI patients with acute coronary syndromes or stable coronary artery disease who were randomly split into training (n=3299) and validation (n=1099) cohorts. The primary endpoint comprising of cardiovascular death, myocardial infarction, stroke, or stent thrombosis within 12 months of PCI was predicted with patient characteristics prior to hospital discharge. First, random forests were used for feature selection with 1,000 bootstraps comprising equal numbers of those with and without ischemic events to minimize the bias of sample imbalance. Features were selected by a consensus on variable-importance over bootstraps. Second, using these features in the training cohort, support vector machines (SVM) with a polynomial kernel was trained with repeated 5-fold cross validation to choose a model with highest area under the receiver operating characteristic curve (AUC) which was then used to predict ischemic events in the validation cohort. Results: The primary endpoint occurred in 2.4% of patients. Using 89 clinical and genetic variables in the random-forest feature selection step, variable importance-based consensus identified 50 top predictors. These 50 predictors achieved AUC=0.703 in the SVM training cohort and AUC=0.744 (specificity=0.84; sensitivity =0.43) in the SVM validation cohort. Conclusions: Machine learning methods using baseline clinical and genetic data enables prediction of infrequent ischemic events in post PCI patients receiving new generation stents. The role of such artificial intelligence algorithms in individualization of DAPT by identifying high or low risk patients needs to be explored.

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

BackgroundUncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion‐weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within‐subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.PurposeEvaluation of the repeatability (same‐day) and reproducibility (multi‐day) of whole‐prostate and focal‐lesion ADC assessment in a multi‐site setting.Study TypeProspective multi‐institutional.SubjectsTwenty‐nine males, ages 53 to 80 (median 63) years, following diagnosis of prostate cancer, 10 with focal lesions.Field Strength/Sequence3T, single‐shot spin‐echo diffusion‐weighted echo‐planar sequence with four b‐values.AssessmentSites qualified for the study using an ice‐water phantom with known ADC. Readers performed DWI analyses at visit 1 (“V1”) and visit 2 (“V2,” 2–14 days after V1), where V2 comprised scans before (“V2pre”) and after (“V2post”) a “coffee‐break” interval with subject removal and repositioning. A single reader segmented the whole prostate. Two readers separately placed region‐of‐interests for focal lesions.Statistical TestsReproducibility and repeatability coefficients for whole prostate and focal lesions derived from median pixel ADC. We estimated the wCV and 95% confidence interval using a variance stabilizing transformation and assessed interreader reliability of focal lesion ADC using the intraclass correlation coefficient (ICC).ResultsThe ADC biases from b0–b600 and b0–b800 phantom scans averaged 1.32% and 1.44%, respectively; mean b‐value dependence was 0.188%. Repeatability and reproducibility of whole prostate median pixel ADC both yielded wCVs of 0.033 (N = 29). In 10 subjects with an evaluable focal lesion, the individual reader wCVs were 0.148 and 0.074 (repeatability) and 0.137 and 0.078 (reproducibility). All time points demonstrated good to excellent interreader reliability for focal lesion ADC (ICCV1 = 0.89; ICCV2pre = 0.76; ICCV2post = 0.94).Data ConclusionThis study met the QIBA claim for prostate ADC. Test–retest repeatability and multi‐day reproducibility were largely equivalent. Interreader reliability for focal lesion ADC was high across time points.Level of Evidence1Technical EfficacyStage 2TOC CategoryPelvis