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Background--Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results--A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N= 1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all f <0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios >4 and <1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions--These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. INSET: CLINICAL PERSPECTIVE. [ABSTRACT FROM AUTHOR]

Introduction: Improved heart failure (HF) outcomes are needed due to patient health, utilization, and government penalty considerations. Previously we created clinical decision tools (CDT) and a CDT-guided multidisciplinary team care pathway (MTCP) for HF inpatients. Objective: This study evaluated outcomes of stepped wedge MTCP implementation in HF inpatient care across Intermountain Healthcare. Methods: HF inpatients (N=6,182) were studied at 19 Intermountain hospitals from January 2013 to November 2016. Starting February 2014, the MTCP intervention was implemented sequentially over 2.5 years in the 8 largest hospitals (accounting for 89% of HF inpatients). Where MTCP was implemented, CDT mortality and readmission risk scores were delivered electronically to clinicians within 24 hours of admission and repeated daily. MTCP was used for CDT "high risk" inpatients (n=1,221); lower risk patients received standard HF care (n=1,220). Controls were categorized retrospectively as high risk (n=1,791) and lower risk (n=1,950) at admission. Results: Patient age averaged 71.1±14.7 years; 45.5% were female. In CDT high-risk patients, the MTCP intervention was associated with 25% lower 30-day readmission (HR=0.75, CI=0.63, 0.88, p<0.001) and 48% lower 30-day mortality (HR=0.52, CI=0.37, 0.72, p<0.001). Cox regression adjustment for demographics, comorbidities, and medications retained both findings (readmission: HR=0.82, CI=0.69, 0.97, p=0.023; mortality: HR=0.54, CI=0.39, 0.76, p<0.001). CDT lower-risk patients in MTCP-implemented hospitals had no significant 30-day changes (readmission: adjusted HR=0.89, p=0.21; mortality: adjusted HR=0.86, p=0.51). LOS was not lower for MTCP recipients (4.5 days vs. controls: 4.6 days, p=0.65) or lower risk (3.8 days vs. controls: 3.9 days, p=0.35). Total variable cost (index stay & any 30-day readmission) was not different for MTCP (median $6,960 vs. controls: $6,741, p=0.08), but was higher in lower risk (median $6,258 vs. controls: $5,933, p=0.034). Conclusions: A CDT-guided precision medicine MTCP for high-risk HF patients was associated with lower 30-day readmission and mortality. Costs increased in lower risk patients where inpatient care was minimized but not higher-risk MTCP recipients. [ABSTRACT FROM AUTHOR]

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown., Methods and Results: We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias., Conclusions: In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal., (© 2017 American Heart Association, Inc.)

Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target., Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib., Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Background: A chromosome 9p21 locus is associated with coronary heart disease in 25 independent populations, but multiple clinically distinct phenotypes have been evaluated. Using angiographic coronary artery disease (CAD) phenotyping, this study evaluated whether 9p21 single-nucleotide polymorphisms predict ischemic events (eg, myocardial infarction [MI]) among CAD patients., Methods and Results: Patients undergoing coronary angiography during 1994 to 2007 (population set 1A: n=1748; set 1B: n=1014) were evaluated for association of a 9p21 tagging single-nucleotide polymorphism (rs2383206, A 224 G) with incident MI and death events among patients with angiographically significant CAD. Another hypothesis evaluated rs2383206 in 2 additional angiographic sets of both CAD and non-CAD patients (set 2A: n=2122; set 2B: n=1466) for prevalent MI versus CAD/no MI (and for MI versus non-CAD and CAD/no MI versus non-CAD). No association of rs2383206 was found with events in set 1A (odds ratio, 0.95 per G allele; P trend=0.48) and set 1B (odds ratio, 0.91 per G allele; P trend=0.28) or with MI versus CAD/no MI in set 2A (odds ratio, 0.96 per G allele; P trend=0.57) and set 2B (odds ratio, 0.89 per G allele; P trend=0.21). In contrast, rs2383206 was associated with CAD/no MI compared with non-CAD (set 2A: P trend=0.0001; set 2B: P trend=0.0008)., Conclusions: The chromosome 9p21 locus was not associated with incident events or prevalent MI, although it did predict CAD diagnosis. This contradicts reports of a 9p21 association with MI, likely because of differences in phenotype assignment. This suggests that high-quality phenotyping for CAD and MI is required to dissect the specific contributions of genetic variation to each stage of coronary heart disease pathophysiology.

Background: Coronary artery bypass surgery (CABG) and percutaneous coronary intervention with stenting (PCI-S) are both safe and effective approaches for revascularization in patients with multivessel coronary artery disease. However, conflicting information exists when comparing the efficacy of the two methods. In this study, we examined the outcomes of major adverse cardiovascular events and death for subgroups of typical "real-world" patients undergoing coronary revascularization in the modern era., Methods and Results: Patients were included if they were revascularized by CABG or PCI-S, had > or = 5 years of follow-up, and had > or = 2-vessel disease. Patients were followed for an average of 7.0+/-3.2 years for incidence of death and major adverse cardiovascular events (death, myocardial infarction, or repeat revascularization). Multivariate regression models were used to correct for standard cardiac risk factors including age, sex, hyperlipidemia, diabetes mellitus, family history of coronary artery disease, smoking, hypertension, heart failure, and renal failure. Subgroup analyses were also performed, stratified by age, sex, diabetes, ejection fraction, and history of PCI-S, CABG, or myocardial infarction. A total of 6369 patients (CABG 4581; PCI-S 1788) were included. Age averaged 66+/-10.9 years, 76% were male, and 26% were diabetic. Multivariate risk favored CABG over PCI-S for both death (hazard ratio 0.85; P=0.001) and major adverse cardiovascular events (hazard ratio 0.51; P<0.0001). A similar advantage with CABG was also found in most substrata, including diabetes., Conclusions: In this large observational study of patients undergoing revascularization for multivessel coronary artery disease, a long-term benefit was found, in relationship to both death and major adverse cardiovascular events, for CABG over PCI-S regardless of diabetic status or other stratifications.

Background: Recent evidence suggests that long-term exposure to particulate air pollution contributes to pulmonary and systemic oxidative stress, inflammation, progression of atherosclerosis, and risk of ischemic heart disease and death. Short-term exposure may contribute to complications of atherosclerosis, such as plaque vulnerability, thrombosis, and acute ischemic events. These findings are inconclusive and controversial and require further study. This study evaluates the role of short-term particulate exposure in triggering acute ischemic heart disease events., Methods and Results: A case-crossover study design was used to analyze ischemic events in 12,865 patients who lived on the Wasatch Front in Utah. Patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a large, ongoing registry of patients who underwent coronary arteriography and were followed up longitudinally. Ambient fine particulate pollution (particles with an aerodynamic diameter < or = 2.5 microm; PM2.5) elevated by 10 microg/m3 was associated with increased risk of acute ischemic coronary events (unstable angina and myocardial infarction) equal to 4.5% (95% confidence interval, 1.1 to 8.0). Effects were larger for those with angiographically demonstrated coronary artery disease., Conclusions: Short-term particulate exposures contributed to acute coronary events, especially among patients with underlying coronary artery disease. Individuals with stable presentation and those with angiographically demonstrated clean coronaries are not as susceptible to short-term particulate exposure.

Background: Atrioventricular (AV) nodal ablation for management of atrial fibrillation (AF) is irreversible and requires permanent pacemaker implantation. We hypothesized that as an alternative, implantation of autologous fibroblasts in the perinodal region would focally modify AV nodal conduction and that this modulation would be enhanced by pretreatment with transforming growth factor-beta1 (TGF-beta1), a stimulant of fibroblasts., Methods and Results: Skin biopsies were taken from 12 mongrel dogs, and derived fibroblasts were dissociated and grown in culture for 2 weeks. Multiple injections (0.25 mL) were made through an 8F NOGA catheter along the fast/slow AV nodal pathways as guided by an electroanatomic mapping system. Seven dogs received fibroblasts alone (1x10(6) cells/mL), 7 dogs received TGF-beta1 (5 microg), 4 dogs received fibroblasts and TGF-beta1 (1x10(6) cells/mL+5 microg), and 4 dogs received saline only. AV node function was assessed at baseline and after 4 weeks. Saline (80 mL) with assigned therapy (0.25 mL per injection) was injected into the peri-AV nodal region in each dog. At baseline, the AH interval (66+/-3 ms) and the average RR interval (331+/-17 ms) in pacing-induced AF were similar in each cohort. The increase in AH interval in normal sinus rhythm was longer after fibroblast (23+/-4 versus 5+/-5 ms; P=0.05) and fibroblast plus TGF-beta1 (50+/-5 versus 5+/-5 ms; P<0.001) injections than with saline alone, with similar findings during high right atrium and distal coronary sinus pacing. The AH interval was not significantly increased after TGF-beta1 injections. The AH interval was significantly longer after fibroblast plus TGF-beta1 injections than with either therapy (TGF-beta1 or fibroblasts) alone. The RR interval during AF was increased in dogs that received fibroblasts alone (110+/-36 versus -41+/-34 ms) and to a greater extent with the addition of TGF-beta1 (294+/-108 versus -41+/-34 ms). No AV block was seen in any cohort at 4 weeks. Labeled fibroblasts that expressed vimentin were identified in all dogs that received cell injections at 4 weeks., Conclusions: AV nodal modification can be achieved with injected fibroblasts without the creation of AV block. The effect on AV node conduction is substantially enhanced by pretreatment of fibroblasts with TGF-beta1. These data have therapeutic potential for the management of rapid ventricular rate during AF without pacemaker implantation.

Background: Cardiac valvular diseases contribute to >42,000 deaths yearly in the United States, but the role of genetics in these deaths is unknown. This study evaluated the familiality of death resulting from aortic, mitral, and all valvular diseases using a population-based genealogy linked to death records., Methods and Results: The Utah Population Database contains >2 million individual records with genealogy data and 250,000 linked death certificates. Nonrheumatic aortic (n=932), mitral (n=1165), and all valvular (n=2504) disease deaths and rheumatic heart disease deaths (n=4713) were studied. Familial relative risks (FRRs) were assessed for first- and second-degree relatives. Familiality was also evaluated with the genealogical index of familiality, which considers all relationships in the Utah Population Database. FRRs were increased only for mitral valve death in both first-degree (FRR, 2.55; P<0.0001) and second-degree (FRR, 1.67; P<0.0001) relatives. Genealogical index of familiality analysis showed significant excess relatedness for all groups (P<0.001). Genealogical index of familiality results (P<0.001) for early age at death cases showed higher mean relatedness, a common characteristic of heritable disorders. Excess familiality extended to distant relatives for mitral (second-degree relatives) and aortic (beyond second-degree relatives) valve death., Conclusions: Deaths resulting from nonrheumatic mitral and aortic diseases clustered among both close and distant relatives, especially among early age at death cases, suggesting a significant genetic component in death resulting from valvular diseases. Future studies should focus on gene discovery.

Background: Enoxaparin has become an attractive therapy for use during acute coronary syndrome (ACS) because of its potential superior efficacy over unfractionated heparin (UFH), its longer activity, and its subcutaneous route of administration. However, because a significant number of patients presenting with ACS may be sent directly to open heart surgery while still on anticoagulation, it is important to understand any potential bleeding risks that may be associated with the use of enoxaparin under these circumstances., Methods: From 1998 to 2001, 1159 consecutive patients presenting with an acute coronary syndrome who received either UFH (n=1008) or enoxaparin (n=151) before proceeding to open heart surgery for urgent therapy during the same hospitalization were included in this study. Incidence of perioperative bleeding as evidenced by the units of blood products (packed red blood cells or platelets) transfused or the need for surgical re-exploration for postoperative bleeding was recorded., Results: Average age was 65+/-11 and 67+/-11 years for patients receiving UFH and enoxaparin, respectively (P=0.005). Seventy-five percent of those receiving UFH and 64% of those receiving enoxaparin (P<0.005) were males. After discharge, the incidence of rehospitalization for hemorrhage requiring return to surgery for re-exploration was 7.9% in the enoxaparin group and 3.7% in the UFH group (adjusted hazard ratio=2.6, P=0.03). The use of blood products did not differ between groups (UFH=2.7+/-6.5 U and enoxaparin=2.3+/-4.5 U; P=NS)., Conclusion: The preoperative use of enoxaparin compared with UFH in patients presenting with an ACS who undergo open-heart surgery during the same hospitalization is associated with a significantly increased incidence of re-exploration for postoperative bleeding. Further study is needed to understand the mechanism of this phenomenon and to develop appropriate guidelines to address this potentially important issue.