John Huntinghouse

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

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 P<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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study.

BACKGROUND Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL). OBJECTIVE The purpose of this study was to test the hypothesis of a relationship between AF and TL. METHODS Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n = 3576) and DNA extracted. TL was determined by multiplex quantitative polymerase chain reaction, normalized to a single copy gene, and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcares electronic records database. Prevalent AF was determined by discharge ICD-9 code. AF subtype (paroxysmal [Px], persistent [Ps], long-standing persistent/permanent [Pm]) was determined by chart review. RESULTS The t/s decreased with age (P <.00001). Subjects with a history of AF (n = 379 [10.6%] had shorter telomeres (mean t/s ± SD = 0.87 ± 0.29) compared to subjects without AF (mean t/s 0.95 ± 0.32, P <.0001). The association remained after adjustment for age (P = .017) and cardiovascular risk factors (P = .016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm, and subjects without AF (0.94 ± 0.40, 0.94 ± 0.27, and 0.95 ± 0.32, respectively). However, the mean t/s for Px (0.81 ± 0.22) was significantly shorter than for Ps (P = .026), Pm (P = .004), or subjects without AF (P <.0001). CONCLUSION The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy.

Validation and Quantification of Genetic Determinants of Lipoprotein-a Levels and Predictive Value for Angiographic Coronary Artery Disease

Lipoprotein(a) (Lp[a]) has gained attention as a heritable coronary artery disease (CAD) risk factor and therapeutic target. Two genetic variants in the LPA gene have been reported to influence Lp(a) levels and increase CAD risk. The aim of this study was to prospectively test these variants for their associations with Lp(a) and CAD risk. Participants (n = 1,400) in the Intermountain Heart Collaborative Study Registry who had Lp(a) cholesterol levels determined at coronary angiography were genotyped for rs3798220 and rs1045587 in LPA. Variants were detected by Taqman polymerase chain reaction. Chi-square and linear and logistic regression tests were used as appropriate among genotypes for Lp(a) and angiographic CAD. Age averaged 63 years; 65% were men; and severe CAD was present in 57%, mild CAD in 12%, and no CAD in 31%. Minor allele frequencies were 0.023 for rs3798220 and 0.090 for rs10455872. In multivariate modeling, only rs10455872 (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.67 to 3.33, p = 1.75 × 10⁻⁹) and rs3798220 (OR 1.99, 95% CI 0.99 to 4.00, p = 0.065) contributed to the prediction of elevated Lp(a) cholesterol. Lp(a) cholesterol was weakly associated with CAD (OR 1.17, 95% CI 1.00 to 1.37, p = 0.055). Rs10455872 strongly predicted prevalent CAD (per allele OR 1.43, 95% CI 1.07 to 1.91, p = 0.0172); the effect size for the rare rs3798220 variant was similar (dominant OR 1.47, 95% CI 0.81 to 2.67, p = 0.20), but power was limited to demonstrate significance. The combined genotype explained only a small percentage (≤4%) of variability in Lp(a) cholesterol and prevalence of angiographic CAD. In conclusion, heritable contributions of LPA rs10455872 and rs3798220 to Lp(a) cholesterol levels and to angiographic CAD were prospectively assessed in this study. The percentage of intersubject variability in Lp(a) cholesterol and the percentage of prevalent CAD explained were small.

METHADONE-INDUCED QTC PROLONGATION IS ASSOCIATED WITH CYP2C19 GENOTYPE AND WITH PLASMA ETHYLIDENE-1,5-DIMETHYL-3,3-DIPHENYLPYRROLIDENE (EDDP) CONCENTRATION: A POSSIBLE MECHANISTIC LINK

Methadone-associated sudden arrhythmic death is due to polymorphic ventricular fibrillation arising from QT prolongation associated with perturbations in the delayed potassium rectifier current. Risk for QT prolongation has been independently associated with both increased formation of the methadone

QTC PROLONGATION CORRELATES WITH PLASMA ETHYLIDENE-1.5-DIMETHYL-3.3-DIPHENYLPYRROLIDENE (EDDP) AMONG SUBJECTS INITIATING METHADONE MAINTENANCE THERAPY

methods: Consenting participants (n=31) initiating methadone maintenance therapy were enrolled in the MEMORIES Trial (Clinical Trials.gov NCT01191242). Peak (4 hr post-oral dose) and trough (24 hr) plasma samples obtained on days 1, 7 and 21 were analyzed for methadone and EDDP (the principal methadone metabolite) by liquid chromatographic tandem mass spectrometry. Pre-treatment and d21 rate-corrected QT interval (QTc) was measured by ECG.

Association of Chromosome 9p21.3 with Disease Location, Including the Number of Diseased Vessels, but not with Greater Burden of Coronary Disease

Introduction: Single nucleotide polymorphisms (SNPs) at chromosome 9p21.3 do not influence myocardial infarction, but their role in coronary artery disease (CAD) progression, burden, and outcomes is controversial. This study evaluated whether rs1333049 impacts CAD burden. Methods: Non-diabetic CAD patients enrolled in the Intermountain Heart Collaborative Study (N=1,757) were evaluated for association of rs1333049 with the Duke CAD Index (primary endpoint) and other CAD measures. Multivariable regression adjusted for potential confounders. Statistical significance of secondary endpoints was corrected for multiple comparisons. Results: No association of rs1333049 with Duke CAD Index was found for 0, 1, and 2 C alleles: 42.4 ± 16.1, 44.0 ± 17.4, 47.4 ± 17.6, respectively (p-trend=0.12, adjusted p-trend=0.11). It also did not predict the number of CAD lesions (adjusted p-trend=0.11) or the maximum CAD stenosis (adjusted p-trend=0.89). The SNP did predict the number of major vessels with proximal or left main lesions (0.56 ± 0.69, 0.62 ± 0.74, and 0.71 ± 0.77 for 0, 1, and 2 C alleles, respectively; adjusted p-trend=0.0056) and another location parameter: the number of major vessels with at least one significant stenosis (p-trend=0.0017). Rs1333049 was not associated with future events, but association with CAD presence was confirmed (p-trend<0.0001). Conclusion: Rs1333049 was not associated with CAD burden, lesion number or severity, or cardiovascular events. The SNP did strongly predict CAD presence and was associated with lesion location. These findings reaffirm that a primary role of 9p21.3 may be related to the presence of CAD rather than the clinical severity of obstructive lesions. Because follow-up angiography was not systematically performed, CAD progression could not be evaluated.