High-sensitivity C-reactive protein in heart failure with preserved ejection fraction: Findings from TOPCAT.

BACKGROUND: Inflammation plays a central role in the genesis and progression of heart failure with preserved ejection fraction (HFpEF). C-reactive protein (CRP) is widely used as means to assess systemic inflammation, and elevated levels of CRP have been associated with poor HF prognosis. Identification of chronic low-grade inflammation in outpatients can be performed measuring high-sensitivity CRP (hsCRP). The clinical characteristics and outcome associations of a pro-inflammatory state among outpatients with HFpEF requires further study. AIMS: Using a biomarker subset of TOPCAT-Americas (NCT00094302), we aim to characterize HFpEF patients according to hsCRP levels and study the prognostic associations of hsCRP. METHODS: hsCRP was available in a subset of 232 participants. Comparisons were performed between patients with hsCRP <2 mg/L and ≥ 2 mg/L. Cox regression models were used to study the association between hsCRP and the study outcomes. RESULTS: Compared to patients with hsCRP <2 mg/L (n = 89, 38%), those with hsCRP ≥2 mg/L (n = 143, 62%) had more frequent HF hospitalizations prior to randomization, chronic obstructive pulmonary disease, orthopnea, higher body mass index, and worse health-related quality-of-life. A hsCRP level ≥ 2 mg/L was associated with an increased risk of cardiovascular death and HF hospitalizations: hsCRP ≥2 mg/L vs <2 mg/L adjusted HR 2.36, 95%CI 1.27-4.38, P = 0.006. Spironolactone did not influence hsCRP levels from baseline to month 12: gMean ratio = 1.11, 95%CI 0.87-1.42, P = 0.39. CONCLUSIONS: A hsCRP ≥2 mg/L identified HFpEF patients with a high risk of HF events and cardiovascular mortality. Spironolactone did not influence hsCRP levels at 12 months.

Influence of Weight and Body Size on the Pharmacokinetics of Heart Failure Pharmacotherapy: A Systematic Review.

OBJECTIVE: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. DATA SOURCES: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. STUDY SELECTION AND DATA EXTRACTION: Articles written in English or French related to the aim of our study were retained for analysis. DATA SYNTHESIS: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. CONCLUSION: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.

Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ß-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes.

BACKGROUND: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves. RESULTS: Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p < 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p < 0.05. CONCLUSION: Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes.

Pharmacogenomic study of heart failure and candesartan response from the CHARM programme.

AIMS: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin-converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan. METHODS: We performed genome-wide association studies in 2727 patients of European ancestry from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan-treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint. RESULTS: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55-2.35; P = 1.7 × 10-9 ). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome-wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene-level collapsing analysis. CONCLUSIONS: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings.

An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites.

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof-of-concept study.

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10-14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

Construction of a femininity score in the UK Biobank and its association with angina diagnosis prior to myocardial infarction.

Gender captures social components beyond biological sex and can add valuable insight to health studies in populations. However, assessment of gender typically relies on questionnaires which may not be available. The aim of this study is to construct a gender metric using available variables in the UK Biobank and to apply it to the study of angina diagnosis. Proxy variables for femininity characteristics were identified in the UK Biobank and regressed on sex to construct a composite femininity score (FS) validated using tenfold cross-validation. The FS was assessed as a predictor of angina diagnosis before incident myocardial infarction (MI) events. The FS was derived for 315,937 UK Biobank participants. In 3059 individuals with no history of MI at study entry who had an incident MI event, the FS was a significant predictor of angina diagnosis prior to MI (OR 1.24, 95% CI 1.10-1.39, P < 0.001) with a significant sex-by-FS interaction effect (P = 0.003). The FS was positively associated with angina diagnosis prior to MI in men (OR 1.37, 95% CI 1.19-1.57, P < 0.001), but not in women. We have provided a new tool to conduct gender-sensitive analyses in observational studies, and applied it to study of angina diagnosis prior to MI.

The genomics of heart failure: design and rationale of the HERMES consortium.

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Isocyanate derivatization coupled with phospholipid removal microelution-solid phase extraction for the simultaneous quantification of (S)-metoprolol and (S)-α-hydroxymetoprolol in human plasma with LC-MS/MS.

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the quantification of (S)-metoprolol (MET) and its main metabolite, (S)-α-hydroxymetoprolol (OH-MET). Human plasma samples (50 µL) were spiked with both analytes and their deuterated internal standards (IS) (S)-MET-(d7) and α-OH-MET-(d5). Phospholipid removal microelution-solid phase extraction (PRM-SPE) was performed using a 4-step protocol with Oasis PRiME MCX µElution 96-well cartridges. The eluates were reconstituted in 100 µL of acetonitrile with 50 µg/mL (S)-α-methylbenzyl isocyanate (MBIC) for chiral derivatization. After 60 min at room temperature, the reaction was quenched using 100 µL of water 2 % formic acid. Chromatographic separation of the derivatized analytes was performed on a Kinetex phenyl-hexyl core-shell stationary phase with an elution gradient. Mobile phases were composed of a mixture of water and methanol, with ammonium formate and formic acid as buffers. Total runtime was 15 min. Analyte detection was performed by an AB/SCIEX 4000 QTRAP mass spectrometer with multiple reaction monitoring. Chromatograms showed MBIC successfully reacted with racemic MET, α-OH-MET, and their respective IS. Detection by positive electrospray ionization did not reveal derivatized by-products. Quantification ranges were validated for (S)-MET and (S)-α-OH-MET between 0.5-500 and 1.25-500 ng/mL, respectively, with correlation coefficients (r2) >0.9906. The PRM-SPE assay showed low matrix effects (86.9-104.0 %) and reproducible recoveries (69.4-78.7 %) at low, medium, and high quality control (QC) levels. Precision and accuracy were all comprised between 85-115 % for all three QCs, and between 80-120 % for the lower limit of quantification, for intra- and inter-day values (n = 6, 3 consecutive days). Non-derivatized analytes were stable at room temperature, after 3 freeze-thaw cycles, and stored for 30 days at -80 °C (n = 4). Reinjection reproducibility of a previously validated batch was achieved after 8 days under auto-sampler conditions, indicating the stability of (S)-MET and (S)-α-OH-MET derivatives. Its clinical use was established in a cohort of 50 patients and could be used to further investigate the clinical impact of (S)-MET concentrations.

Genetics of symptom remission in outpatients with COVID-19.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10-8) in interaction with colchicine (P = 1.19 × 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

Comparative effectiveness and safety of high-dose rivaroxaban and apixaban for atrial fibrillation: A propensity score-matched cohort study.

STUDY OBJECTIVE: Observational studies assessing direct oral anticoagulant (DOACs) dosage in atrial fibrillation (AF) reported that a lower proportion of patients received high-dose DOACs compared to those in randomized controlled trials (RCTs). Effectiveness and safety of high-dose DOACs relative to apixaban in a real-world AF population need to be addressed. The aim is to assess comparative effectiveness and safety of high-dose rivaroxaban relative to apixaban. DESIGN: We conducted a cohort study. Setting We built a cohort of patients hospitalized and discharged in community with a primary or secondary AF diagnosis from 2011-2017 using Quebec administrative databases (Med-Echo and RAMQ). Patients Cohort entry was defined as the first OAC claim in new users of high-dose rivaroxaban and apixaban, with no OAC claims in the prior year. Intervention To compare effectiveness and safety of high-dose rivaroxaban to apixaban. Measurement We ascertained patient demographics, comorbidities, CHA2DS2-VASc and HASBLED scores and Charlson score within 3 years prior to cohort entry. Primary effectiveness and safety were a composite of ischemic stroke/systemic thrombosis, death, myocardial infarction, and of intracranial bleeding (ICH), extracranial major bleeding, in the first year following drug initiation. We conducted propensity score matching and estimated hazard ratios (HRs) for outcomes using Cox proportional hazard models. All the analyses were conducted to account for competing risks. Main results The cohort consisted of 4,632 and 6,771 patients received high-dose rivaroxaban and apixaban, respectively. High-dose rivaroxaban users were younger with a mean age of 73.2 years, presented less associated comorbidities and had lower CHA2DS2-VASc scores compared to apixaban. High-dose rivaroxaban at the intention to treat was associated with a higher risk of stroke/SE/death (HR 1.21, 95% CI 1.04-1.40) and worse composite effectiveness (HR 1.21: 1.05-1.40); under treatment exposure, those values were at HR (1.66: 1.21-2.29) and HR (1.58:1.19-2.10), respectively. And, rivaroxaban presented a less favorable safety profile relative to apixaban. Conclusion In this study, composite effectiveness and safety varied between rivaroxaban and apixaban. High-dose apixaban was observed to have a better effectiveness and safety.

Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.

BACKGROUND: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. METHODS: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. RESULTS: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. CONCLUSIONS: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial.

AIMS: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature. METHODS AND RESULTS: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone. CONCLUSIONS: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.

Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation.

Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety. Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs). Results: The cohort comprised 22,969 patients (mean age: 80-86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42-0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53-0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30-0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09-2.29]). Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.

Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure.

Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed-Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop-PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7-22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF.

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

AIMS: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. METHODS AND RESULTS: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found. CONCLUSIONS: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

Care Gaps in Adherence to Heart Failure Guidelines: Clinical Inertia or Physiological Limitations?

OBJECTIVES: This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF). BACKGROUND: Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist. METHODS: Medical records of all patients with HFrEF followed for at least 6 months at the authors' HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps. RESULTS: Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p < 0.0001) and history of stroke or transient ischemic attack (TIA) (no vs. yes, OR: 0.264; p = 0.0336). CONCLUSIONS: Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a "one-size-fits-all" approach may be required.

Obese-Inflammatory Phenotypes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Comorbidity-driven microvascular inflammation is posited as a unifying pathophysiologic mechanism for heart failure with preserved ejection fraction (HFpEF). Obesity is proinflammatory and common in HFpEF. We hypothesized that unique obesity-inflammation HFpEF phenotypes exist and are associated with differences in clinical features, fibrosis biomarkers, and functional performance. METHODS: Patients (n=301) from 3 HFpEF clinical trials were studied. Unsupervised machine learning (hierarchical clustering) with obese status and 13 inflammatory biomarkers as input variables was performed. Associations of clusters with HFpEF severity and fibrosis biomarkers (PIIINP [procollagen III N-terminal peptide], CITP [C-telopeptide for type I collagen], IGFBP7 [insulin-like growth factor-binding protein-7], and GAL-3 [galectin-3]) were assessed. RESULTS: Hierarchical clustering revealed 3 phenotypes: pan-inflammatory (n=129; 64% obese), noninflammatory (n=83; 55% obese), and obese high CRP (C-reactive protein; n=89; 98% obese). The pan-inflammatory phenotype had more comorbidities and heart failure hospitalizations; higher left atrial volume, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and fibrosis biomarkers; and lower glomerular filtration rate, peak oxygen consumption, 6-minute walk distance, and active hours/day (P<0.05 for all). The noninflammatory phenotype had the most favorable values for all measures. The obese high CRP phenotype resembled the noninflammatory phenotype except for isolated elevation of CRP and lower functional performance. Hierarchical cluster assignment was independent of CRP genotype combinations that alter CRP levels and more biologically plausible than other clustering approaches. Multiple traditional analytic techniques confirmed and extended the hierarchical clustering findings. CONCLUSIONS: Unique obesity-inflammation phenotypes exist in HFpEF and are associated with differences in comorbidity burden, HFpEF severity, and fibrosis. These data support comorbidity-driven microvascular inflammation as a pathophysiologic mechanism for many but not all HFpEF patients.