The Impact of Body Weight and Renal Function on the Risk of Bleeding With Direct Oral Anticoagulants in Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke and direct oral anticoagulants (DOACs) are first-line agents for prevention. Gaps in the literature cause reluctance in prescribing DOACs for patients with renal dysfunction and/or extremes in body weight. OBJECTIVE: To evaluate the impact body weight and renal function have on major and clinically relevant nonmajor (CRNM) bleeding events and ischemic strokes in AF patients receiving a DOAC. METHODS: This retrospective cohort study included adults with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL) receiving a DOAC ≥12 months. The primary outcome was a composite of major and CRNM bleeding events. Secondary outcomes included ischemic stroke and risk factors for bleeding events. RESULTS: Of the 233 patients analyzed, 25 patients experienced a bleeding event. Patients who bled weighed 10 kg less (P = 0.043) than those who did not and had a higher HASBLED score (P = 0.003). Multivariate logistic regression identified weight (P = 0.048), serum creatinine (SCr; P = 0.027), and HASBLED score (P = 0.024) as the significant predictors for experiencing a bleed. Three patients experienced a stroke. CONCLUSION AND RELEVANCE: This study demonstrates an association between higher baseline SCr, elevated HASBLED score, and lower weight, with an increased risk of bleeding in patients with NVAF or AFL receiving a DOAC. These findings add to prescribing considerations when initiating DOACs. Closer monitoring is advised for patients with significant renal dysfunction and/or low body weight, even with renal dose adjustments.

Concomitant use of levofloxacin and fluconazole leading to possible torsades de pointes.

Prolongation of the corrected QT interval can lead to the deadly arrhythmia torsades de pointes. There are many risk factors for corrected QT prolongation, one being medication. The goal of this case report is to add to the limited literature surrounding the possibility of torsades de pointes when levofloxacin and fluconazole are used concomitantly. Additionally, provide guidance for patient factors that need to be assessed when prescribing the two drugs.

Outcomes of a Pharmacist-Managed Heart Failure Medication Titration Assistance Clinic.

BACKGROUND: National guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) and ß-blockers (BBs) at target doses for morbidity and mortality benefits in heart failure with reduced ejection fraction (HFrEF); regardless, titration of these therapies in practice remains suboptimal. We implemented an outpatient pharmacist-managed HFrEF medication titration assistance clinic (MTAC) at one institution to improve titration for general cardiology (GC) patients. OBJECTIVE: To evaluate MTAC impact by determining the proportion of patients on target or maximum tolerated ACE inhibitor/ARB and BB doses. METHODS: A retrospective chart review of adult patients with documented ejection fraction ≤40% managed in the MTAC or GC from 2011 to 2013 was conducted. HFrEF medication regimens were collected at initial visit and months 1, 2, 3, 6, 9, and 12 to assess titration. Target doses were defined per guideline or dose at which ejection fraction recovered during the study. Maximum tolerated doses were defined as the highest dose patients tolerated without physiological limitations. RESULTS: Of 148 patients, the MTAC managed 51 and GC managed 97. At baseline, 90% of MTAC versus 82% of GC patients were prescribed ACE inhibitors/ARBs and BBs. In the MTAC, 4% were at target or maximum tolerated doses compared with 32% of GC patients ( P < 0.001). At 12 months, 95% of patients in the MTAC and 87% in GC were prescribed ACE inhibitors/ARBs and BBs. Of those prescribed ACE inhibitors/ARBs and BBs, 64% in the MTAC versus 40% in GC reached target or maximum tolerated doses ( P = 0.01). CONCLUSIONS: The pharmacist-managed MTAC increased the proportion of patients on optimal HFrEF therapies and are a resource for GC patients.

Circulating Procollagen Type III N-Terminal Peptide and Mortality Risk in African Americans With Heart Failure.

BACKGROUND: Procollagen type III N-terminal peptide (PIIINP) is a biomarker of cardiac fibrosis that is associated with heart failure prognosis in whites. Its prognostic significance in African Americans is unknown. We sought to determine whether PIIINP is associated with outcomes in African Americans with heart failure. METHODS AND RESULTS: Blood was collected from 138 African Americans with heart failure for determining PIIINP and genetic ancestry, and patients were followed prospectively for death or hospitalization for heart failure. PIIINP was inversely correlated with West African ancestry (R(2) = 0.061; P = .010). PIIINP > 4.88 ng/mL was associated with all-cause mortality on univariate (hazard ratio [HR] 4.9, 95% confidence interval [CI] 2.2-11.0; P < .001) and multivariate (HR 5.8; 95% CI 1.9-17.3; P = .002) analyses over a median follow-up period of 3 years. We also observed an increased risk for the combined outcome of all-cause mortality or hospitalization for heart failure with PIIINP > 4.88 ng/mL on univariate (HR 2.6, 95% CI 1.6-5.0; P < .001) and multivariate (HR 2.4, 95% CI 1.2-4.7; P = .016) analyses. CONCLUSIONS: High circulating PIIINP is associated with poor outcomes in African Americans with chronic heart failure, suggesting that PIIINP may be useful in identifying African Americans who may benefit from additional therapy to combat fibrosis as a means of improving prognosis.

Automatic Errors: A Case Series on the Errors Inherent in Electronic Prescribing.

The adoption of electronic prescribing is on the rise, as it reduces medication errors compared to handwritten orders. The inadvertent dispensing of discontinued medications is a type of medication error that is less well described, but one that can lead to adverse events. Software for electronic prescriptions transmits orders for refills or new prescriptions, but not discontinuations, to the pharmacy. Medications that have been stopped are displayed only at the prescribing facility's electronic medical record (EMR). This report describes five cases in which the pharmacy dispensed electronically discontinued medications, two of which contributed to adverse outcomes.

Impact of Transcatheter Aortic Valve Implantation Among Patients With Co-existing Mild to Moderate Mitral Regurgitation.

A subset of patients with severe aortic stenosis (AS) who are who underwent transcatheter aortic valve implantation (TAVI) also has mitral regurgitation (MR). Clinical outcomes in these patients with combined MR and AS have varied. The purpose of this study was to assess clinical outcomes and echocardiographic outcomes after TAVI in patients with preprocedural MR. A retrospective chart review from March 2018 to June 2020 identified all TAVI patients. Patients were assigned an MR class of mild, moderate, or severe based upon pre-TAVI transthoracic echocardiogram (TTE). Patients were excluded if they were discharged from the hospital and did not have a 6-month follow-up after TAVI. Clinical outcomes at 6 months included all-cause mortality, major adverse cardiovascular events, clinically significant bleeding, changes in ejection fraction (EF) category, and changes in MR severity. Of 118 included patients (age 76 ± 10 years, 79% male, 46% White), 33% had MR, with 26% being mild and 7% moderate MR. Before TAVI, AS + MR patients were more likely to have a reduced EF (<50%) by category compared with those with AS only (33.3% vs 8.8%, p = 0.01) but were more likely to show an increase in EF by category after TAVI (19.4% vs 5.5%, p = 0.039). No significant differences were observed between the 2 groups in terms of all-cause mortality (12.8 vs 5.1%, p = 0.14), major adverse cardiovascular events (17.9 vs 8.9%, p = 0.15), or clinically significant bleeding (10.3 vs 6.3%, p = 0.45). Patients with AS and co-existing MR experienced similar clinical outcomes at 6 months to those with AS only after TAVI. They were more likely to show increases in EF category 6 months after valve implantation. Our results support the conclusion that in addition to treating the aortic valve, TAVI also potentially benefits left ventricular function in the setting of mild or moderate MR.

Flexible diuretic titration in chronic heart failure: where is the evidence?

BACKGROUND: Several sets of heart failure (HF) consensus/guideline statements support the use of a flexible diuretic dosing regimen for HF outpatient management of fluid overload-related signs and symptoms. However, despite the widespread acceptance of such an approach, the evidence supporting the effectiveness of this approach in improving clinical outcomes is unknown. The primary objective of this manuscript was to summarize and review the evidence supporting the use of a flexible diuretic regimen in the management of outpatient heart failure patients. METHODS AND RESULTS: A systematic review was performed, and 9 studies were identified relevant to the question of flexible diuretic titration in the setting of chronic heart failure. Among the 9 studies, 5 were randomized. Three of the randomized trials included flexible diuretic titration as part of a broader multifaceted disease management program, and only 2 were designed to specifically evaluate the sole contribution of flexible diuretic titration. Collectively, data from all of the studies reviewed supported the idea that flexible and individualized diuretic dosing is potentially associated with reduced emergency room visits, reduced rehospitalization, and improved quality of life in HF patients with reduced ejection fraction. CONCLUSIONS: To date, only 2 randomized clinical studies were identified that were designed to determine the effects of a flexible diuretic dosing regimen in outpatient HF patients with reduced ejection fraction. Data are lacking in HF patients with preserved ejection fraction. There is a critical need to test this strategy in well designed prospective randomized clinical trials.

Elderly Medication Adherence Intervention Using the My Interventional Drug-Eluting Stent Educational App: Multisite Randomized Feasibility Trial.

BACKGROUND: A lifesaving treatment for myocardial infarction is the placement of a stent in a closed or obstructed coronary artery. The largest modifiable risk factor after receiving a stent is medication adherence to Dual AntiPlatelet Therapy, a combination of P2Y12 inhibitors and aspirin. OBJECTIVE: This study aimed to determine the acceptability of a protocol and an intervention using the My Interventional Drug-Eluting Stent Educational App (MyIDEA) and to evaluate medication adherence using the proportion of days covered (PDC) and platelet activation tests in a multisite randomized controlled trial. METHODS: Potential participants who received a post percutaneous coronary intervention (PCI) procedure with a drug-eluting stent were approached. All patients older than 50 years and who spoke English were recruited. Participants were recruited, baseline demographics were collected, and the Hospital Anxiety and Depression Scale (HADS), Rapid Estimate of Adult Literacy in Medicine-Short Form, Burden-Benefit questionnaire, 36-Item Short Form Health Survey, and PCI knowledge questionnaire were administered. Block randomization was used to randomize participants to either usual care or MyIDEA supplementation. MyIDEA is a personalized educational intervention based on the Kolb experiential learning theory using patient narratives for education. During the visits, participants' blood was collected to measure platelet suppression from medication. During the second and third encounters, the Morisky medication adherence score and cardiology outcomes were measured. The study was conducted at the University of Illinois Hospital and John H Stroger Jr Cook County Hospital with appropriate ethical approvals. Platelet suppression was measured through aspirin reactive units and P2Y12 reactive units. Medication adherence was measured using the PDC. The analysis team was blinded to the participants' group membership. The primary outcome was a feasibility analysis of recruitment and retention. RESULTS: The mean age of participants was 60.4 years (SD 7.1); the majority of patients were black and non-Hispanic. The majority of patients' reading levels were seventh grade or above, and they were not very familiar with other electronic devices for information and communication. The number of control subjects was 21, and the number of participants in the interventional arm was 24. The interventional group was able to use MyIDEA in both the hospital and outpatient setting. However, there was no significant difference in platelet suppression or medication adherence between groups. There were also differences between the groups in terms of depression and anxiety, initially, as measured by HADS. No documented adverse event associated with the intervention was found. CONCLUSIONS: Elderly patients are willing to use tablet devices to be educated about health conditions. Additional studies are required to measure the effectiveness and determine the most suitable timing and location for patient education. TRIAL REGISTRATION: ClinicalTrials.gov NCT04439864; https://clinicaltrials.gov/ct2/show/NCT04439864.

Association of beta-blocker dose with serum procollagen concentrations and cardiac response to spironolactone in patients with heart failure.

STUDY OBJECTIVE: To determine whether beta-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. DESIGN: Prospective clinical study. SETTING: Two heart failure centers. PATIENTS: Eighty-eight spironolactone-naïve patients with heart failure who were taking beta-blockers. INTERVENTION: In a subset of 29 patients, spironolactone was started at 12.5 mg/day, with the dosage titrated to 25 mg/day if tolerated. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (> or = 50% of recommended target dose) of beta-blockers. Patients receiving low-dose beta-blockers had higher mean +/- SD PIIINP concentrations (6.6 +/- 3.5 vs 4.9 +/- 2.6 microg/L, p=0.03) and tended to have higher PINP concentrations (74.0 +/- 44.1 vs 57.1 +/- 28.6 microg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) beta-blocker groups. Low beta-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] -14.3 microg/L [-9.8 to -19.3 microg/L] vs -2.5 microg/L [5.9 to -9.8 microg/L], p=0.02) and PIIINP (-1.4 microg/L [-0.9 to -2.4 microg/L] vs 0.1 microg/L [0.9 to -1.3 microg/L], p=0.045) with spironolactone therapy than high beta-blocker doses. In addition, 100% of the patients in this subset taking low-dose beta-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. CONCLUSION: Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of beta-blocker dosages, at least in terms of its effects on cardiac remodeling.

Markers of cardiac collagen turnover are similar in patients with mild and more severe symptoms of heart failure.

Cardiac fibrosis plays an important role in the pathophysiology of heart failure. The authors sought to determine whether biomarkers of cardiac fibrosis for milder clinical degrees of heart failure are comparable to those of more advanced disease. Procollagen types I and III amino-terminal peptides (PINP and PIIINP) and type I collagen telopeptide (ICTP) were compared between aldosterone-antagonistnaive patients with heart failure and New York Heart Association class I or II (n=22/23) and class III or IV (n=42/3) symptoms. Median (interquartile) range concentrations of PINP (63.3 [44.2-88.8] vs 48.6 [37.8-74.9] microg/L), ICTP (7.0 [5.4-16.8] vs 6.5 [4.7-12.7] microg/L), and PIIINP (4.7 [3.2-7.0] vs 4.7 [2.9-7.3] microg/L) were comparable between patients with mild and moderate to severe disease, respectively. These data suggest that patients with mild heart failure may have similar degrees of cardiac fibrosis to patients with more severe disease and support the examination of antifibrotic therapy, including aldosterone antagonists, in milder degrees of heart failure.

Implementation of a New Clinic-Based, Pharmacist-Managed PCSK9 Inhibitor Consultation Service.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab were approved by the FDA in 2015. In anticipation of provider interest and a potential increase in referrals to the on-site specialty pharmacy, we created a pharmacist-managed consultation service. PROGRAM DESCRIPTION: The development of a clinic-based pharmacist-managed consultation service for the management of the PCSK9 inhibitor agents alirocumab and evolocumab is described. Key implementation steps included (a) creation of a pharmacy team and collaboration with cardiology; (b) completion of a needs assessment; (c) service creation; (d) collaboration with the on-site specialty pharmacy; (e) development of an electronic consult order and consult pool; (f) personnel training; and (g) service approval and marketing. The service development occurred over 9 months (July 2015-April 2016) and was implemented hospital-wide in May 2016. OBSERVATIONS: The University of Illinois Hospital and Health Sciences System PCSK9 inhibitor consultation service successfully integrated the benefits of a clinical review process, information technology capabilities of an electronic medical record system, and collaboration with the on-site specialty pharmacy to provide a comprehensive service that aimed to facilitate appropriate medication management from prescribing to patient administration and provide monitoring for this class of specialty medications. IMPLICATIONS/RECOMMENDATIONS: The PCSK9 pharmacist-managed consultation service provides a method for complex therapies to be managed comprehensively through the collaboration of ambulatory care clinics and outpatient specialty pharmacies. DISCLOSURES: No outside funding supported this study. Groo reports speaker bureau fees from Pfizer and Bristol-Myers Squibb. The other authors have nothing to disclose. All the authors contributed to study concept and design. Atande took the lead in data collection, and data interpretation was performed by Groo and Atanda. The manuscript was written by Atanda and revised by all the authors.

Racial differences in potassium response to spironolactone in heart failure.

Evidence of racial differences in aldosterone concentrations and K+ disposition suggests that response to aldosterone antagonism might vary by race. The authors sought to determine whether K+ response to spironolactone differs between African Americans and Caucasians with heart failure. Heart failure patients of African-American (n = 34) or Caucasian (n = 17) race were started on spironolactone 12.5 mg/d, with up-titration as tolerated. Laboratory values and drug therapy were similar between racial groups at baseline. Spironolactone was titrated to a median dose of 25 mg/d in both groups. Neither concomitant medications nor serum creatinine changed significantly in either group during spironolactone dose titration. Median serum K+ concentrations increased by 0.5 mEq/L (range, -0.7 to 1.6 mEq/L) in Caucasians, but only 0.1 mEq/L (range, -0.8 to 0.9 mEq/L) in African Americans; p < 0.01. These data suggest that African Americans with heart failure may be less responsive to the renal effects of spironolactone.

Patient-Centered Tablet Application for Improving Medication Adherence after a Drug-Eluting Stent.

BACKGROUND/AIMS: This study's objective was to evaluate a patient-centered educational electronic tablet application, "My Interventional Drug-Eluting Stent Educational App" (MyIDEA) to see if there was an increase in patient knowledge about dual antiplatelet therapy (DAPT) and medication possession ratio (MPR) compared to treatment as usual. METHODS: In a pilot project, 24 elderly (≥50 years old) research participants were recruited after a drug-eluting stent. Eleven were randomized to the control arm and 13 to the interventional arm. All the participants completed psychological and knowledge questionnaires. Adherence was assessed through MPR, which was calculated at 3 months for all participants who were scheduled for second and third follow-up visits. RESULTS: Relative to control, the interventional group had a 10% average increase in MPR. As compared to the interventional group, more patients in the control group had poor adherence (<80% MPR). The psychological data revealed a single imbalance in anxiety between the control and interventional groups. On average, interventional participants spent 21 min using MyIDEA. DISCUSSION: Consumer health informatics has enabled us to engage patients with their health data using novel methods. Consumer health technology needs to focus more on patient knowledge and engagement to improve long-term health. MyIDEA takes a unique approach in targeting DAPT from the onset. CONCLUSION: MyIDEA leverages patient-centered information with clinical care and the electronic health record highlighting the patients' role as a team member in their own health care. The patients think critically about adverse events and how to solve issues before leaving the hospital.

My Interventional Drug-Eluting Stent Educational App (MyIDEA): Patient-Centered Design Methodology.

BACKGROUND: Patient adherence to medication regimens is critical in most chronic disease treatment plans. This study uses a patient-centered tablet app, "My Interventional Drug-Eluting Stent Educational App (MyIDEA)." This is an educational program designed to improve patient medication adherence. OBJECTIVE: Our goal is to describe the design, methodology, limitations, and results of the MyIDEA tablet app. We created a mobile technology-based patient education app to improve dual antiplatelet therapy adherence in patients who underwent a percutaneous coronary intervention and received a drug-eluting stent. METHODS: Patient advisers were involved in the development process of MyIDEA from the initial wireframe to the final launch of the product. The program was restructured and redesigned based on the patient advisers' suggestions as well as those from multidisciplinary team members. To accommodate those with low health literacy, we modified the language and employed attractive color schemes to improve ease of use. We assumed that the target patient population may have little to no experience with electronic tablets, and therefore, we designed the interface to be as intuitive as possible. RESULTS: The MyIDEA app has been successfully deployed to a low-health-literate elderly patient population in the hospital setting. A total of 6 patients have interacted with MyIDEA for an average of 17.6 minutes/session. CONCLUSIONS: Including patient advisers in the early phases of a mobile patient education development process is critical. A number of changes in text order, language, and color schemes occurred to improve ease of use. The MyIDEA program has been successfully deployed to a low-health-literate elderly patient population. Leveraging patient advisers throughout the development process helps to ensure implementation success.

Racial differences in patients' potassium concentrations during spironolactone therapy for heart failure.

STUDY OBJECTIVE: To determine whether the effects of spironolactone on potassium homeostasis vary by race by comparing serum potassium concentrations and potassium supplement use in African-American and Caucasian patients receiving spironolactone for heart failure. DESIGN: Retrospective medical record review. SETTING: Two heart failure centers. PATIENTS: Fifty African-American and 67 Caucasian patients with heart failure who were receiving a stable dosage of spironolactone in addition to standard heart failure therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. MEASUREMENTS AND MAIN RESULTS: Medical records of eligible patients were reviewed by pharmacists and physicians who specialize in heart failure management. No significant differences were observed in diuretic therapy or renal function between racial groups; however, African-Americans were receiving higher doses of ACE inhibitors. African-Americans had lower serum potassium concentrations (4.2 +/- 0.4 vs 4.5 +/- 0.5 mEq/L, p<0.01) and a higher prevalence of potassium supplementation (48% vs 15%, p<0.01). In a subset of patients, spironolactone therapy was associated with a 2-fold greater increase in serum potassium concentration and a 3-fold greater reduction in potassium supplement use among Caucasians than African-Americans. CONCLUSION: Our findings suggest that a large percentage of patients with heart failure, particularly African-Americans, still require potassium supplementation despite treatment with spironolactone and standard vasodilator therapy.

Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure.

STUDY OBJECTIVES: To compare the frequency of achieving a therapeutic serum digoxin concentration (SDC), defined as 0.5-0.9 ng/ml, by using a simplified nomogram to individualize digoxin dosing with standard dosing practices in patients with heart failure, and to characterize the relationship between genetic polymorphisms of the ABCB1 gene and SDC. DESIGN: Prospective study with a historical control group. SETTING: Outpatient care center of an urban academic medical center. PATIENTS: A total of 131 adults with heart failure due to left ventricular dysfunction who were treated with digoxin. INTERVENTION: Digoxin doses were determined either by the dosing nomogram (65 patients) or standard care (SC; 66 patients) by using historical controls who were randomly selected from a list of SDCs obtained from laboratory records and who had their digoxin doses determined by standard dosing practices. MEASUREMENTS AND MAIN RESULTS: The primary end point was the proportion of patients achieving a steady-state SDC of 0.5-0.9 ng/ml; secondary end points were mean SDC and proportion of patients achieving a steady-state SDC lower than 1.0 ng/ml. Postdistributive steady-state SDCs were measured 2-4 weeks after digoxin dosage adjustment or initiation. Therapeutic SDCs were achieved with similar frequency in both groups (38.7% in the nomogram group vs 34.5% in the SC group, p=0.65); however, more patients in the nomogram group had SDCs lower than 1.0 ng/ml than in the SC group (85.0% vs 44.9%, p<0.001). Mean daily digoxin doses were lower in the nomogram group (149 ± 67 µg vs 177 ± 74 µg, p=0.02), resulting in lower mean SDCs compared with those in the SC group (0.52 ± 0.30 ng/ml vs 1.12 ± 0.58 ng/ml, p<0.001). Patients in the pharmacogenetic substudy provided blood samples for genotyping of three common ABCB1 single nucleotide polymorphisms: C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642). SDCs were not significantly associated with ABCB1 genotypes. CONCLUSION: Our simplified digoxin dosing nomogram resulted in lower SDCs compared with standard dosing practices but achieved therapeutic SDCs with similar frequency. A greater proportion of patients dosed according to our nomogram had SDCs lower than 1.0 ng/ml, consistent with consensus guidelines. Genetic polymorphisms of the ABCB1 gene were not associated with SDC.

Association of aldosterone synthase polymorphism (CYP11B2 -344T>C) and genetic ancestry with atrial fibrillation and serum aldosterone in African Americans with heart failure.

The objective of this study was to examine the extent to which aldosterone synthase genotype (CYP11B2) and genetic ancestry correlate with atrial fibrillation (AF) and serum aldosterone in African Americans with heart failure. Clinical data, echocardiographic measurements, and a genetic sample for determination of CYP11B2 -344T>C (rs1799998) genotype and genetic ancestry were collected from 194 self-reported African Americans with chronic, ambulatory heart failure. Genetic ancestry was determined using 105 autosomal ancestry informative markers. In a sub-set of patients (n = 126), serum was also collected for determination of circulating aldosterone. The CYP11B2 -344C allele frequency was 18% among the study population, and 19% of patients had AF. Multiple logistic regression revealed that the CYP11B2 -344CC genotype was a significant independent predictor of AF (OR 12.7, 95% CI 1.60-98.4, p = 0.0150, empirical p = 0.011) while holding multiple clinical factors, left atrial size, and percent European ancestry constant. Serum aldosterone was significantly higher among patients with AF (p = 0.036), whereas increased West African ancestry was inversely correlated with serum aldosterone (r = -0.19, p = 0.037). The CYP11B2 -344CC genotype was also overrepresented among patients with extreme aldosterone elevation (≥90th percentile, p = 0.0145). In this cohort of African Americans with chronic ambulatory heart failure, the CYP11B2 -344T>C genotype was a significant independent predictor of AF while holding clinical, echocardiographic predictors, and genetic ancestry constant. In addition, increased West African ancestry was associated with decreased serum aldosterone levels, potentially providing an explanation for the lower risk for AF observed among African Americans.

Association of aldosterone concentration and mineralocorticoid receptor genotype with potassium response to spironolactone in patients with heart failure.

STUDY OBJECTIVE: To identify patient-specific factors associated with spironolactone-induced potassium level elevation in patients with heart failure. DESIGN: Prospective cohort study. SETTING: Two adult heart failure clinics. PATIENTS: Sixty-two adult (mean +/- SD age 54 +/- 16 yrs) aldosterone antagonist-naïve patients with heart failure. INTERVENTION: Patients received spironolactone 12.5 mg/day, titrated to 25 mg/day if tolerated. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at baseline, 1 week after spironolactone initiation, and 1 week after spironolactone dose titration for assessment of baseline aldosterone level, serum chemistry, and angiotensinogen (AGT) c.-6G>A and p.M268T and mineralocorticoid receptor (NR3C2) c.215C>G and p.I180V genotypes. Patient characteristics, laboratory values, and genotypes were compared between those whose potassium levels increased by more than 0.5 mEq/L (15 patients) and those with lower potassium level elevations (47 patients) after spironolactone initiation and dose titration. Patients with a greater potassium level elevation had a higher mean +/- SD aldosterone concentration (178 +/- 92 vs 102 +/- 57 pg/ml, p=0.007) and NR3C2 215G allele frequency (50% vs 22%, p<0.01). Aldosterone concentrations positively correlated with diuretic dose (r=0.313, p=0.014) and negatively correlated with serum potassium level (r= -0.319, p=0.012). On regression analysis, factors predictive of potassium level increases greater than 0.5 mEq/L with spironolactone were aldosterone level greater than 150 pg/ml (odds ratio [OR] 30, 95% confidence interval [CI] 3.2-287] and NR3C2 215G carrier status (OR 17, 95% CI 1.6-167). CONCLUSION: Our data suggest that potassium should be monitored with particular caution when spironolactone is started in patients with heart failure who have evidence of elevated aldosterone levels, such as high diuretic requirements, or the NR3C2 215G allele.