Development of a comprehensive cardiovascular disease genetic risk assessment test.

Background: Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden. Methods: We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals. Results: The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed ~6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, ~1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min. Conclusions: A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives.

National Landscape of Hospitalizations in Patients with Left Ventricular Assist Device. Insights from the National Readmission Database 2010-2015.

The number of patients with left ventricular assist devices (LVAD) has increased over the years and it is important to identify the etiologies for hospital admission, as well as the costs, length of stay and in-hospital complications in this patient group. Using the National Readmission Database from 2010 to 2015, we identified patients with a history of LVAD placement using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code V43.21. We aimed to identify the etiologies for hospital admission, patient characteristics, and in-hospital outcomes. We identified a total of 15,996 patients with an LVAD, the mean age was 58 years and 76% were males. The most common cause of hospital readmission after LVAD was heart failure (HF, 13%), followed by gastrointestinal (GI) bleed (11.8%), device complication (11.5%), and ventricular tachycardia/fibrillation (4.2%). The median length of stay was 6 days (3-11 days) and the median hospital costs was $12,723 USD. The in-hospital mortality was 3.9%, blood transfusion was required in 26.8% of patients, 20.5% had acute kidney injury, 2.8% required hemodialysis, and 6.2% of patients underwent heart transplantation. Interestingly, the most common cause of readmission was the same as the diagnosis for the preceding admission. One in every four LVAD patients experiences a readmission within 30 days of a prior admission, most commonly due to HF and GI bleeding. Interventions to reduce HF readmissions, such as speed optimization, may be one means of improving LVAD outcomes and resource utilization.

Performance of the Meta-Analysis Global Group in Chronic Heart Failure Score in Black Patients Compared With Whites.

BACKGROUND: Risk stratification is critical in heart failure (HF) and the Meta-Analysis Global Group in Chronic HF (MAGGIC) score is a validated tool derived from ~40,000 patients. However, few of these patients self-identified as black, raising uncertainty regarding performance in blacks with HF. METHODS AND RESULTS: This study analyzed a racially diverse group of 4046 patients (1646 black and 2400 white) from a single center from 2007 to 2015. Baseline characteristics were collected to tabulate MAGGIC score and test its discrimination and calibration within race groups. The primary end point was all-cause mortality. Death was detected using system records and the social security death master file. Discrimination was tested using Cox models of MAGGIC score stratified by race, and combined analysis including MAGGIC, race, and MAGGIC×race. Calibration was assessed using linear regression models and plots of observed versus predicted data. Overall, 901 (21%) patients died during 1-year follow-up. MAGGIC score discrimination was similar in both race groups in terms of C statistic (0.707±0.027 versus 0.725±0.014, for black versus white; P=0.556) and the hazard ratio (HR) per MAGGIC point was 1.12 in black patients (95% CI, 1.10-1.14) and 1.13 in white patients (95% CI, 1.12-1.14). Race was a significant correlate of survival, with better survival in black patients compared with white (HR, 0.66; 95% CI, 0.56-0.78), but the interaction of MAGGIC×race was not significant (ß=-0.013; P=0.16), and adding race to the model did not improve discrimination (C statistic for MAGGIC versus MAGGIC+race, 0.721 versus 0.722; P=0.79). In calibration testing, the slope was not significantly different from 1 in either group, but the groups differed from each other, and it was closer to unity among black patients (0.94 versus 1.4; P=0.004). CONCLUSIONS: These data support the use of the MAGGIC score to risk stratify black patients with HF.

Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope-Dependent Advanced Heart Failure Patients: Insights From the ROADMAP Study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients).

BACKGROUND: Timing of left ventricular assist device (LVAD) implantation in advanced heart failure patients not on inotropes is unclear. Relevant prediction models exist (SHFM [Seattle Heart Failure Model] and HMRS [HeartMate II Risk Score]), but use in this group is not established. METHODS AND RESULTS: ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) is a prospective, multicenter, nonrandomized study of 200 advanced heart failure patients not on inotropes who met indications for LVAD implantation, comparing the effectiveness of HeartMate II support versus optimal medical management. We compared SHFM-predicted versus observed survival (overall survival and LVAD-free survival) in the optimal medical management arm (n=103) and HMRS-predicted versus observed survival in all LVAD patients (n=111) using Cox modeling, receiver-operator characteristic (ROC) curves, and calibration plots. In the optimal medical management cohort, the SHFM was a significant predictor of survival (hazard ratio=2.98; P<0.001; ROC area under the curve=0.71; P<0.001) but not LVAD-free survival (hazard ratio=1.41; P=0.097; ROC area under the curve=0.56; P=0.314). SHFM showed adequate calibration for survival but overestimated LVAD-free survival. In the LVAD cohort, the HMRS had marginal discrimination at 3 (Cox P=0.23; ROC area under the curve=0.71; P=0.026) and 12 months (Cox P=0.036; ROC area under the curve=0.62; P=0.122), but calibration was poor, underestimating survival across time and risk subgroups. CONCLUSIONS: In non-inotrope-dependent advanced heart failure patients receiving optimal medical management, the SHFM was predictive of overall survival but underestimated the risk of clinical worsening and LVAD implantation. Among LVAD patients, the HMRS had marginal discrimination and underestimated survival post-LVAD implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01452802.

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

Policies and events affecting prescription opioid use for non-cancer pain among an insured patient population.

BACKGROUND: Rising prescription opioid use and abuse have prompted widespread concern. However, to date there have been few rigorous investigations into the policies and events which may have contributed to these trends. OBJECTIVE: This study investigates trends in opioid use and related adverse events among individuals with non-cancer pain before and after implementation of major national policies. STUDY DESIGN: The study used a longitudinal prospective study design. The analysis was limited to adults (age = 18 years) without a recorded cancer diagnosis. Pharmacy claims were used to assess rates of prescription opioid use, the strength of opioids dispensed, the proportion using opioids chronically, and related adverse events. Time trend analysis was used to identify changes in these rates over time. The study was Institutional Review Board approved. SETTING: Study patients were members of a large, health maintenance organization in southeast Michigan, with longitudinal records of prescription opioid use. RESULTS: The analysis comprised 523,623 individuals and 1,066,700 opioid pharmacy fills from January 1, 1997, to December 31, 2011. Contemporaneous with the implementation of health organization accreditation criteria requiring assessment and treatment of pain in all patients beginning January 2001, we observed a consistent and unabated increase in the rate of opioid fills and the proportion of chronic use. A parallel increase in the annual rate of adverse events was also observed. Similarly, we observed a continuous rise in the average strength of opioid fills following January 2001 with the exception of a single drop in December 2010, which was attributable to the withdrawal of propoxyphene from the U.S. market. LIMITATIONS: This was an observational study and not a trial. Other long-term opioid-related benefits or harms, including functional status, quality of life, and substance use disorder, were not assessed. CONCLUSIONS: This study provides temporal evidence for a rise in prescription opioid use after implementation of health organization accreditation criteria requiring standardized management of all individuals with pain.

Ventricular assist devices: is destination therapy a viable alternative in the non-transplant candidate?

The topic of this article, stated a more familiar way, is whether left ventricular assist devices (LVADs) are ready for 'Primetime' as a therapeutic option in and of themselves. In order to provide an update and insight on this question, we briefly review from where the field has come, and in more detail describe its current state and where we are heading. We believe the short answer to this question is 'Yes', but like many things, a short answer is not adequate. Here we attempt to deliver a more comprehensive answer, providing some historical context, outlining the great achievements that have been made, as well as the many challenges that still remain before LVADs become a truly mainstream therapy.

Assessment of the heart failure pharmacotherapy of patients with continuous flow left-ventricular assist devices.

PURPOSE: The purpose of this project was to characterize the use of heart failure medications during the first year after left-ventricular assist device (LVAD) implantation. METHODS: All patients who received a HeartMate II at our institution between January 1, 2007, and August 1, 2009, and were followed by our multidisciplinary team for at least 6 months were eligible for inclusion. Use of heart failure medications, including dosages, was collected for each patient prior to LVAD implantation, at time of discharge, and at each subsequent monthly office visit for up to 1 year after implantation. The primary end point was the prescription rate for each medication class at discharge. Secondary end points included the use and dosage of these agents during follow up. RESULTS: A total of 28 patients were included (mean age = 50±11.5 years; sex 75% male; race 57.1% white; bridge-to-transplant rate 25%). There was a statistically significant decrease in use of digoxin (42.9% vs. 7.1%), spironolactone (50% vs. 17.9%), nitrates (39.3% vs. 7.1%), and milrinone (71.4% vs. 3.6%) postimplantation compared with baseline (p<0.05, for all comparisons). More than 50% of patients received vasodilators, beta-blockers, and hydralazine both preimplantation and postimplantation (p>0.05 for each class). Furthermore, more patients reached target doses of beta-blockers (0% vs. 28.6%; p=0.04) after LVAD implantation. CONCLUSION: Our pilot study shows consistent prescription of heart failure pharmacotherapy in LVAD patients at our institution, with more patients able to tolerate target doses of beta-blockers.

ACCF/AHA/HFSA 2011 survey results: current staffing profile of heart failure programs, including programs that perform heart transplant and mechanical circulatory support device implantation.

OBJECTIVES: There have been no published recommendations about staffing needs for a heart failure (HF) clinic or an office setting focused on heart transplant. The goal of this survey was to understand the current staffing environment of HF, transplant, and mechanical circulatory support device (MCSD) programs in the United States and abroad. This report identifies current staffing patterns but does not endorse a particular staffing model. METHODS: An online survey, jointly sponsored by the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and the Heart Failure Society of America (HFSA), was sent to the members of all 3 organizations who had identified themselves as interested in HF, heart transplant, or both, between March 12, 2009, and May 12, 2009. RESULTS: The overall response rate to the 1,823 e-mail surveys was 23%. There were 257 unique practices in the United States (81% of total sites) and 58 international sites (19%); approximately 30% of centers were in a cardiovascular group practice and 30% in a medical school hospital setting. The large majority of practices delivered HF care in both an inpatient and outpatient environment, and slightly more centers were implanting MCSDs (47%) than performing cardiac transplantation (39%). Most practices (43%) were small, with <4 staff members, or small- to medium-sized (34%), with 4 to 10 staff members, with only 23% being medium (11-20 staff) or large programs (>20 staff). On average, a U.S. HF practice cared for 1,641 outpatients annually. An average HF program with transplant performed 10 transplants. Although larger programs were able to perform more transplants and see more outpatient HF visits, their clinician staffing volume tended to double for approximately every 500 to 700 additional HF visits annually. The average staffing utilization was 2.65 physician full-time equivalents (FTEs), 2.21 nonphysician practitioner (nurse practitioner or physician assistant) FTEs, and 2.61 nurse coordinator FTEs annually. CONCLUSIONS: The HF patient population is growing in number in the United States and internationally, and the clinicians who provide the highly skilled and time-consuming care to this population are under intense scrutiny as a result of focused quality improvement initiatives and reduced financial resources. Staffing guidelines should be developed to ensure that an adequate number of qualified professionals are hired for a given practice volume. These survey results are an initial step in developing such standards.

Comparing methods for identifying patients with heart failure using electronic data sources.

BACKGROUND: Accurately identifying heart failure (HF) patients from administrative claims data is useful for both research and quality of care efforts. Yet, there are few comparisons of the various claims data criteria (also known as claims signatures) for identifying HF patients. We compared various HF claim signatures to assess their relative accuracy. METHODS: In this retrospective study, we identified 4174 patients who received care from a large health system in southeast Michigan and who had >or=1 HF encounter between January 1, 2004 and December 31, 2005. Four hundred patients were chosen at random and a detailed chart review was performed to assess which met the Framingham HF criteria. The sample was divided into 300 subjects for derivation and 100 subjects for validation. Sensitivity, specificity,, and area under the curve (AUC) were determined for the various claim signatures. The criteria with the highest AUC were retested in the validation set. RESULTS: Of the 400 patients sampled, 65% met Framingham HF criteria, and 56% had at least one B-type Natriuretic Peptide (BNP) measurement. There was substantial variation between claims signatures in terms of sensitivity (range 15%-77%) and specificity (range 69%-100%). The best performing criteria in the derivation set was if patients met any one of the following: >or=2 HF encounters, any hospital discharge diagnosis of HF, or a BNP >or=200 pg/ml. These criteria showed a sensitivity of 76%, specificity of 75%, and AUC of 0.754 for meeting the Framingham HF criteria. This claims signature performed similarly in the validation set. CONCLUSION: Claim signatures for HF vary greatly in their relative sensitivity and specificity. These findings may facilitate efforts to identify HF patients for research and quality improvement efforts.