Assessment of provider-perceived barriers to clinical use of pharmacogenomics during participation in an institutional implementation study.

OBJECTIVE: The objective of this study was to study provider attitudes of and perceived barriers to the clinical use of pharmacogenomics before and during participation in an implementation program. PARTICIPANTS AND METHODS: From 2012 to 2017, providers were recruited. After completing semistructured interviews (SSIs) about pharmacogenomics, providers received training on and access to a clinical decision support tool housing patient-specific pharmacogenomic results. Thematic analysis of SSI was conducted (inter-rater reliability κ≥0.75). Providers also completed surveys before and during study participation, and provider-perceived barriers to pharmacogenomic implementation were analyzed. RESULTS: Seven themes emerged from the SSI (listed from most frequent to least): decision-making, concerns with pharmacogenomic adoption, outcome expectancy, provider knowledge of pharmacogenomics, patient attitudes, individualized treatment, and provider interest in pharmacogenomics. Although there was prestudy enthusiasm among all providers, concerns with clinical utility, time, results accession, and knowledge of pharmacogenomics were frequently stated at baseline. Despite this, adoption of pharmacogenomics was robust, as patient-specific results were accessed at 64% of visits, and medication changes were influenced by provided pharmacogenomic information 42% of the time. Providers reported they had enough time to evaluate the information and the results were easily understood on 74 and 98% of surveys, respectively. Nevertheless, providers consistently felt there was insufficient pharmacogenomic information for most drugs they prescribed and clear guidelines for using pharmacogenomic information were lacking. CONCLUSION: Despite initial concerns about adequate time and knowledge for adoption, providers frequently utilized pharmacogenomic results. Provider-perceived barriers to wider use included lack of clear guidelines and evidence for most drugs, highlighting important considerations for the field of pharmacogenomics.

Patient-provider communications about pharmacogenomic results increase patient recall of medication changes.

Effective doctor-patient communication is critical for disease management, especially when considering genetic information. We studied patient-provider communications after implementing a point-of-care pharmacogenomic results delivery system to understand whether pharmacogenomic results are discussed and whether medication recall is impacted. Outpatients undergoing preemptive pharmacogenomic testing (cases), non-genotyped controls, and study providers were surveyed from October 2012-May 2017. Patient responses were compared between visits where pharmacogenomic results guided prescribing versus visits where pharmacogenomics did not guide prescribing. Provider knowledge of pharmacogenomics, before and during study participation, was also analyzed. Both providers and case patients frequently reported discussions of genetic results after visits where pharmacogenomic information guided prescribing. Importantly, medication changes from visits where pharmacogenomics influenced prescribing were more often recalled than non-pharmacogenomic guided medication changes (OR = 3.3 [1.6-6.7], p = 0.001). Case patients who had separate visits where pharmacogenomics did and did not, respectively, influence prescribing more often remembered medication changes from visits where genomic-based guidance was used (OR = 3.4 [1.2-9.3], p = 0.02). Providers also displayed dramatic increases in personal genomic understanding through program participation (94% felt at least somewhat informed about pharmacogenomics post-participation, compared to 61% at baseline, p = 0.04). Using genomic information during prescribing increases patient-provider communications, patient medication recall, and provider understanding of genomics, important ancillary benefits to clinical use of pharmacogenomics.

The Evolution from Hypertension to Heart Failure.

Hypertensive heart disease includes the development of diastolic dysfunction, left ventricular hypertrophy, and heart failure with preserved and reduced ejection fraction. The development of heart failure can occur because of complications of ischemic heart disease or from progression of diastolic dysfunction to heart failure with preserved ejection fraction degenerating to a dilated heart with systolic dysfunction or heart failure with reduced ejection fraction. Hypertension clinical trials have shown that the treatment of hypertension can prevent the development of heart failure. In addition, lifestyle modification with exercise and weight loss can improve diastolic function and reduce the risk for heart failure.

Adoption of a clinical pharmacogenomics implementation program during outpatient care--initial results of the University of Chicago "1,200 Patients Project".

Pharmacogenomic testing is viewed as an integral part of precision medicine. To achieve this, we originated The 1,200 Patients Project which offers broad, preemptive pharmacogenomic testing to patients at our institution. We analyzed enrollment, genotype, and encounter-level data from the first year of implementation to assess utility of providing pharmacogenomic results. Results were delivered via a genomic prescribing system (GPS) in the form of traffic lights: green (favorable), yellow (caution), and red (high risk). Additional supporting information was provided as a virtual pharmacogenomic consult, including citation to relevant publications. Currently, 812 patients have participated, representing 90% of those approached; 608 have been successfully genotyped across a custom array. A total of 268 clinic encounters have occurred at which results were accessible via the GPS. At 86% of visits, physicians accessed the GPS, receiving 367 result signals for medications patients were taking: 57% green lights, 41% yellow lights, and 1.4% red lights. Physician click frequencies to obtain clinical details about alerts varied according to color severity (100% of red were clicked, 72% yellow, 20% green). For 85% of visits, clinical pharmacogenomic information was available for at least one drug the patient was taking, suggesting relevance of the delivered information. We successfully implemented an individualized health care model of preemptive pharmacogenomic testing, delivering results along with pharmacogenomic decision support. Patient interest was robust, physician adoption of information was high, and results were routinely utilized. Ongoing examination of a larger number of clinic encounters and inclusion of more physicians and patients is warranted.

Bleeding risk prediction models in atrial fibrillation.

Novel, nonvitamin K antagonist oral anticoagulants (OACs) have demonstrated similar or superior efficacy to warfarin for ischemic stroke prevention in patients with atrial fibrillation (AF). As the prevalence of AF rises in a growing elderly population, these agents are becoming central to the routine practice of clinicians caring for these patients. Though the benefits are clear, the decision to treat the elderly patient with AF with long-term oral OACs is often a dilemma for the clinician mindful of the risk of major bleeding. Several bleeding risk prediction models have been created to help the clinician identify patients for whom the risk of bleeding is high, and would potentially outweigh the benefits of OAC therapy. In this review, we discuss the features of 8 bleeding risk prediction models, including the recently described HEMORR2HAGES, HAS-BLED, and ATRIA models, and approaches to assessing bleeding risk in clinical practice.

The Bucksbaum Institute for Clinical Excellence and the Doctor-Patient Relationship: Origins, Programs, and Future Directions.

The Bucksbaum Institute for Clinical Excellence at the University of Chicago was established in 2011 with the mission to improve patient care, strengthen the doctor-patient relationship, enhance communication and decision making in health care, and reduce health care disparities. The Bucksbaum Institute supports the development and activities of medical students, junior faculty, and senior clinicians who devote themselves to improving doctor-patient communication and clinical decision making. The institute seeks to enhance the skills of physicians as advisers, counselors, and navigators to help patients make informed decisions when facing complex treatment choices. To achieve its mission, the institute recognizes and supports the activities of physicians who excel in clinical care, supports an array of educational programs, and funds research into the doctor-patient relationship. As the Bucksbaum Institute enters a second decade, its focus will begin to extend beyond the University of Chicago, leveraging alumni and other relationships to improve patient care everywhere.

Lipid effects of antihypertensive medications.

Thiazide diuretics and beta-blockers are first-line therapies for hypertension unless there are compelling indications for other drug classes. Diuretics and beta-blockers, however, may worsen dyslipidemia and glucose tolerance whereas antihypertensive agents in other drug classes may have neutral or beneficial effects. Initial clinical trials of antihypertensive regimens suggested that blood pressure lowering was the most important aspect of therapy and that the adverse effects on lipids and glucose tolerance did not impact clinical outcomes. Newer trials, however, question this finding and implicate these pleotropic effects as contributing to the results of the trials. Patients with cardiometabolic risk factors may have compelling indications for agents that inhibit the renin-angiotensin-aldosterone system, relegating diuretics and beta-blockers to third-line therapy.

ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: American College of Cardiology Foundation Appropriate Use Criteria Task Force Society for Cardiovascular Angiography and Interventions American Association for Thoracic Surgery American Heart Association, American Society of Echocardiography American Society of Nuclear Cardiology Heart Failure Society of America Heart Rhythm Society, Society of Critical Care Medicine Society of Cardiovascular Computed Tomography Society for Cardiovascular Magnetic Resonance Society of Thoracic Surgeons.

The American College of Cardiology Foundation, in collaboration with the Society for Cardiovascular Angiography and Interventions and key specialty and subspecialty societies, conducted a review of common clinical scenarios where diagnostic catheterization is frequently considered. The indications (clinical scenarios) were derived from common applications or anticipated uses, as well as from current clinical practice guidelines and results of studies examining the implementation of noninvasive imaging appropriate use criteria. The 166 indications in this document were developed by a diverse writing group and scored by a separate independent technical panel on a scale of 1 to 9, to designate appropriate use (median 7 to 9), uncertain use (median 4 to 6), and inappropriate use (median 1 to 3). Diagnostic catheterization may include several different procedure components. The indications developed focused primarily on 2 aspects of diagnostic catheterization. Many indications focused on the performance of coronary angiography for the detection of coronary artery disease with other procedure components (e.g., hemodynamic measurements, ventriculography) at the discretion of the operator. The majority of the remaining indications focused on hemodynamic measurements to evaluate valvular heart disease, pulmonary hypertension, cardiomyopathy, and other conditions, with the use of coronary angiography at the discretion of the operator. Seventy-five indications were rated as appropriate, 49 were rated as uncertain, and 42 were rated as inappropriate. The appropriate use criteria for diagnostic catheterization have the potential to impact physician decision making, healthcare delivery, and reimbursement policy. Furthermore, recognition of uncertain clinical scenarios facilitates identification of areas that would benefit from future research. © 2012 Wiley Periodicals, Inc.

The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in multiple tissues, including the small intestine. The effect of PCSK9 inhibition on cholesterol absorption is not known. OBJECTIVES: Measure serum cholesterol absorption markers before and after initiation of PCSK9 inhibitors. METHODS: Single-center retrospective cohort of patients administered evolocumab and alirocumab between July 2015 and January 2017. Paired t tests were used to compare mean serum cholesterol marker concentrations, and ratios to total cholesterol, before and after PCSK9 inhibitor initiation. Analyses were repeated for those taking and not taking statins and taking or not taking ezetimibe at both initiation and follow-up, for each PCSK9 inhibitor, and based on follow-up time (<60, 60-120, and >120 days). RESULTS: There were 62 possible participants, 34 were excluded for lack of data or unknown PCSK9 inhibitor initiation date. Average follow-up was 92.5 days. Mean campesterol (before 3.14 µg/mL, 95% CI: 2.79-4.38 µg/mL; after 2.09 µg/mL, 95% CI: 1.87-2.31 µg/mL; P < .0001), sitosterol (before 2.46 µg/mL, 95% CI: 2.23-2.70 µg/mL; after 1.62 µg/mL, 95% CI: 1.48-1.75 µg/mL; P < .0001), and cholestanol (before 3.25 µg/mL, 95% CI: 3.04-3.47 µg/mL; after 2.08 µg/mL, 95% CI: 1.96-2.21 µg/mL; P < .0001) all significantly decreased at follow-up. There was no significant change in absorption marker to total cholesterol ratios. Findings were not influenced by statin or ezetimibe use or nonuse, which PCSK9 inhibitor was prescribed, or time to follow-up. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 inhibition was associated with decreased cholesterol absorption markers.

Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial.

BACKGROUND: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Diets and cardiovascular disease: an evidence-based assessment.

With rising obesity, despite low-fat diet recommendations, there is an increased interest in weight loss and alternative dietary approaches for cardiovascular health. Physicians must have an understanding of the literature to better counsel their patients about diets and cardiovascular disease. This review examines several dietary approaches to cardiovascular health and evaluates the available scientific evidence regarding these diets.

Implications of the metabolic syndrome: the new epidemic.

On the basis of traditional risk factors, a large number of individuals in the United States can be classified as at intermediate risk for the development of ischemic heart disease. The diagnosis of the metabolic syndrome can help determine whether patients at intermediate risk should be considered for more aggressive risk-factor reduction. The measurement of novel risk factors, such as inflammatory markers, can identify a group of patients at high intermediate risk. The Adult Treatment Panel of the National Cholesterol Education Program suggests considering a more aggressive low-density lipoprotein cholesterol treatment goal in this group of individuals. In addition, the presence of the metabolic syndrome is highly predictive of the development of diabetes mellitus. A treatment strategy focusing on aerobic exercise and weight loss can help delay or prevent the development of diabetes and can help reduce cardiovascular risk. For significant risk reduction to be achieved, treatment strategies must focus on therapy for all risk factors, including dyslipidemia, hypertension, and insulin resistance.

The effect of preoperative statin therapy on cardiovascular outcomes in patients undergoing infrainguinal vascular surgery.

BACKGROUND: Patients undergoing vascular surgery are at increased risk for perioperative cardiovascular (CV) complications. Our goal was to determine the effect of preoperative statin therapy on perioperative cardiac and vascular outcomes, and long-term survival in patients undergoing infrainguinal vascular bypass surgery. METHODS: We retrospectively reviewed consecutive infrainguinal vascular bypass surgeries on 446 patients performed between 1995-2001 at the University of Chicago Medical Center. Information was collected on preoperative statin and beta-blocker use, baseline characteristics, perioperative cardiac and major vascular complications, and length of stay (LOS). Long-term survival was assessed using the Social Security Death Index (SSDI). RESULTS: Thirty day perioperative complications included all-cause mortality (2.5%), CV mortality (1.8%), myocardial infarction (MI) (4.7%), stroke (1.1%), and major peripheral vascular complications (12.8%), and the composite of cardiac and vascular complications [combined CV complications] (17.9%). Statin therapy was associated with fewer combined CV complications (6.9% vs 20.1%, p=0.008), and a shorter LOS (6.4 vs 9.7 days, p=0.007). On multivariate logistic regression analysis, adjusting for significant baseline characteristics including beta-blocker use, statin therapy was independently associated fewer combined CV complications (odds ratio (OR) 0.36, 95% confidence interval (CI) 0.14-0.93, p=0.035) and a shorter LOS (OR 1.49, 95% CI 1.14-1.95, p=0.003). In a mean follow up period of 5.5 years, 215 deaths (48%) occurred. Statin therapy was independently associated with improved long-term survival (OR 0.52, 95% CI 0.32-0.84, p<0.004), after adjusting for significant baseline characteristics. CONCLUSION: Preoperative statin therapy is associated with fewer combined perioperative cardiac and major vascular complications, a shorter length of stay, and improved long-term survival in patients undergoing infrainguinal vascular bypass surgery.

Evidence for Clinical Implementation of Pharmacogenomics in Cardiac Drugs.

OBJECTIVE: To comprehensively assess the pharmacogenomic evidence of routinely used drugs for clinical utility. METHODS: Between January 2, 2011, and May 31, 2013, we assessed 71 drugs by identifying all drug/genetic variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methods, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation. RESULTS: Positive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%), representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were recommended for clinical implementation using AGREE II, with mean ± SD overall quality scores of 5.18±0.91 (of 7.0; range, 3.67-7.0). Drug guidelines had highest mean ± SD scores in AGREE II domain 1 (Scope) (91.9±6.1 of 100) and moderate but still robust mean ± SD scores in domain 3 (Rigor) (73.1±11.1), domain 4 (Clarity) (67.8±12.5), and domain 5 (Applicability) (65.8±10.0). Clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Seven of the 9 most commonly prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information. CONCLUSION: Considerable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted.

Beta-blockers for congestive heart failure.

The prognosis of patients with congestive heart failure (CHF) can be significantly improved with drug therapy targeted at the renin-angiotensin and adrenergic nervous system. beta-adrenergic blocking drugs, once contraindicated in CHF, have now been shown to improve survival in CHF.

Early intervention strategies to lower cardiovascular risk in early nephropathy: focus on dyslipidemia.

Patients with chronic kidney disease (CKD) are at high cardiovascular risk and we can consider them to have a risk equivalent to coronary heart disease, putting them into the high-risk category. A mixed dyslipidemia with high triglyceride levels; low high-density lipoprotein (HDL) levels; and small, dense low-density lipoprotein (LDL) particles is a common pattern in patients with CKD, contributing to their high cardiovascular disease (CVD) risk. A treatment strategy to reduce LDL cholesterol to the current high-risk category goals reduces risk similar to patients without CKD. Emerging evidence suggests that targeting non-HDL cholesterol can have the potential to bring about further CVD risk reduction. Non-HDL cholesterol should be a secondary target for all patients with CKD. Further studies are needed to determine the magnitude of the risk reduction we can expect to gain by targeting non-HDL cholesterol and the most effective way to treat this target.