Emily C. O’Brien

Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry

BACKGROUND Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. DESIGN The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. SUMMARY The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)

BACKGROUND Warfarin reduces thromboembolic risks in atrial fibrillation (AF), but therapeutic durability remains a concern. METHODS We used clinical data from ORBIT-AF, a nationwide outpatient AF registry conducted at 176 sites with follow-up data at 6 and 12 months, to examine longitudinal patterns of warfarin discontinuation. We estimated associations between patient and provider characteristics and report of any warfarin discontinuation using discrete time proportional odds models. RESULTS Of 10,132 AF patients enrolled in ORBIT-AF from June 2010 to August 2011, 6,110 (60.3%) were prescribed warfarin, had follow-up data, and were not switched to an alternative oral anticoagulant enrolled from June 2010 to August 2011. Over 1 year, 617 patients (10.1% of baseline warfarin users) discontinued warfarin therapy. Among incident warfarin users (starting therapy within 1 year of baseline survey), warfarin discontinuation rates rose to 17.1%. The most commonly reported reasons for warfarin discontinuation were physician preference (47.7%), patient refusal/preference (21.1%), bleeding event (20.2%), frequent falls/frailty (10.8%), high bleeding risk (9.8%), and patient inability to adhere to/monitor therapy (4.7%). In multivariable analysis, the factors most strongly associated with warfarin discontinuation were bleeding hospitalization during follow-up (odds ratio 10.91, 95% CI 7.91-15.03), prior catheter ablation (1.83, 1.37-2.45), noncardiovascular/nonbleeding hospitalization (1.77, 1.40-2.24), cardiovascular hospitalization (1.64, 1.33-2.03), and permanent AF (0.25, 0.17-0.36). CONCLUSIONS Discontinuation of warfarin is common among patients with AF, particularly among incident users. Warfarin is most commonly discontinued because of physician preference, patient refusal, and bleeding events.

Treatment Gaps in Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry

Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Patient-centered interventions to improve medication management and adherence: A qualitative review of research findings

OBJECTIVE Patient-centered approaches to improving medication adherence hold promise, but evidence of their effectiveness is unclear. This review reports the current state of scientific research around interventions to improve medication management through four patient-centered domains: shared decision-making, methods to enhance effective prescribing, systems for eliciting and acting on patient feedback about medication use and treatment goals, and medication-taking behavior. METHODS We reviewed literature on interventions that fell into these domains and were published between January 2007 and May 2013. Two reviewers abstracted information and categorized studies by intervention type. RESULTS We identified 60 studies, of which 40% focused on patient education. Other intervention types included augmented pharmacy services, decision aids, shared decision-making, and clinical review of patient adherence. Medication adherence was an outcome in most (70%) of the studies, although 50% also examined patient-centered outcomes. CONCLUSIONS We identified a large number of medication management interventions that incorporated patient-centered care and improved patient outcomes. We were unable to determine whether these interventions are more effective than traditional medication adherence interventions. PRACTICE IMPLICATIONS Additional research is needed to identify effective and feasible approaches to incorporate patient-centeredness into the medication management processes of the current health care system, if appropriate.

Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study

Objective To examine the association between warfarin treatment and longitudinal outcomes after ischemic stroke in patients with atrial fibrillation in community practice. Design Observational study. Setting Hospitals (n=1487) participating in the Get With The Guidelines (GWTG)-Stroke program in the United States, from 2009 to 2011. Participants 12 552 warfarin naive atrial fibrillation patients admitted to hospital for ischemic stroke and treated with warfarin compared with no oral anticoagulant at discharge, linked to Medicare claims for longitudinal outcomes. Main outcome measures Major adverse cardiovascular events (MACE) and home time, a patient centered outcomes measure defined as the total number of days free from institutional care after discharge. A propensity score inverse probability weighting method was used to account for all differences in observed characteristics between treatment groups. Results Among 12 552 survivors of stroke, 11 039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke. Conclusions Among ischemic stroke patients with atrial fibrillation, warfarin treatment was associated with improved long term clinical outcomes and more days at home. Clinical trial registration Clinical trials NCT02146274.

Association of Body Mass Index and Long-Term Outcomes in Older Patients With Non–ST-Segment–Elevation Myocardial Infarction

Background—Prior studies have found that obese patients have paradoxically lower in-hospital mortality after non–ST-segment–elevation myocardial infarction than their normal-weight counterparts, yet whether these associations persist long term is unknown. Methods and Results—We linked detailed clinical data for patients with non–ST-segment–elevation myocardial infarction aged ≥65 years in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) Registry to Medicare claims data to obtain longitudinal outcomes. Using height and weight measured on admission, patients were categorized into 6 body mass index (BMI [kilograms per meter squared]) groups. Multivariable Cox proportional hazards models were used to estimate the association between BMI and (1) all-cause mortality, (2) all-cause readmission, (3) cardiovascular readmission, and (4) noncardiovascular readmission for 3 years after hospital discharge. Among older patients with non–ST-segment–elevation myocardial infarction (n=34 465), 36.3% were overweight and 27.7% were obese. Obese patients were younger and more likely to have hypertension, diabetes mellitus, and dyslipidemia than normal or underweight patients. Relative to normal-weight patients, long-term mortality was lower for patients classified as overweight (BMI, 25.0–29.9), obese class I (BMI, 30.0–34.9), and obese class II (BMI, 35.0–39.9), but not obese class III (BMI ≥40.0). In contrast, 3-year all-cause and cardiovascular readmission were similar across BMI categories. Relative to normal-weight patients, noncardiovascular readmissions were similar for obese class I but higher for obese class II and obese class III. Conclusions—All-cause long-term mortality was generally lower for overweight and obese older patients after non–ST-segment–elevation myocardial infarction relative to those with normal weight. Longitudinal readmissions were similar or higher with increasing BMI.

Effect of the 2014 atrial fibrillation guideline revisions on the proportion of patients recommended for oral anticoagulation.

Effect of the 2014 Atrial Fibrillation Guideline Revisions on the Proportion of Patients Recommended for Oral Anticoagulation In 2014, the American Heart Association, American College of Cardiology, and Heart Rhythm Society published a revised guideline for atrial fibrillation (AF) treatment recommending use of a refined stroke risk score and revised threshold for oral anticoagulation (OAC) initiation.1 We assessed the potential effect of this new guideline by comparing the proportion of patients with AF recommended for OAC under the 2011 and 2014 guidelines.1,2

Good Clinical Practice Guidance and Pragmatic Clinical Trials Balancing the Best of Both Worlds

Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. Although the application of Good Clinical Practice principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, the growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials. The central tenets of Good Clinical Practice and pragmatic clinical trials represent potential tensions in trial design (stringent quality and highly efficient operations). In the present article, we highlight potential areas of discordance between Good Clinical Practice guidelines and the principles of pragmatic clinical trials and suggest strategies to streamline study conduct in an ethical manner to optimally perform clinical trials in the electronic age.

Incident Cardiovascular Disease Among Adults With Blood Pressure <140/90 mm Hg

Background: Data from before the 2000s indicate that the majority of incident cardiovascular disease (CVD) events occur among US adults with systolic and diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg. Over the past several decades, BP has declined and hypertension control has improved. Methods: We estimated the percentage of incident CVD events that occur at SBP/DBP <140/90 mm Hg in a pooled analysis of 3 contemporary US cohorts: the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), the MESA (Multi-Ethnic Study of Atherosclerosis), and the JHS (Jackson Heart Study) (n=31 856; REGARDS=21 208; MESA=6779; JHS=3869). Baseline study visits were conducted in 2003 to 2007 for REGARDS, 2000 to 2002 for MESA, and 2000 to 2004 for JHS. BP was measured by trained staff using standardized methods. Antihypertensive medication use was self-reported. The primary outcome was incident CVD, defined by the first occurrence of fatal or nonfatal stroke, nonfatal myocardial infarction, fatal coronary heart disease, or heart failure. Events were adjudicated in each study. Results: Over a mean follow-up of 7.7 years, 2584 participants had incident CVD events. Overall, 63.0% (95% confidence interval [CI], 54.9−71.1) of events occurred in participants with SBP/DBP <140/90 mm Hg; 58.4% (95% CI, 47.7−69.2) and 68.1% (95% CI, 60.1−76.0) among those taking and not taking antihypertensive medication, respectively. The majority of events occurred in participants with SBP/DBP <140/90 mm Hg among those <65 years of age (66.7%; 95% CI, 60.5−73.0) and ≥65 years of age (60.3%; 95% CI, 51.0−69.5), women (61.4%; 95% CI, 49.9−72.9) and men (63.8%; 95% CI, 58.4−69.1), and for whites (68.7%; 95% CI, 66.1−71.3), blacks (59.0%; 95% CI, 49.5−68.6), Hispanics (52.7%; 95% CI, 45.1−60.4), and Chinese-Americans (58.5%; 95% CI, 45.2−71.8). Among participants taking antihypertensive medication with SBP/DBP <140/90 mm Hg, 76.6% (95% CI, 75.8−77.5) were eligible for statin treatment, but only 33.2% (95% CI, 32.1−34.3) were taking one, and 19.5% (95% CI, 18.5−20.5) met the SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria and may benefit from a SBP target goal of 120 mm Hg. Conclusions: Although higher BP levels are associated with increased CVD risk, in the modern era, the majority of incident CVD events occur in US adults with SBP/DBP <140/90 mm Hg. While absolute risk and cost-effectiveness should be considered, additional CVD risk-reduction measures for adults with SBP/DBP <140/90 mm Hg at high risk for CVD may be warranted.

Depressive Symptoms and Risk of Cardiovascular Events in Blacks Findings From the Jackson Heart Study

Background—Most studies of depression and cardiovascular risk have been conducted in white populations. We investigated this association in a community-based cohort of blacks. Methods and Results—We used data from the Jackson Heart Study to investigate associations of baseline depressive symptoms between 2000 and 2004 with incident stroke and coronary heart disease (CHD) during 10 years. We used Kaplan–Meier estimates and Cox proportional hazards models to assess cardiovascular event risk using 3 exposure variables: any depressive symptoms (Center for Epidemiological Studies Depression score ≥16); none (score <16), minor (score 16 to <21), and major depression (score≥21); and Center for Epidemiological Studies Depression score per 1-SD increase. Models were adjusted for a stroke or CHD risk score and behavioral risk factors. Of 3309 participants with no stroke history, 738 (22.3%) had baseline depressive symptoms. A similar proportion with no previous CHD had baseline depressive symptoms (21.8%). The unadjusted 10-year risk of stroke was similar among participants with any compared with no depressive symptoms (3.7% versus 2.6%; P=0.12). Unadjusted CHD rates were higher among participants with depressive symptoms (5.6% versus 3.6%; P=0.03), and differences persisted after adjustment for clinical and behavioral risk factors but not after adjustment for coping strategies. In adjusted models comparing major versus no depressive symptoms, patients with major depressive symptoms had a 2-fold greater hazard of stroke (hazard ratio, 1.95; 95% confidence interval, 1.02–3.71; P=0.04). In continuous models, a 1-SD increase in Center for Epidemiological Studies Depression score was associated with a 30% increase in adjusted incident stroke risk (P=0.04). Similar associations were observed for incident CHD in models adjusted for clinical and behavioral risk factors, but associations were not significant after adjustment for coping strategies. Conclusions—In a community-based cohort of blacks, major depressive symptoms were associated with greater risks of incident stroke and CHD after adjustment for clinical and behavioral risk factors.