Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Pragmatic guidance for embedding pragmatic clinical trials in health plans: Large simple trials aren't so simple.

BACKGROUND: There are unique opportunities related to the design and conduct of pragmatic trials embedded in health insurance plans, which have longitudinal data on member/patient demographics, dates of coverage, and reimbursed medical care, including prescription drug dispensings, vaccine administrations, behavioral healthcare encounters, and some laboratory results. Such trials can be large and efficient, using these data to identify trial-eligible patients and to ascertain outcomes. METHODS: We use our experience primarily with the National Institutes of Health Pragmatic Trials Collaboratory Distributed Research Network, which comprises health plans that participate in the US Food & Drug Administration's Sentinel System, to describe lessons learned from the conduct and planning of embedded pragmatic trials. RESULTS: Information is available for research on more than 75 million people with commercial or Medicare Advantage health plans. We describe three studies that have used or plan to use the Network, as well as a single health plan study, from which we glean our lessons learned. CONCLUSIONS: Studies that are conducted in health plans provide much-needed evidence to drive clinically meaningful changes in care. However, there are many unique aspects of these trials that must be considered in the planning, implementation, and analytic phases. The type of trial best suited for studies embedded in health plans will be those that require large sample sizes, simple interventions that could be disseminated through health plans, and where data available to the health plan can be leveraged. These trials hold potential for substantial long-term impact on our ability to generate evidence to improve care and population health.

Melding regulatory, pharmaceutical industry, and U.S. payer perspectives on improving approaches to heterogeneity of treatment effect in research and practice.

Effective pursuit of the science and management of heterogeneity of treatment effect (HTE) relies on the mutual understanding of the perspectives of, and collaboration among, the various stakeholders in health care. In this article, we compare, contrast, and endeavor to find areas of alignment across the perspectives of three such stakeholders -regulators, the biopharmaceutical and device industry, and U.S. payers. First, we discuss how evidence of HTE is generated and could be improved upon. For pharmaceuticals, much of the initial research is conducted by the pharmaceutical industry, guided by basic science but also delimited by potential markets, regulatory approval requirements, trial size considerations, and payer expectations for evidence of value. Once a drug is marketed, further evidence can be generated via combining trial data, conducting meta-analysis, and analyzing real-world results through observational research designs; we explore how these efforts can benefit from cooperation across these stakeholders. Second, we discuss the equally important utilization of HTE evidence so that physicians and patients have access to and can benefit from the learnings from this research. Research findings must be translated into actionable information and guidelines that can be incorporated into everyday practice. Doing so requires interaction and collaboration among all involved, based on facilitated communication as well as further evaluation research. We provide examples of several cross-sectorial initiatives that are under way in this area. Finally, we explore some economic aspects of HTE research as part of the drug development, marketing, and treatment process. Understanding the economic incentives present is fundamental to aligning those incentives to improve the availability and utilization of HTE evidence. Clear understandings among regulators, pharma, and payers about high-value targets, methods to efficiently generate and communicate information, and value propositions can lead to "win-win" scenarios for patients, individual payers, the health care system overall, and the future of drug development in producing new medicines.

Lipid-lowering treatment among older patients with atherosclerotic cardiovascular disease.

BACKGROUND: The contemporary uptake of lipid-lowering therapies (LLT), including more intensive treatment with high-intensity statins and non-statin LLT, among U.S. older adults (≥75 years old) with ASCVD is unknown. METHODS: In this multicenter retrospective cohort study of a large geographically diverse sample of commercially insured U.S. older adults with ASCVD, we assessed treatment with LLT. Secondary measures included LDL-C above target ≥70 mg/dl, persistence and adherence to therapy. RESULTS: Treatment with statins, high-intensity statins, ezetimibe, and PCSK9 inhibitors was assessed in 194,503 older adults (49.9% female) with known ASCVD on January 31st, 2019. 49.3% of older adults with ASCVD were on any statin, with 16.6% receiving a high-intensity statin and 32.7% on low-or moderate-intensity statins. Treatment with ezetimibe (2.4%) or PCSK9 inhibitors (0.24%) was rare and 62.6% of the overall cohort had an LDL-C above target at ≥70 mg/dl. Patients on high-intensity statins were more frequently male, had a diagnosis of coronary artery disease, and were more frequently seen by a cardiologist compared with those on low-or moderate-intensity statins and untreated individuals (p < 0.0001). The majority of older adults on high-intensity statins remained on therapy at 12 months (91.9%) and 85.7% had ≥75% adherence to treatment. CONCLUSIONS: Less than half of eligible older adults with ASCVD are on statins and only a minority of patients are receiving more intensive lipid-lowering to improve outcomes.

The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus.

BACKGROUND: Few large-scale, real-world studies have assessed the relative associations of lipid fractions with diabetic microvascular events. The main objective of this study was to evaluate the association of the lipid profile components, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high density lipoprotein cholesterol (non-HDL-C) with microvascular complications (MVCs) in type 2 diabetes mellitus (T2DM) patients. METHODS: This observational cohort study queried the HealthCore Integrated Research Database (HIRDSM) for newly-diagnosed (Index Date) 18-64-year-old patients with diabetes mellitus between 01/01/2005-06/30/2010. Inclusion required ≥ 12 months pre-index continuous health plan eligibility and ≥ 1 pre-index lipid profile result. Patients with polycystic ovary syndrome and prior MVCs were excluded. Incident complications were defined as the earliest occurrence of diabetic retinopathy, peripheral neuropathy, and/or nephropathy post-index. Cox proportional models and Kaplan-Meier (KM) curves were used to evaluate associations among variables. RESULTS: Of the patients (N=72,267), 50.05% achieved HDL-C, 64.28% LDL-C, 59.82% TG, and 56.79% non-HDL-C American Diabetes Association goals at baseline. During follow-up (mean, 21.74 months), there were 5.21 microvascular events per 1,000 patient-months. A 1-mg/dL increase in HDL-C was associated with 1% decrease in any MVC risk (P< .0001), but for LDL-C, TG, and non-HDL-C, 1-mg/dL increase resulted in increases of 0.2% (P< .0001), 0.1% (P<0.001) and 0.3% (P<0.001) in MVC risk. Patients achieving HDL-C goals had a 11% lower risk of MVC versus non-achievers (RR 0.895, [95% CI, 0.852-0.941], P< .0001). Similarly, TG goal attainment was associated with a lowered risk for any MVC (RR 0.849, [95% CI, 0.808-0.892], P< .0001). Evaluation of KM survival curves demonstrated no significant difference in the risk of MVCs between patients achieving vs. not achieving LDL-C goals, but did demonstrate a difference in MVC risk between patients achieving vs. not achieving non-HDL-C goals. CONCLUSION: This study demonstrates significant independent associations among lipid fractions and risk for microangiopathy. These findings suggest that attaining established ADA goals for HDL-C, TG, and non-HDL-C may reduce risk for microvascular events among patients with diabetes.

Clinical and economic outcomes of the Cincinnati Pharmacy Coaching Program for diabetes and hypertension.

PURPOSE: Value-based insurance designs (VBID) have been developed by health insurance companies and used by employers to allocate health care resources appropriately and to lower patients' out-of-pocket costs for services related to chronic conditions. The purpose of this study was to evaluate the effect of the Cincinnati Pharmacy Coaching Program (CPCP) on clinical and economic outcomes. The CPCP is a VBID implemented by Anthem Blue Cross & Blue Shield in Ohio. It provided tailored pharmacist-based educational services and financial incentives to participants. METHODS: This was a quasi-experimental pre/post longitudinal study in which patients were identified as they enrolled in the CPCP between Jan. 1, 2008, and Dec. 31, 2009. Patients could participate in a Diabetes Coaching Program (DCP) or a Heart Healthy Coaching Program (HHCP). Control subjects were selected from patients who were invited but did not choose to participate. Control subjects were matched to intervention cohorts using propensity score matching. Clinical (blood pressure, lipid levels, and hemoglobin A1c) and economic (all-cause and disease-attributable) outcomes were evaluated using within-subject (pre-post) and between-subject comparison (intervention-control) design. RESULTS: A total of 607 patients were enrolled in intervention groups, and 557 control subjects were selected after matching. Significant reductions were found in blood pressure, lipid levels, and hemoglobin A1c after enrollment, and a significantly greater proportion of patients, compared with controls, achieved their clinical goals according to national guidelines in both programs. Hypertension-related cost trends were favorable for HHCP relative to the control cohort. Diabetes-related costs increased for all groups from pre- to post-index, largely driven by office visits and medication costs in the DCP and inpatient/ER visits in the control cohort. CONCLUSION: Results showed significant improvements in all diabetes- and hypertension-related clinical measures. This study shows the effect of a comprehensive VBID on the health of patients with chronic disease.

High-Intensity Statin Use Among Patients With Atherosclerosis in the U.S.

BACKGROUND: Preventive therapy among patients with established atherosclerotic cardiovascular disease (ASCVD) is generally underused. Whether new guideline recommendations and a focus on implementation have improved the use of high-intensity statins is unknown. OBJECTIVES: This study sought to evaluate the patterns and predictors of statin use among patients with ASCVD. METHODS: In this retrospective cohort study, pharmacy and medical claims data from a commercial health plan were queried for patients with established ASCVD between January 31, 2018, and January 31, 2019. Statin use on an index date of January 31, 2019, was evaluated, as was 12-month adherence and discontinuation. Multivariable logistic regression was used to determine independent associations with statin use of varying intensities. RESULTS: Of the 601,934 patients with established ASCVD, 41.7% were female, and the mean age was 67.5 ± 13.3 years. Overall, 22.5% of the cohort were on a high-intensity statin, 27.6% were on a low- or moderate-intensity statin, and 49.9% were not on any statin. In multivariable analysis, younger patients, female patients, and those with higher Charlson comorbidity score were less likely to be prescribed any statin. Among statin users, female patients, older patients, and those with peripheral artery disease were less likely to be on a high-intensity formulation, whereas a cardiology encounter in the prior year increased the odds. The majority of high-intensity stain users achieved high levels of adherence. CONCLUSIONS: Substantial underuse of statins persists in a large, insured, and contemporary cohort of patients with ASCVD from the United States. In particular, concerning gaps in appropriate statin use remain among younger patients, women, and those with noncoronary ASCVD.

Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose?

BACKGROUND: The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose. METHODS: Patients were ≥18 years of age from three US healthcare systems and exposed to an SGA for ≥45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference. RESULTS: Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile. CONCLUSIONS: In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.

Clopidogrel use and clinical events after drug-eluting stent implantation: findings from the HealthCore Integrated Research Database.

BACKGROUND: Relationships between long-term use and level of dual antiplatelet therapy and outcomes after drug-eluting stent implantation are not well established. METHODS: This is a retrospective cohort study of 9,256 patients receiving drug-eluting stents between January 2003 and August 2006. We classified patients according to tertiles of clopidogrel use during the 12 months after stent implantation. We used inverse probability weighting to account for differential selection into levels of clopidogrel use and logistic regression to estimate propensity scores for levels of clopidogrel use. We used Cox proportional hazards models to estimate effects of level of clopidogrel use on risk of bleeding events, death, and death or nonfatal myocardial infarction. RESULTS: There were 3,102 patients in the high-use group, 3,069 in the medium-use group, and 3,085 in the low-use group. Compared with the high-use group, risk of death or nonfatal myocardial infarction was greater in the medium-use group (hazard ratio [HR] 1.46, 95% CI 1.09-1.99, P = .01) and the low-use group (HR 1.59, 95% CI 1.18-2.14, P = .002). The risk of bleeding events was lower in the medium-use group (HR 0.84, 95% CI 0.71-0.98, P = .03) and the low-use group (HR 0.77, 95% CI 0.65-0.90, P = .002). CONCLUSIONS: Higher clopidogrel use 12 months after drug-eluting stent implantation was associated with a greater risk of subsequent bleeding events. Lower use was associated with a greater risk of death or nonfatal myocardial infarction.

Cardiovascular safety of ADHD medications: rationale for and design of an investigator-initiated observational study.

PURPOSE: To describe the design and rationale of an investigator-initiated observational study to examine the cardiovascular safety of the following commonly-used medications to treat attention deficit hyperactivity disorder (ADHD): amphetamines, methylphenidate, and atomoxetine. METHODS: We are conducting an observational cohort study using data from five large Medicaid programs and the HealthCore Integrated Research Database (HIRD(SM)), which is derived from administrative data from commercial health plans. Our primary outcomes of interest are (1) sudden death/ventricular arrhythmia, (2) stroke, (3) myocardial infarction, and (4) stroke or myocardial infarction as a composite outcome. These claims diagnoses have been previously validated in adults, and the positive predictive value in children will be examined as part of this study. Secondary outcomes are (1) all-cause death, (2) non-suicide death, and (3) non-accident death. All design decisions have been made to minimize bias toward the null. Based on our pilot data, we expect to have at least 90% power to detect a minimum detectable hazard ratio (HR) of 3.0 in children and adolescents who initiate an ADHD medication for each outcome of interest (except for MI, for which the expected minimum detectable HR is 7.9). The expected minimum detectable HR is 1.7 for each outcome for adult incident ADHD medication users. RESULTS: Forthcoming. CONCLUSIONS: Potential limitations to this study include a low expected event rate in children and adolescents, potentially incomplete ascertainment of outcomes, and potential confounding by unmeasured variables. Nevertheless, this study will provide important information about the cardiovascular safety of ADHD medications.

Epidemiologic study of aripiprazole use and the incidence of suicide events.

PURPOSE: Because second generation antipsychotics (SGA) might affect the risk of suicide, systematic assessment of suicide risk associated with SGA in the postmarketing setting is important and of interest to regulatory authorities. To fulfill a postmarketing request, our objective was to determine suicide event (attempted or completed) incidence in patients with schizophrenia or bipolar disorder, prescribed aripiprazole. METHODS: Using administrative data from three US sources, we assessed study endpoints of suicide attempts and death by suicide in patients aged ≥18 enrolled continuously for ≥3 months in their health plans before receiving their first ever antipsychotic (November 2002-December 2005). RESULTS: Among 20 489 antipsychotic users (8985 patient-years), unadjusted suicide event rates (per 1000 patient-years) were: 20.69 (aripiprazole); 23.99 (olanzapine); 32.33 (quetiapine); 19.69 (risperidone); 48.52 (ziprasidone). Compared with current users of other SGA combined, aripiprazole users did not have an increased risk of suicide events (crude hazard ratio (HR) = 0.79, 95%CI: 0.48-1.30; adjusted HR = 0.69, 95%CI: 0.42-1.14-(controlling for study site, age, sex, index prescription year, antipsychotic use history, other pharmacotherapy exposure, comorbidity presence, schizophrenia/bipolar disorder, suicide attempts, number inpatient/outpatient encounters). CONCLUSIONS: In this large, multi-site study, compared with other SGA combined, aripiprazole is not associated with an increased risk of suicide events in an inception cohort of patients with ICD-9/ICD-10 codes indicative of schizophrenia or bipolar disorder.

Awareness, Knowledge, and Utility of RCT Data vs RWE: Results From a Survey of US Cardiologists: Real-world Evidence in Clinical Decision Making.

Real-world evidence (RWE) provides a potential rich source of additional information to the body of data available from randomized clinical trials (RCTs), but there is a need to understand the strengths and limitations of RWE before it can be applied to clinical practice. To gain insight into current thinking in clinical decision making and utility of different data sources, a representative sampling of US cardiologists selected from the current, active Fellows of the American College of Cardiology (ACC) were surveyed to evaluate their perceptions of findings from RCTs and RWE studies and their application in clinical practice. The survey was conducted online via the ACC web portal between 12 July and 11 August 2017. Of the 548 active ACC Fellows invited as panel members, 173 completed the survey (32% response), most of whom were board certified in general cardiology (n = 119, 69%) or interventional cardiology (n = 40, 23%). The survey results indicated a wide range of familiarity with and utilization of RWE amongst cardiologists. Most cardiologists were familiar with RWE and considered RWE in clinical practice at least some of the time. However, a significant minority of survey respondents had rarely or never applied RWE learnings in their clinical practice, and many did not feel confident in the results of RWE other than registry data. These survey findings suggest that additional education on how to assess and interpret RWE could help physicians to integrate data and learnings from RCTs and RWE to best guide clinical decision making.

HER2 testing and subsequent trastuzumab treatment for breast cancer in a managed care environment.

BACKGROUND: Degree of physician adherence to 2001 guidelines recommending routine testing of human epidermal growth factor receptor 2 (HER2) status among newly diagnosed, recurrent, and metastatic breast cancer (BC) cases, and frequency of trastuzumab use in HER2-positive patients are not well documented. METHODS: Patients newly diagnosed with BC managed by an identifiable hematologist/oncologist between June 1, 2005 and June 30, 2006 were identified from an administrative claims database of three health plans (n = 3,521). From these, a subset of 380 patients was identified for medical chart review. HER2 testing (occurrence, type of test used), HER2 status (positive, negative, unknown), and trastuzumab usage were evaluated. RESULTS: HER2 testing occurred in 88% of all newly diagnosed patients with BC and in 98.1% of those with stage 1 or higher breast cancer (n = 322), for whom testing is recommended. Among those with HER2 testing performed (n = 335), 21.5% were positive (HER2(+)), 77.3% were negative (HER2(-)), and 1.2% were unknown. Of the 52 patients who used trastuzumab, only one patient did not have documented HER2 overexpression. Of the 45 HER2(+) women who had stage 2 or higher BC, 13% did not receive trastuzumab. CONCLUSIONS: HER2 testing status was extremely high among newly diagnosed BC patients treated by hematologists/oncologists in a managed care environment. There was almost no evidence of inappropriate prescribing of trastuzumab, but 1 of every 7.5 patients with HER2-overexpressing stage 2 or higher breast cancer did not receive the agent.

Acute coronary syndrome emergency treatment strategies: Improved treatment and reduced mortality in patients with acute coronary syndrome using guideline-based critical care pathways.

BACKGROUND: An acute coronary syndrome (ACS) emergency treatment strategies (ACSETS) critical care pathway (CCP), embedding guideline-based treatment, was evaluated in a 4-hospital system in Buffalo, NY, for its impact on ACS drug utilization, length of stay, and mortality. METHODS: The study used an observational design comparing pre- (n = 1,240) and post- (n = 1,709) ACSETS implementation cohorts followed over 1 year. Both myocardial infarction (MI) (59%) and unstable angina (UA) (41%) patients were studied. Multivariate regression analysis was used to analyze possible differences in major end points. RESULTS: Appropriate ACS medication use was significantly higher in the ACSETS group in the first 24 hours and at discharge. In a subgroup of managed care health insurance patients (n = 884 ), prescription refills for statins, beta-blockers, angiotensin-converting enzyme inhibitors, and clopidogrel were significantly greater in the ACSETS group up to and including 7 months after discharge, although at 7 months, actual refill rate was poor (30%-50%) for both groups. Length of stay was significantly reduced (HR 0.82 [0.72-0.90]). Inpatient mortality was not significantly reduced. One-year adjusted mortality was reduced significantly compared to non-ACSETS in the MI group (by 19%) (HR 0.81 [0.66-0.99]) but not in the UA group (HR 1.13 [0.71-1.79]). CONCLUSIONS: ACSETS contributes to the proof of concept of critical care pathway (CCP) improvement of ACS care, as revealed by increased acute and chronic evidence-based use of medication, decreased length of stay, and, in the case of MI patients, decreased adjusted 1-year mortality. One-year mortality benefit was observed in MI but not UA patients.

A Pragmatic Clinical Trial to Compare the Real-World Effectiveness of V-Go versus Standard Delivery of Insulin in Patients with Advanced Type 2 Diabetes.

BACKGROUND: Many patients with type 2 diabetes mellitus (T2DM) do not have adequate glycemic control, leading to poor patient outcomes and high healthcare costs. OBJECTIVE: This prospective pragmatic clinical trial evaluated V-Go, a wearable insulin delivery device, compared with standard treatment optimization (STO) among insulin-treated patients with T2DM in a real-world, community-based practice setting. METHODS: Study sites, rather than individual patients, were randomized to V-Go or STO via cluster randomization. Patients were treated according to routine clinical practice and followed up to 4 months. T2DM medications and supplies were purchased utilizing usual insurance and co-pay systems. The primary analysis was an unadjusted treatment group comparison of glycosylated hemoglobinA1c (HbA1c) change from baseline to end of study (EOS). A cost of therapy analysis was completed on patients who had received comparable baseline T2DM treatment with multiple daily basal-bolus insulin injections (MDI). RESULTS: Analysis included 415 patients (169 V-Go, 246 STO) enrolled from 52 US sites. Mean baseline HbA1c (9.6%) was higher in V-Go (9.9%, range 8.0% - 14.2%) than STO (9.3%, range 7.9% - 13.9%, p <.001). HbA1c decreased from baseline to EOS in both V-Go (-1.0%, p<.001) and STO (-0.5%, p<.001); V-Go had significantly larger decrease (p=.002). V-Go had a significant reduction (p<.001) in mean insulin total daily dose (TDD; 0.76 U/kg baseline, 0.57 U/kg EOS), not seen in STO (0.72 U/kg baseline and EOS). The MDI group included 95 (56.2%) V-Go and 113 STO (45.9%) patients. Mean baseline HbA1c was significantly higher in V-Go (9.9%) than STO (9.4%). V-Go also experienced larger decrease in HbA1c from baseline (-1.0%) than STO (-0.36%) (p=.006) with a decrease in TDD, while STO TDD remained unchanged. EOS mean per patient per day cost of diabetes treatment was lower for V-Go ($30.59) vs STO ($32.20) (p=.006). V-Go was more cost effective than STO ($24.02 per 1% drop in HbA1c vs $58.86, respectively). CONCLUSIONS: This pragmatic clinical trial demonstrated improved HbA1c levels, lower cost, and decreased insulin dose in patients with T2DM initiating V-Go vs STO in a real-world community-based practice setting. Observed baseline HbAlc indicated use of V-Go in more difficult to manage diabetes patients.

Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting.

BACKGROUND: Most clinicians recognize the importance of reducing low-density lipoprotein cholesterol (LDL-C) and, therefore, address this therapeutic need to decrease cardiovascular disease risk. In addition to the critical role that LDL-C plays, recent studies have shown the contribution of other lipid fractions, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), to overall cardiovascular health. Managed care initiatives to reduce cardiovascular risk typically focus on highly effective statin therapies, which are primarily LDL-C-lowering agents and have lesser TG-lowering and HDL-C-raising effects. However, clinical and epidemiologic data illustrate the need to expand the scope of therapies to reduce the residual cardiovascular risk associated with low HDL-C levels and elevated TG levels, even when LDL-C is managed successfully. OBJECTIVE: To address the value of treating beyond LDL-C level to improve patient health outcomes and reduce health care-related costs. SUMMARY: Several large trials and meta-analyses have investigated the effects of lipid-lowering statin therapy and have consistently demonstrated that statin therapy significantly reduces LDL-C levels and incidence of cardiovascular events. In spite of the efficacy of statin therapy in these studies, statins did not eliminate cardiovascular risk. Rather, significant residual cardiovascular risk remains after treatment with statins, especially in high-risk patients such as those with diabetes. Residual cardiovascular risk stems, at least partially, from low HDL-C and elevated TG. Low HDL-C levels have been identified as a significant, independent predictor of cardiovascular risk, and increases in HDL-C are associated with reductions in cardiovascular events. High TG levels are a significant risk factor for cardiovascular disease and are a marker for atherogenic remnant lipo-proteins, such as very low-density lipoprotein cholesterol (VLDL-C). Additionally, with elevated TG levels, a combination of LDL-C with VLDL-C in the measure of non-HDL-C may be a better predictor of cardiovascular risk than LDL-C alone. Recent national treatment guidelines suggest that combination therapy may be necessary to address multiple lipid targets (i.e., LDL-C, non-HDL-C, HDL-C, and TG); adding niacin or a fibrate to a statin is a therapeutic option that should be considered. As monotherapy agents, fibrates and niacin have been demonstrated to alter several lipid parameters and reduce cardiovascular events. Niacin appears to exert the greatest beneficial effects on the widest range of lipoprotein abnormalities, in addition to possessing an established safety profile. Moreover, niacin/statin combination therapy may provide greater benefits, as manifested through a correction of atherogenic lipid abnormalities, a slowing of atherosclerosis progression in coronary heart disease (CHD) patients, and a reduction of residual cardiovascular risk. Pharmacoeconomic modeling studies have been used to describe the potential effects on both cardiovascular events and health care costs by the achievement of, or failure to achieve, combined optimal lipid values (OLVs). Achievement of OLVs is predicted to be associated with a reduced risk of cardiovascular events, in which greater magnitudes of risk reduction accompany the achievement of a greater number of lipid goals. Based on patient baseline lipid values and product labeling information, mathematical models estimate that OLVs are achieved more frequently with extended-release niacin (niacin ER)/simvastatin combination therapy than with other high-potency agents. These modeling estimates were maintained in different patient groups, including those with diabetes or the metabolic syndrome. Finally, these modeling studies estimated that a fixed-dose niacin ER/simvastatin combination therapy would reduce direct medical costs of CHD events more effectively than would high-dose simvastatin monotherapy. CONCLUSION: Statins are highly effective for lowering LDL-C levels and, consequently, cardiovascular event rates. However, statins do not eliminate cardiovascular risk. Even in the presence of tightly controlled LDL-C levels, evidence indicates that high TG and low HDL-C levels are independent cardiovascular risk factors. Treating lipid parameters beyond LDL-C may require the addition of niacin or a fibrate to statin therapy. Niacin is the most effective agent for raising HDL-C levels, and pharmacoeconomic modeling suggests that niacin ER/statin combination therapy may promote the cost-effective achievement of OLVs in several at-risk patient populations.

Attainment of combined optimal lipid values and the impact of lipid medication on cardiovascular outcomes and costs in a commercially insured population in the US.

OBJECTIVE: To determine factors associated with the achievement of optimal lipid values (OLVs) and subsequent impact on clinical and economic outcomes. METHODS: An observational managed care database analysis was conducted among treatment-naïve adults with elevated cardiovascular (CV) risk, >or=12 months follow-up and full lipid panel from the 1st January 2002 to the 28th February 2005. Achievement of guideline-based levels for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides was evaluated via laboratory data. Annual CV-attributable resource utilisation was assessed via medical and pharmacy claims data. Clinical and economic outcomes associated with the achievement of OLVs were assessed using multivariate regression. RESULTS: A total of 52,778 patients were followed for a mean (standard deviation) of 27 (10) months with 13% achieving combined OLVs at baseline and 23% after 4 years. Of patients, 69% did not initiate lipid-modifying medication. The achievement of combined OLVs reduced the risk of CV event (odds ratio=0.86; 95% confidence interval 0.78-0.95), resource utilisation (inpatient visits: 3.36 vs. 4.41 per 100 patient years, p<0.0001; emergency department visits: 1.1 vs. 2.4 per 100 patient years, p<0.05) and costs: $703 vs. $903 per patient year, p<0.0001. CONCLUSIONS: Simultaneous achievement of OLVs was rare in this patient population. Physicians should be encouraged to manage multiple risk factors aggressively to improve clinical and economic outcomes associated with CV disease.