Nancy M. Allen LaPointe

Long-Term Adherence to Evidence-Based Secondary Prevention Therapies in Coronary Artery Disease

Background— Studies have examined the use of evidence-based therapies for coronary artery disease (CAD) in the short term and at hospital discharge, but few have evaluated long-term use. Methods and Results— Using the Duke Databank for Cardiovascular Disease for the years 1995 to 2002, we determined the annual prevalence and consistency of self-reported use of aspirin, &bgr;-blockers, lipid-lowering agents, and their combinations in all CAD patients and of angiotensin-converting enzyme inhibitors (ACEIs) in those with and without heart failure. Logistic-regression models identified characteristics associated with consistent use (reported on ≥2 consecutive follow-up surveys and then through death, withdrawal, or study end), and Cox proportional-hazards models explored the association of consistent use with mortality. Use of all agents and combinations thereof increased yearly. In 2002, 83% reported aspirin use; 61%, &bgr;-blocker use; 63%, lipid-lowering therapy use; 54%, aspirin and &bgr;-blocker use; and 39%, use of all 3. Consistent use was as follows: For aspirin, 71%; &bgr;-blockers, 46%; lipid-lowering therapy, 44%; aspirin and &bgr;-blockers, 36%; and all 3, 21%. Among patients without heart failure, 39% reported ACEI use in 2002; consistent use was 20%. Among heart failure patients, ACEI use was 51% in 2002 and consistent use, 39%. Except for ACEIs among patients without heart failure, consistent use was associated with lower adjusted mortality: Aspirin hazard ratio (HR), 0.58 and 95% confidence interval (CI), 0.54 to 0.62; &bgr;-blockers, HR, 0.63 and 95% CI, 0.59 to 0.67; lipid-lowering therapy, HR, 0.52 and 95% CI, 0.42 to 0.65; all 3, HR, 0.67 and 95% CI, 0.59 to 0.77; aspirin and &bgr;-blockers, HR, 0.61 and 95% CI, 0.57 to 0.65; and ACEIs among heart failure patients, HR, 0.75 and 95% CI, 0.67 to 0.84. Conclusions— Use of evidence-based therapies for CAD has improved but remains suboptimal. Although improved discharge prescription of these agents is needed, considerable attention must also be focused on understanding and improving long-term adherence.

Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients

Many drugs prolong the QT interval and increase the risk of torsade de pointes. Concurrent use of two or more of these drugs can further increase the risk, but the prevalence of concurrent prescription of QT-prolonging drugs is not known. Using the administrative claims database of a national pharmaceutical benefit manager, we conducted a retrospective cohort study in 4,825,345 subjects aged 18 years or older. After identifying 50 drugs with QT-prolonging potential, and an additional 26 drugs that inhibit the metabolic clearance of QT-prolonging drugs, we measured the frequency of overlapping prescriptions for two or more of these drugs in the outpatient setting in 1999. Nearly 1.1 million subjects (22.8%) filled 4.4 million prescriptions for QT-prolonging drugs. Of these, 103,119 subjects (9.4%) filled overlapping prescriptions for two or more of the drugs or for a QT-prolonging drug and another drug that inhibits its clearance; 7249 subjects (0.7%) filled overlapping prescriptions for three or more of these drugs. Twenty-two percent of subjects who filled overlapping prescriptions were aged 65 or older; 74% were women. Antidepressants were involved in nearly 50% of the cases. Concurrent prescription of QT-prolonging drugs is common in the outpatient setting, and antidepressants are involved in half of these cases. Large pharmaceutical claims databases are useful for detecting potentially harmful prescribing behaviors, but better clinical evidence on medication safety is needed before such a system can be implemented fully.

Transfusion practice and outcomes in non-ST-segment elevation acute coronary syndromes.

OBJECTIVES To describe the association between transfusion and outcomes as a function of nadir hematocrit (HCT) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). BACKGROUND The adverse outcomes associated with transfusion in NSTE ACS is uncertain and may vary by nadir HCT of the transfused. METHODS Using data from 44242 patients with NSTE ACS in 400 US hospitals in the CRUSADE initiative (January 2004-December 2005), we describe blood transfusion as a function of nadir HCT and associated outcomes across nadir HCT groups (<or=24%, 24.1%-27%, 27.1%-30%, >30%). We further explore patient and process variation across hospital quartiles defined by transfusion use. RESULTS Overall, 22.2% of patients with NSTE ACS are anemic and 10.4% receive a blood transfusion during their care. Likelihood of transfusion rose from 1% when nadir HCT was >30% to 70% when nadir HCT was <or=24%. The threshold for transfusion is a median nadir HCT of 25.7% (interquartile range 23.8%-27.5%). Although nadir HCT of transfused remains constant across quartiles of transfusion use, occurrence of bleeding increases. Inhospital mortality is higher in lower nadir HCT groups. In those with a nadir HCT of <or=24%, transfusion tended to have a beneficial impact on mortality (HCT <or=24% adjusted odds ratio [OR] 0.68 [0.45-1.02]). In the median range where transfusion occurs, transfusion had a neutral impact on mortality (HCT 24%-27% adjusted OR 1.01 [0.79-1.30]). Although rare, those transfused with nadir HCT of 27% to 30% (adjusted OR 1.18 [0.92-1.50]) or HCT of >30% (adjusted OR 3.47 [2.30-5.23]) had higher mortality. CONCLUSION Anemia and transfusion are common in the care of NSTE ACS. The observed association between transfusion and adverse outcomes is neutral in the nadir HCT range where transfusions are most often given and trends strongly to benefit when nadir HCT is <or=24%. Although reassuring, randomized trials are needed to confirm the safety of transfusion in NSTE ACS. In the meantime, avoiding the need for transfusion is the best approach.

Rate- and Rhythm-Control Therapies in Patients With Atrial Fibrillation: A Systematic Review

Atrial fibrillation (AF) is a major public health problem in the United States. More than 2.3 million Americans are estimated to have AF (1). The known association between AF and substantial mortality, morbidity, and health care costs compounds the effect of this condition. Not only is the risk for death in patients with AF twice that of patients without it, but AF can result in myocardial ischemia and infarction, exacerbate heart failure (HF), and cause tachycardia-induced cardiomyopathy if the ventricular rate is not well-controlled (25). The most dreaded complication of AF is thromboembolism, especially stroke (6). In some patients, AF or therapies to manage this condition can severely depreciate quality of life (710). Furthermore, the management of AF and its complications is responsible for nearly

Underuse of Aspirin in a referral population with documented coronary artery disease

16 billion in additional costs to the U.S. health care system per year (11). Despite the substantial public health effect of AF, uncertainties around its management remain. In particular, the comparative safety and effectiveness of different rate- and rhythm-control therapies for patients with AF are unclear. We conducted this systematic review to evaluate the comparative safety and effectiveness of rate- versus rhythm-control strategies; medications used for ventricular rate control; strict versus more lenient rate-control strategies; nonpharmacologic rate-control therapies versus medications; electrical cardioversion and antiarrhythmic medications for restoration of sinus rhythm; and catheter ablation, surgical ablation, and antiarrhythmic medications for maintenance of sinus rhythm. Methods We developed and followed a standard protocol for our review. Full details of our methods, search strategies, results, and conclusions are presented in a comparative effectiveness review commissioned by the Agency for Healthcare Research and Quality (AHRQ) and are available at www.effectivehealthcare.ahrq.gov (12). Data Sources and Searches We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for studies published between 1 January 2000 and 12 November 2013. Data before 2000 have been summarized in an AHRQ report on the management of new-onset AF published in 2001 (1315). Study Selection We identified randomized, controlled trials (RCTs) published in English that were comparative assessments of pharmacologic or nonpharmacologic rate- or rhythm-control therapies aimed at treating adults with AF. Observational studies were also allowed for comparisons of strict versus lenient rate control or cardiac resynchronization therapy versus other rhythm-control therapies. The following outcomes were considered: restoration of sinus rhythm (conversion), maintenance of sinus rhythm, recurrence of AF at 12 months, development of cardiomyopathy, death (all-cause and cardiac), myocardial infarction, cardiovascular hospitalizations, HF symptoms, control of AF symptoms, quality of life, functional status, stroke and other embolic events, bleeding events, and adverse effects of therapy. Data Extraction and Quality Assessment One investigator abstracted and another confirmed data related to study setting and design, patient characteristics, details of treatment, comparators, and relevant outcomes. The quality of individual studies was evaluated using the approach described in AHRQs Methods Guide for Effectiveness and Comparative Effectiveness Reviews (16). Investigators also assessed factors that limited applicability of the evidence. Data Synthesis and Analysis For each treatment comparison and outcome of interest, we determined the feasibility of completing a quantitative synthesis (meta-analysis) based on the volume of relevant literature, conceptual homogeneity of the studies (both in terms of study population and outcomes), and completeness of the reporting of results. We considered meta-analysis for outcomes that at least 3 studies reported. For our evaluation of rate- versus rhythm-control strategies, we grouped all rate-control strategies together and all rhythm-control strategies together, regardless of the specific medication or procedure. We grouped pharmacologic interventions by class, considering rate-controlling calcium-channel blockers and all -blockers each to be similar enough to be grouped together. We categorized procedures into electrical cardioversion, atrioventricular node (AVN) ablation, AF ablation by pulmonary vein isolation (PVI) (by open surgical, minimally invasive, or transcatheter procedures), and different types of surgical maze procedures and explored comparisons among these categories. In addition, for the comparisons focusing on medications versus procedures, we also explored grouping all medications together and comparing them with all procedures. When a meta-analysis was appropriate, we used a random-effects model to synthesize the available evidence quantitatively using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We used a standardized approach to rank the overall strength of evidence (SOE) for each outcome (16). Role of the Funding Source Primary funding was provided by AHRQ. Neither the technical experts nor AHRQ representatives had a role in the literature search, data analysis, interpretation of the data, or decision to submit the manuscript for publication. Results We screened 10495 abstracts, evaluated 570 full-text articles, and included 200 articles representing 162 studies involving 28836 patients (Figure 1). Tables 1 to 6 of the Supplement provide details about these studies and their populations for each topic described here. Table 7 of the Supplement lists identified and potential limitations of the studies. The full AHRQ report highlights additional findings (12). Figure 1. Summary of evidence search and selection. AAD = antiarrhythmic drug; CRT = cardiac resynchronization therapy; RCT = randomized, controlled trial. * Some studies were relevant to more than 1 topic. Supplement. Tables Rate- Versus Rhythm-Control Strategies We included 16 RCTs in this analysis: 13 compared pharmacologic rhythm-control versus rate-control strategies (1729) and 3 compared a rhythm-control strategy with PVI versus a rate-control strategy that involved AVN ablation and implantation of a pacemaker in 1 study (30) and rate-controlling medications in the other 2 (31, 32). Ten RCTs (17, 18, 2022, 2428) provided information on outcomes of interest and were combined quantitatively (Figure 2). Of these, 5 included only patients with persistent AF (2022, 25, 28), 1 included only patients with paroxysmal AF (17), and 4 included patients with paroxysmal or persistent AF (18, 24, 26, 27). Two studies (17, 22) compared a single-chamber pacemaker plus AVN ablation versus a dual-chamber pacemaker plus AVN ablation plus an antiarrhythmic medication; all others compared largely unspecified rate-control with rhythm-control strategies. Figure 2. Meta-analysis forest plots. AAD = antiarrhythmic drug; PVI = pulmonary vein isolation. A. All-cause mortality for rate- vs. rhythm-control strategies. B. Cardiovascular mortality for rate- vs. rhythm-control strategies. C. Stroke for rate- vs. rhythm-control strategies. D. Restoration of sinus rhythm for monophasic vs. biphasic waveforms. E. Maintenance of sinus rhythm for PVI vs. AAD therapy. Figure 2. Continued. Data from the included studies showed moderate SOE that pharmacologic rate- and rhythm-control strategies are of comparable efficacy with regard to their effect on all-cause mortality (odds ratio [OR], 1.34 [95% CI, 0.89 to 2.02]; Q= 21.71; P= 0.003) (Figure 2, A) (18, 2022, 24, 2628), cardiac mortality (OR, 0.96 [CI, 0.77 to 1.20]; Q= 3.55; P= 0.47) (Figure 2, B) (18, 21, 22, 24, 25), and stroke (OR, 0.99 [CI, 0.76 to 1.30]; Q= 7.02; P= 0.43) (Figure 2, C) (17, 18, 2022, 24, 27, 28). Although the meta-analysis for all-cause mortality showed a potential benefit, it did not reach statistical significance and 6 of the 8 studies (6069 patients [95%]) had ORs that crossed 1, resulting in a final moderate SOE. For cardiac mortality (Figure 2, B), point estimates were inconsistent and CIs were wide for 2 of the 5 studies (18, 21), but there was no evidence of heterogeneity; therefore, our SOE rating was not affected. For the outcome of stroke, there was no evidence of heterogeneity, but the findings were mostly driven by 1 large, good-quality RCT (4060 patients), which was inconsistent with several of the smaller studies, reducing our confidence in the finding and in the SOE. These studies largely included older patients with mild AF symptoms. Three RCTs compared pharmacologic rate-control strategies with rhythm-control strategies using antiarrhythmic medications (17, 18, 22). These RCTs showed fewer cardiovascular hospitalizations with the rhythm-control strategies (17, 18, 22). Although data from 5 RCTs suggest that there is no difference between pharmacologic rate- and rhythm-control strategies in their effect on HF symptoms (17, 22, 24, 26, 46) (Table 1), a prespecified substudy of the Atrial Fibrillation and Congestive Heart Failure study showed that a higher proportion of time spent in sinus rhythm was associated with a greater improvement in New York Heart Association class (29). Table 1. Summary of SOE and Effect Estimates for Rate- Versus Rhythm-Control Strategies Three studies compared a rhythm-control strategy involving catheter ablation with a rate-control strategy involving rate-controlling medications (32) or AVN ablation combined with implantation of a pacemaker (30) or rate-controlling medications (31). One study showed that catheter ablation was better than pharmacologic rate control at improving symptoms, neurohormonal status, and objective physiologic exercise capacity (32). Another study showed that PVI isolation was superior to AVN ablation and pacemaker implantation in improving quality of life, 6-minute walk distance, and ejection fraction (30). Another study showed that PVI resulted in long-term restoration o

Patient-focused intervention to improve long-term adherence to evidence-based medications: a randomized trial

Despite substantial evidence that antiplatelet therapy saves lives and reduces adverse events in patients with coronary artery disease (CAD), use of the most widely available and lowest cost antiplatelet agent, aspirin, continues to be disappointingly low. In a large database of patients with known CAD, we (1) explored trends in the use of aspirin over time, (2) characterized patients most likely to take aspirin regularly, and (3) estimated the effectiveness of aspirin use by examining long-term outcomes. Using patients entered in the Duke Databank for Cardiovascular Diseases, we explored the use of aspirin from 1969 to 1999. More than 25,000 patients were sent a questionnaire that included several questions about medication use, including 1 question specifically about aspirin. Patients who failed to respond to the questionnaire received a follow-up telephone call. Aspirin use increased substantially over the most recent 4 years in the study, from 59% in 1995 to 81% in 1999. Predictors of aspirin use included younger age, male sex, being a nonsmoker, and having had a myocardial infarction or revascularization procedure. Patients who never took aspirin had a risk ratio for death of 1.85 compared with patients who regularly took aspirin. Despite the well-known beneficial effects of aspirin, too many patients without contraindications to aspirin fail to take it regularly. The health care system currently lacks effective methods to ensure that patients who have CAD have adequate follow-up concerning aspirin use.

Extent of and Reasons for Nonuse of Implantable Cardioverter Defibrillator Devices in Clinical Practice Among Eligible Patients With Left Ventricular Systolic Dysfunction

BACKGROUND Nonadherence to cardiovascular medications is a significant public health problem. This randomized study evaluated the effect on medication adherence of linking hospital and community pharmacists. METHODS Hospitalized patients with coronary artery disease discharged on aspirin, β-blocker, and statin who used a participating pharmacy were randomized to usual care or intervention. The usual care group received discharge counseling and a letter to the community physician; the intervention group received enhanced in-hospital counseling, attention to adherence barriers, communication of discharge medications to community pharmacists and physicians, and ongoing assessment of adherence by community pharmacists. The primary end point was self-reported use of aspirin, β-blocker, and statin at 6 months postdischarge; the secondary end point was a ≥ 75% proportion of days covered (PDC) for β-blocker and statin through 6 months postdischarge. RESULTS Of 143 enrolled patients, 108 (76%) completed 6-month follow-up, and 115 (80%) had 6-month refill records. There was no difference between intervention and control groups in self-reported adherence (91% vs 94%, respectively, P = .50). Using the PDC to determine adherence to β-blockers and statins, there was better adherence in the intervention versus control arm, but the difference was not statistically significant (53% vs 38%, respectively, P = .11). Adherence to β-blockers was statistically significantly better in intervention versus control (71% vs 49%, respectively, P = .03). Of 85 patients who self-reported adherence and had refill records, only 42 (49%) were also adherent by PDC. CONCLUSIONS The trend toward better adherence by refill records with the intervention should encourage further investigation of engaging pharmacists to improve continuity of care.

Outpatient Prescribing of Antiarrhythmic Drugs from 1995 to 2000

Background— Several studies that used claims and registry data have reported that 40% to 80% of patients eligible for an implantable cardioverter defibrillator (ICD) fail to receive one in clinical practice, and the rates are especially high among women and blacks. The extent and documented reasons for nonuse of ICDs among patients with left ventricular systolic dysfunction are unknown. Methods and Results— Using hospital claims and clinical data, we identified patients hospitalized with a heart failure diagnosis and left ventricular ejection fraction ⩽30% between January 1, 2007, and August 30, 2007, at a tertiary-care center. Using claims data, we determined placement of an ICD or cardiac resynchronization therapy with defibrillation device at any time up to 1 year after hospitalization. Medical records for patients without an ICD were abstracted to determine reasons for nonuse. Patients with an ICD were compared with patients without an ICD and also with patients without an ICD who did not have any contraindication for an ICD as identified through chart abstraction. Of the 542 potentially eligible patients identified, 224 (41%) did not have an ICD. In the initial adjusted analysis, female sex (odds ratio=1.90; 95% CI, 1.28 to 2.81) and increasing age (odds ratio=1.07; 95% CI, 1.04 to 1.11) were associated with a higher likelihood of not having an ICD. After detailed chart review, of the 224 patients without an ICD, 117 (52%) were ineligible for the device and 38 (17%) patients refused the device, resulting in only 69 (13%) patients eligible for an ICD who failed to receive one. In this subsequent adjusted analysis, remaining factors associated with a higher likelihood of not having an ICD were absence of ventricular arrhythmias (odds ratio=4.93; 95% CI, 2.56 to 9.50), noncardiology hospital service (odds ratio=3.73; 95% CI, 1.98 to 7.04), and lack of health insurance (odds ratio=3.10; 95% CI, 1.48 to 6.46). Conclusions— On the basis of a detailed chart review, the true rate of ICD underuse may be substantially lower than previous estimates. In addition, after accounting for ICD eligibility criteria, patient sex and age disparities in ICD therapy were no longer present.

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

There is growing evidence that some class III antiarrhythmic drugs, unlike class I agents, are not associated with an increased risk of death in patients with prior myocardial infarction and left ventricular dysfunction. 1‐14 For this reason, we evaluated the extent to which the current prescribing of antiarrhythmic medications complies with the evidence that supports the use of class III rather than class I agents. Using pharmaceutical marketing research data, we reviewed outpatient antiarrhythmic drug prescriptions in the United States from 1995 through the third quarter of 2000, to characterize the prescribing of these drugs and to examine drug use trends over this period. ••• Data on antiarrhythmic drug prescribing were derived from 2 audits owned by IMS Health (Plymouth Meeting, Pennsylvania): the National Prescription Audit (NPA) Plus and the National Disease and Therapeutic Index (NDTI). The NPA Plus audit measures the retail outflow of prescriptions in the United States. This includes prescriptions dispensed by retail pharmacies and mailorder pharmacies. The NDTI audit contains data on drug mentions associated with a diagnosis during a specific clinic visit. These data are collected by a continuing survey of 343,655 physicians in officebased practices in the United States. An NDTI panel of physicians, a subset of 343,655, is selected every 2 weeks to provide demographic information, diagnoses, and recommended drugs for each diagnosis on all patients encountered. This is then projected to the national level. The NPA Plus audit was queried for all class I and class III antiarrhythmic drugs for which an oral dosage form was marketed and sold in the United States between January 1995 and September 2000. The numbers presented for the year 2000 represent a 9-month period. Class I agents included the class IA agents quinidine, procainamide, and disopyramide, the class IB agents mexiletine and tocainide, and the class IC agents flecainide, propafenone, and moricizine. Class III agents included amiodarone and sotalol. We limited this analysis to class I and III antiarrhythmic drugs because it would be difficult to determine whether blockers (class II antiarrhythmic agents) and calcium channel blockers (class IV antiarrhythmic agents) were prescribed solely for an arrhythmic indication. The NDTI audit was queried for all oral class I and class III antiarrhythmic agents strati fied by physician specialty and diagnoses for which the agent(s) was used. Trends in antiarrhythmic drug prescriptions were evaluated based on physician specialty and the diagnosis for which each agent or class of agents was reported to be prescribed.

The Potential Impact of Pharmacogenetic Testing on Medication Adherence

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.