Jeffrey L. Anderson

Improvements in 1-Year Cardiovascular Clinical Outcomes Associated with a Hospital-Based Discharge Medication Program

Context Despite evidence to support the effectiveness of a variety of interventions for the secondary prevention of cardiovascular disease, many eligible patients do not receive these interventions. Contribution Compared with a baseline period, patients hospitalized with cardiovascular disease who received an intervention that focused on discharge medications had higher rates of prescription of aspirin, -blockers, statins, angiotensin-converting enzyme inhibitors, and warfarin at hospital discharge. The risk for death and readmission was lower in the intervention period than in the baseline period. Cautions The prepost design of this study does not permit conclusions about a causal relationship between the intervention and the observed improvements. The Editors Cardiovascular disease remains the most common source of morbidity and mortality in western countries (1). During the past 2 decades, a variety of significant medical advances have been made in the treatment and prevention of complications associated with major cardiovascular disorders, including coronary artery disease, congestive heart failure (CHF), and atrial fibrillation. Many of these advances in secondary prevention relate simply to the appropriate use of certain medications, for example, aspirin and statins for coronary artery disease, -blockers and angiotensin-converting enzyme inhibitors for CHF, and warfarin for prevention of stroke and other embolic events in patients with atrial fibrillation. Each of these medical therapies has been proven in large, multicenter, randomized, double-blind, placebo-controlled trials to save lives under appropriate circumstances (2-7). However, despite the overwhelming evidence supporting the benefit of these medications, many studies have documented a significant treatment gap. Often, far fewer than 50% of potential beneficiaries actually receive treatment (8-13), and studies from our institution and others have shown that many patients do not receive indicated medications at hospital discharge (14, 15). On the other hand, the chances of long-term adherence are significantly higher when medications are provided at hospital discharge, and this difference is associated with decreased mortality rates (13, 16). Hospital discharge is a critical juncture in the process of care. Patients are available for consultation and are often more disposed to adopt health care recommendations. A hospital dischargebased intervention could be more easily implemented, more effectively managed and measured, and more cost-effective than other potential outpatient intervention strategies. Consequently, there is substantial justification for focusing on hospital discharge as the ideal time to improve prescription of medications for secondary prevention of cardiovascular disease. In the current study, our objectives were to 1) determine the feasibility of implementing a comprehensive quality improvement initiative in a large multihospital network to significantly increase rates of prescription at discharge of evidence-based, secondary prevention medications for life-threatening cardiovascular diseases; 2) ascertain the effect of such a program on long-term clinical outcomes; and 3) determine whether good adherence to such an initiative is sustainable. Methods Intermountain Health Care (IHC) is a nonprofit, integrated health care system including 20 hospitals, a system of health plans, and both employed and affiliated physicians. The approximately 400 employed physicians mainly practice primary care, and the approximately 2500 affiliated physicians are mostly specialists. Intermountain Health Care serves approximately 60% of the population of Utah and southern Idaho. The systems 10 largest hospitals were included in the quality improvement initiative, accounting for more than 90% of the total population of cardiovascular patients. The major intent of this initiative was to ensure that appropriate secondary prevention medications were prescribed at discharge to all patients (excluding those with documented contraindications) who were hospitalized with a principal cardiovascular diagnosis of acute myocardial infarction (MI), coronary heart disease (CHD), CHF, or atrial fibrillation. Table 1 shows the guidelines that were developed for each of the diagnostic categories, and Appendix Figure 1 shows the reference card that was developed to aid physicians and clinical staff. All of the guidelines were based on the current class IA American Heart Association/American College of Cardiology recommendations, except for the recommendation of a statin in all patients with CHD, including those with a low-density lipoprotein cholesterol level less than 2.59 mmol/L (<100 mg/dL). Our research (17) showed that a statin provided significant benefit in this population, a notion that has since been supported by a large clinical trial (18). -Blocker therapy for patients with CHF was deferred until after discharge. Table 1. Discharge Medication Guidelines for the Secondary Prevention of Cardiovascular Disorders Design and Implementation of the Quality Improvement Program In 1998, before the new discharge medication program (DMP) was initiated, a new institution-wide database was developed to assist in its implementation and long-term management. Simultaneously, all participating institutions began prospectively tracking prescription of applicable discharge medications for all cardiac patients discharged from their respective cardiovascular departments (Appendix Figure 2). The DMP was implemented on 1 January 1999, and tracking of discharge prescriptions continued. Maintenance of the discharge medication database is ongoing, and information through February 2002 was included in this study. Appendix Figure 2. Data collection form for the discharge medication program. Implementation of the DMP required support and commitment from every level of the health care system, including administration, physicians, nurses, and other staff. To gain this support, the IHC Cardiovascular Clinical Program leadership conducted an extensive education campaign in all participating hospitals. Before the actual initiation of the DMP, this group conducted an extensive tour to engage physicians, residents, and nurses with the program, its goals, and its rationale. The actual DMP implementation and documentation process varied from hospital to hospital but always included the essential core elements. The appropriate indication for each medication was printed directly on the patient discharge form, so physicians needed only to check the correct box or record the specific contraindication (Appendix Figure 3). This form served as a project management and data collection tool. When an appropriate medication was not prescribed, the discharge-planning nurse contacted the attending physician or resident directly, after which the missing medication could be added to the discharge prescriptions or an appropriate contraindication for its use could be documented. All information was entered into a computerized database for tracking. Other than the additional resources for data management, the DMP used existing hospital personnel. No organized effort was made to guarantee long-term adherence to prescribed medications after discharge. Appendix Figure 2. Discharge orders form.. Documentation of Short-Term Success of the Program To measure and manage the short-term success of the program, monthly reports were generated showing the proportion of cardiovascular patients discharged with prescriptions for the indicated secondary prevention medications at each of the 10 hospitals. These reports were shared extensively with all participating health care providers from each contributing institution in an effort to further increase adherence. Long-Term Follow-up To monitor the effect of DMP implementation on long-term clinical outcomes, the baseline characteristics (age, sex, and discharge diagnosis) of each cardiovascular patient discharged from the 10 participating facilities were compiled from the centralized IHC informatics database. Each patient was followed prospectively for up to 1 year for hospital readmission due to a cardiovascular indication or for death. If no evidence of hospital readmission or death could be found for a patient, we assumed that the patient had not experienced either event. Information was included from 1996, 3 years before DMP initiation, to February 2002, more than 3 years afterward. Rehospitalizations (cardiovascular only) were determined through the IHC informatics systems electronic data warehouse, and death was ascertained by using the IHC system and the Social Security Administrations death records. Such electronic follow-up, in our experience (16), has proven more thorough and accurate than telephone surveys. Although a limited proportion of patients may have been readmitted to other hospitals for subsequent care, they were probably randomly distributed between the pre-DMP and DMP samples. Characteristics of patients admitted before (1996 to 1998) and after (1999 to 2002) DMP implementation were evaluated separately and compared. Statistical Analysis The chi-square test was used to evaluate differences in the proportions of patients receiving appropriate discharge prescriptions in the pre-DMP and DMP groups. To evaluate the effect of the DMP, we formed 4 mutually exclusive diagnostic or procedural categories for patients with the following index admissions: CHD without CHF, MI, or coronary artery bypass grafting (CABG); CHF without MI or CABG; MI without CABG; and CABG. The category of atrial fibrillation was not mutually exclusive of the other 4 categories. These categories reflected different patient samples and were not designed to evaluate groups on the basis of indications for each separate medication, since more than 1 medication could have been indicated in any given patient. Differences between baseline characteristics of the pre-DMP and DMP groups were eva

A Policy Model to Evaluate the Benefits, Risks and Costs of Warfarin Pharmacogenomic Testing

AbstractBackground: In 2007, the US FDA added information about pharmacogenomics to the warfarin label based on the influence of the CYP2C9 and VKORC1 genes on anticoagulation-related outcomes. Payers will be facing increasing demand for coverage decisions regarding this technology, but the potential clinical and economic impacts of testing are not clear.n Objective: To develop a policy model to evaluate the potential outcomes of warfarin pharmacogenomic testing based on the most recently available data.n Methods: A decision-analytic Markov model was developed to assess the addition of genetic testing to anticoagulation clinic standard care for a hypothetical cohort of warfarin patients. The model was based on anticoagulation status (international normalized ratio), a common outcome measure in clinical trials that captures both the benefits and risks of warfarin therapy. Initial estimates of testing effects were derived from a recently completed randomized controlled trial (n = 200). Healthcare cost (

Infectious Serology and Atherosclerosis How Burdensome Is the Risk

US, year 2007 values) and health-state utility data were obtained from the literature. The perspective was that of a US third-party payer. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results.n Results: The policy model included thromboembolic events (TEs) and bleeding events and was populated by data from the COUMAGEN trial. The rate of bleeding calculated for standard care approximated bleeding rates found in an independent cohort of warfarin patients.According to our model, pharmacogenomic testing provided an absolute reduction in the incidence of bleeds of 0.17%, but an absolute increase in the incidence of TEs of 0.03%. The improvement in QALYs was small, 0.003, with an increase in total cost of

Altered composition of triglyceride-rich lipoproteins and coronary artery disease in a large case-control study.

US162 (year 2007 values). The incremental cost-effectiveness ratio (ICER) ranged from testing dominating to standard care dominating, and the ICER was <

Medical Therapy for Elderly Patients Who Have Had Myocardial Infarction: Too Little to the Late in Life?

US50 000 per QALY in 46% of simulations. Results were most sensitive to the cost of genotyping and the effect of genotyping.n Conclusion: Our model, based on initial clinical studies to date, suggests that warfarin pharmacogenomic testing may provide a small clinical benefit with significant uncertainty in economic value. Given the uncertainty in the analysis, further updates will be important as additional clinical data become available.

Clinical guidelines and performance measures: Responsible guidance and accountability

In recent years, atherosclerosis has come to be recognized as active and inflammatory, rather than simply a passive process of lipid infiltration.1 Inflammation occurs in response to vascular oxidative stress and injury through known and unknown stimuli. Inflammatory triggers undoubtedly include oxidized and glycosylated products (eg, modified lipoproteins). Given their association with inflammation, infectious agents also are being explored as potential inciters of vascular inflammation and promoters of atherosclerosis.2,3nnSee p 251 nnThe role of infection in human atherosclerosis remains elusive. However, the ability of infectious agents to induce several (if not all) of the inflammatory mechanisms active in atherothrombosis has been demonstrated experimentally. Several direct and indirect cellular and molecular mechanisms by which vascular and selected extra-vascular infections may promote atherosclerosis are listed in Table 14 and are discussed elsewhere.2 In response to pathogens, pathogen-induced products (eg, reactive oxygen species, oxidized low-density lipoprotein) or cross-reacting, autologous molecules, local and systemic (circulating) inflammatory mediators are induced (including chemokines, cytokines, and adhesion molecules), inflammatory cells are recruited and proliferate (monocyte/macrophages, T lymphocytes, smooth muscle cells), and proinflammatory, prothrombotic, and matrix-degrading molecules are expressed. Endothelial dysfunction ensues, lipid accumulation is promoted, and plaque growth and, subsequently, destabilization and thrombosis occur. nnView this table:nnTABLE 1. Cellular and Molecular Mechanisms by Which Infections May Promote Atherosclerosis nnnnPotential atherogenic mechanisms have been most extensively explored for Chlamydia pneumoniae (Cpn) and cytomegalovirus (CMV) (and other Herpesviridae). Cpn and CMV infect vascular wall cells (and selected nonvascular cells) and may provoke or accelerate atherosclerosis by a variety of these mechanisms (Table 1). Relative to CMV, an intriguing proposed molecular mechanism is the binding and inhibition of the tumor suppressor gene p53 by an early CMV gene product (IE2-84).2 This mechanism may explain how abortive CMV infection leads to, among other effects, increased expression of …

Parathyroid hormone, vitamin D, renal dysfunction, and cardiovascular disease: Dependent or independent risk factors?

BACKGROUNDnTraditional beta-quantification of plasma lipoproteins by ultracentrifugation separates triglyceride-rich lipoproteins (TGRL) from higher density lipoproteins. The cholesterol in the TGRL fraction is referred to as measured very low-density lipoprotein cholesterol (VLDL-C) recognizing that other TGRL may be present. The measured VLDL-C to total plasma triglyceride (VLDL-C/TG) has long been considered an index of average TGRL composition with abnormally high VLDL-C/TG ratios (>or=0.30 with TG>150mg/dL) indicative of atherogenic remnant accumulation (type III hyperlipidemia). However, virtually no reports are available which examine potential associations between CAD and VLDL-C/TG at the lower end of the spectrum.nnnMETHODS AND RESULTSnWe performed ultracentrifugation in 1170 cases with premature-onset, familial CAD and 1759 population-based controls and examined the VLDL-C/TG ratio as an index of TGRL composition. As expected, we found very high CAD risk associated with severe type III hyperlipidemia (OR 10.5, p=0.02). Unexpectedly, however, we found a robust, graded, and independent association between CAD risk and lower than average VLDL-C/TG ratios (p<0.0001 as ordered categories or as a continuous variable). Among those in the lowest VLDL-C/TG category (a ratio <0.12), CAD risk was clearly increased (OR 4.5, 95% CI 2.9-6.9) and remained significantly elevated in various subgroups including those with triglycerides below 200mg/dl, in males and females separately, as well as among those with no traditional CAD risk factors (OR 5.8, 95% CI 1.5-22). Significant compositional differences by case status were confirmed in a subset whose samples were re-spun with measurement of lipids and apolipoprotein B (apo B) in each subfraction.nnnCONCLUSIONSnWe found a strong, graded, independent, and robust association between CAD and lower VLDL-C/TG ratios. We consider this a novel, hypothesis-generating observation which will hopefully generate additional future studies to provide confirmation and further insight into potential mechanisms.

The cholesteryl ester transfer protein Taq 1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease

Despite striking progress, cardiovascular diseases remain the leading cause of death in the United States [1]. The short- and long-term effects of myocardial infarction contribute most to this toll. Because the elderly are at greater risk for both total coronary heart disease and death related to acute myocardial infarction (risks increased 6-fold for persons 75 to 84 years of age and 15-fold for those aged 85 years and older compared with persons aged 55 to 64 years) [2], application of effective preventive and treatment measures might be associated with particularly large survival benefits. In this issue, two articles [3, 4] describe opportunities to improve the outcome of elderly patients during and after myocardial infarction. The understanding of the pathogenesis of myocardial infarction has advanced substantially during the past 15 years. Pathologic, angiographic, and angioscopic observations have led to the concept that coronary occlusion begins with the rupture of a lipid-rich atherosclerotic plaque, which leads to the formation of a thrombus consisting of platelets, fibrin, and other blood elements and to local vasoconstriction [5]. Other observations in animal models and early clinical trials have suggested that reperfusion therapy was feasible and could limit both the size of the infarction and mortality [6]. In the past decade, collaborative research has developed a large and compelling database supporting the survival benefit of antithrombotic (thrombolytic [fibrinolytic] and antiplatelet) therapies in acute myocardial infarction. Thrombolytic therapy was evaluated in nine randomized, controlled trials, each of which consisted of more than 1000 patients suspected of having had acute myocardial infarction (58 600 patients total). An overview of these trials [7] conclusively showed the beneficial effect of therapy in patients presenting with ST-segment elevation or bundle-branch block (respective relative mortality reductions at 5 weeks, 21% [P < 0.001] and 25% [P < 0.01]). Benefit was seen regardless of age, sex, blood pressure, heart rate, or history of myocardial infarction or diabetes and was greater the earlier treatment was begun. An international collaborative study involving more than 17 000 cases of suspected acute myocardial infarction (Second International Study of Infarct Survival [ISIS-2]) [8] also showed the important role of antiplatelet therapy with aspirin. When aspirin was added to streptokinase, the reduction in odds of vascular death increased from 25% to 42%. Moreover, when both drugs were given within 4 hours of symptom onset, the odds of death were reduced by 53% (P < 0.001), a dramatic result. Aspirin also reduced (by 49%) the incidence of early recurrent nonfatal reinfarction. On the basis of this experience, a 1990 task force of the American College of Cardiology and American Heart Association designated thrombolytic therapy as a class I indication (therapy usually indicated and considered effective) in patients younger than 70 years of age who had no contraindications, presented with chest pain consistent with acute myocardial infarction, had ST-segment elevation, and could receive therapy within 6 hours of pain onset [9]. (The therapeutic window has since been extended to 12 hours [7].) The task force recommended aspirin as a class I indication in patients of all ages who were suspected of having had acute myocardial infarction and had no contraindications. According to the guidelines, aspirin therapy should be started immediately and continued indefinitely (at a dose of 162 to 325 mg/d). Long-term therapy after myocardial infarction has also been shown to be of benefit. In an overview of 10 randomized, placebo-controlled trials of antiplatelet agents (primarily aspirin), a 25% reduction in vascular events was noted (P < 0.001) (mortality reduction, 13%; rate of nonfatal reinfarction, 31%; rate of nonfatal stroke, 42%) [10]. These data provide a strong rationale for the long-term (indefinite) use of aspirin after myocardial infarction in doses as small as 80 to 325 mg/d. The use of thrombolytic and antiplatelet therapy in clinical practice has been increasing. According to one recent U.S. registry report [11], as many as 70% of patients who have had ST-segment elevation myocardial infarction received reperfusion therapy, and, overall, only 12% of patients with no contraindications did not receive thrombolysis or primary angioplasty. Recent in-hospital use of aspirin has exceeded 90% among thrombolysis candidates but has been lower among other patients and long-term users (70% to 75%). Although these therapies are broadly used in younger patients, acceptance of them has been more gradual in older patients who have had myocardial infarction. Treatment decisions must always balance benefit and risk [12]. The hemorrhagic consequences of thrombolytic therapy may be severe (death or disability), and the risk for intracerebral hemorrhage increases substantially (more than two-fold) with age [13], from 0.5% overall to as much as 1.5% to 4% or more with some therapeutic regimens in persons older than 70 to 75 years of age [7, 13-17]. When considering thrombolytic therapy for elderly patients, physicians are well aware of the hemorrhage-related death and disability caused by treatment but are uncertain about which patients have specifically benefited: Primum non nocere. Unfortunately, evidence for clear benefit in elderly patients, despite their high baseline risk, has been slow in coming. Beginning with the first major mortality trial [18], a clear mortality benefit in the elderly has been difficult to show. Indeed, many early trials excluded patients older than 70 to 75 years of age on the basis of safety concerns, and initial Food and Drug Administration-approved labeling for use of thrombolytic agents in myocardial infarction contained only indications for persons 75 years of age and younger. In the 1990 guidelines [9], the task force recommended thrombolytic therapy as a class IIA indication (of uncertain efficacy, with weight of evidence in favor of usefulness) for persons aged 70 to 75 years and as a class IIB indication (acceptable, but not well established by evidence) for those older than 75 years of age. For younger patients, the task force considered thrombolytic therapy to be a class I indication. In their study, the results of which are published in this issue, Gurwitz and colleagues [3] examined recent trends in the use of thrombolytic therapy in elderly patients who have had acute myocardial infarction and determined the extent to which late presentation and failure to meet electrocardiographic criteria (that is, ST-segment elevation) account for differences in use. Their experience derives from more than 1200 hospitals and 350 000 patients. Thrombolytic therapy was indeed used less frequently in the elderly: 19% of those aged 75 to 84 years and 7% of those 85 years of age and older (compared with 33% to 51% for younger patients). However, temporal increases in use were seen in these oldest two age groups, averaging 34% and 73%, respectively, from 1990 to 1994. As expected, increasing age at myocardial infarction was associated with female sex, late presentation (> 6 hours after myocardial infarction), and entry electrocardiogram without ST-segment elevation. After adjustment for baseline factors, the odds ratio for treatment was 0.3 for patients aged 75 to 84 years and 0.1 for those 85 years of age and older, suggesting that age itself did affect treatment decisions. Limitations of Gurwitz and colleagues study [3] include the fact that no information was provided on either the percentage of patients with contraindications to therapy (such as previous stroke, hemorrhage, or hypertension) or the benefit-risk ratio of therapy in the very elderly. Therefore, the optimal percentage that should be treated remains unclear. The study does, however, document an increasing trend among physicians toward giving thrombolytic agents to elderly patients who have had myocardial infarction. A recent overview [7] has enriched our understanding of the benefit of thrombolytic therapy in the elderly. Among 6000 patients 75 years of age or older, mortality after 5 weeks was reduced modestly, from 25.3% to 24.3% (a saving of 10 lives per 1000 persons treated). These data can be used either to support (smaller proportional benefit but an absolute benefit similar to that for persons younger than 55 years of age) or to argue against the use of therapy in the elderly (P equals not significant compared with control and substantially less than the 27 lives saved per 1000 persons for persons aged 65 to 74 years). Smaller benefits coupled with higher complication rates do suggest that a more cautious approach be used in the very elderly. Careful assessment of the potential for both risk (such as for cerebral hemorrhage) and benefit (for example, if a patient is examined within 4 to 6 hours of having ST-segment elevation myocardial infarction) should be part of the decision making. Consideration of body weight and risk for bleeding may lead to modification of the type and dose of the thrombolytic agent and heparin. If the anticipated benefit is small (small, late, or evolved myocardial infarction) and the risk (such as risk for cerebral hemorrhage) is great, thrombolytic therapy may indeed be inappropriate [19], whereas a favorable riskbenefit profile should weigh in favor of therapy regardless of age [19]. Thus, it appears reasonable to modify the 1990 guidelines for treating myocardial infarction to recommend thrombolytic therapy as a class I indication for persons 75 years of age and younger and as a class IIA indication for persons older than 75 years of age. Given the importance of death from myocardial infarction in the elderly, further progress is needed, both through education and additional clinical trials. Also in this issue, Krumholz and colleagues [4] explore a second aspect of ther

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