Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study.

BACKGROUND: The multidisciplinary approach to managing heart failure has been shown to improve outcomes. The role of a clinical pharmacist in treating heart failure has not been evaluated. METHODS: One hundred eighty-one patients with heart failure and left ventricular dysfunction (ejection fraction <45) undergoing evaluation in clinic were randomized to an intervention or a control group. Patients in the intervention group received clinical pharmacist evaluation, which included medication evaluation, therapeutic recommendations to the attending physician, patient education, and follow-up telemonitoring. The control group received usual care. The primary end point was combined all-cause mortality and heart failure clinical events. All clinical events were adjudicated by a blinded end point committee. RESULTS: Baseline characteristics were similar except for slightly higher age in the intervention group. Median follow-up was 6 months. All-cause mortality and heart failure events were significantly lower in the intervention group compared with the control group (4 vs 16; P= .005). In addition, patients in the intervention group received higher angiotensin-converting enzyme inhibitor doses as reflected by the median fraction of target reached (25th and 75th percentiles), 1.0 (0.5 and 1) and 0.5 (0.1875 and 1) in the intervention and control groups, respectively (P<.001). The use of other vasodilators in angiotensin-converting enzyme inhibitor-intolerant patients was higher in the intervention group (75% vs 26%; P= .02). CONCLUSIONS: Outcomes in heart failure can be improved with a clinical pharmacist as a member of the multidisciplinary heart failure team. This observation may be due to higher doses of angiotensin-converting enzyme inhibitors and/or closer follow-up.

The benefit of implementing a heart failure disease management program.

BACKGROUND: To handle the increasing complexity of congestive heart failure (CHF) care, several new models for the care of patients with CHF have been developed to replace traditional strategies. We undertook this study to evaluate the potential benefit of implementing a CHF disease management program at a tertiary care center, particularly in terms of beta-blocker use and cost to the health care system. METHODS: After reviewing the literature regarding therapies and management strategies for patients with CHF, we developed the Duke Heart Failure Program. All enrolled patients had 1 of the following: recent CHF hospitalization, ejection fraction less than 20%, or symptoms consistent with New York Heart Association class III or IV. We compared preenrollment and postenrollment medication use and resource utilization. RESULTS: We enrolled 117 patients from July 1998 to April 1999. Mean enrollment time was 4.7 months. beta-Blocker use and dose significantly increased (52% vs 76% for beta-blocker, P<.01; 6% vs 13% of target dose, P<.01). The hospitalization rate decreased (1.5 vs 0 hospitalizations per patient-year, P<.01), while the number of clinic visits increased (4.3 vs 9.8 clinic visits per patient-year, P<.01). The Duke University Health System saved a median of $8571 per patient-year. CONCLUSIONS: Implementing a CHF disease management program was associated with improved CHF medication dosing and with decreased hospitalization for patients with CHF. A CHF disease management program is an effective method for a health care system to care for patients with CHF.

Clinical characteristics and long-term outcomes of patients with heart failure and preserved systolic function.

Although the syndrome of heart failure with preserved systolic function may occur in up to 40% of all heart failure patients, the clinical, angiographic characteristics, and long-term outcomes of these patients are poorly understood. We prospectively evaluated 2,498 consecutive patients with New York Heart Association class II to IV symptoms and ejection fractions of >40%, who underwent cardiac catheterization between January 1984 and December 1996 at Duke University Medical Center. The median age for the entire cohort was 63 years; 25% of the population was >71 years old. In addition, 55% of the patients were women, 65% had ischemic heart disease, 28% had a history of diabetes, and 62% had a history of hypertension. The median ejection fraction was 58%. One third of the patients had multivessel disease by coronary angiography. The overall 5-year mortality of the total population was 28%. The independent predictors of mortality (p <0.05) using a multivariable Cox proportional hazard model were age, class IV symptoms, ejection fraction, coronary artery disease index, diabetes, peripheral vascular disease, and minority ethnic group. Heart failure with preserved systolic function is characterized by unique clinical and angiographic characteristics associated with a 5-year mortality rate of 28%. Furthermore, several clinical and angiographic characteristics are predictive of long-term survival.

Reasons for underuse of angiotensin-converting enzyme inhibitors in patients with heart failure and left ventricular dysfunction.

We reviewed the records of 242 patients admitted over 1 year with heart failure and an ejection fraction < or = 45% to assess the use of angiotensin-converting enzyme inhibitors. Most patients were treated with angiotensin-converting enzyme inhibitors. However, an important minority (8%) had no apparent reason for the lack of this treatment, highlighting the need for strategies to increase the use of these beneficial agents.

Depression, coronary events, platelet inhibition, and serotonin reuptake inhibitors.

There is substantial clinical evidence that the incidence of depression and mortality after acute coronary events are strongly related. As mediators of coronary thrombosis, platelets may represent a link between these events, and could be possibly targeted by therapy with serotonin reuptake inhibitors.

Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS).

The Coumadin Aspirin Reinfarction Study demonstrated that combination treatment with fixed dose warfarin (1 or 3 mg) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infarction for reducing nonfatal reinfarction, nonfatal stroke, and cardiovascular death. In this analysis, we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke. The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg. In the Coumadin Aspirin Reinfarction Study, 2,028 patients were randomized to aspirin 80 mg plus warfarin 1 mg, and 3,393 were randomized to aspirin 160 mg alone. A predictive model for ischemic stroke was developed using the Cox proportional-hazards model. A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups. The incidence of ischemic stroke was lower in patients treated with aspirin 160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg (0.6% vs 1.1%; p = 0.0534). Age, previous stroke or transient ischemic attack, and aspirin dose were independent predictors of ischemic stroke. In addition, the highest risk patients, those with Q-wave myocardial infarction and male patients, appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg. The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infarction patients.

Beta-blocker therapy in advanced heart failure: clinical characteristics and long-term outcomes.

AIMS: To evaluate the clinical characteristics and long-term outcomes of advanced heart failure patients (NYHA Class IIIb-IV) receiving beta-blocker therapy vs. those patients not receiving beta-blockers at randomization in the FIRST trial, a randomized, double-blind, placebo-controlled trial of epoprostenol vs. usual care in advanced heart failure. METHODS AND RESULTS: The patient population consisted of 471 patients enrolled in FIRST with Class IIIb-IV heart failure, left ventricular ejection fraction (LVEF) of <30%, advanced hemodynamic abnormalities, and standard pharmacologic treatment of ACE-inhibitor, diuretics, and/or digoxin. The study cohort consisted of 448 patients not receiving beta-blockers and 23 patients receiving beta-blockers at randomization for the FIRST trial. Patients in the beta-blocker group had decreased rates of any clinical event (P = 0.03), worsening heart failure (P = 0.001), and death or worsening heart failure (P = 0.0008) than patients not receiving beta-blockers. After adjusting for prognostically important variables, the favorable effect of beta-blockers on worsening heart failure (P = 0.02) and death or worsening heart failure (P = 0.02) persisted. CONCLUSION: Patients with advanced heart failure who receive beta-blocker therapy have a lower rate of hospitalization and are less likely to experience worsening heart failure or death at 6 months than patients who are not treated with beta-blockers. These observational data contribute to the growing body of data demonstrating a favorable effect of beta-blockers on clinical outcomes in heart failure.

Clinical utility of the platelet function analyzer (PFA-100) for the assessment of the platelet status in patients with congestive heart failure (EPCOT trial).

BACKGROUND: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of platelet function analyzer (PFA-100) in the CHF population. METHODS: Blood samples were obtained for measurement of adenosine diphosphate (ADP)/collagen and epinephrine/collagen shear-induced closure time (CT), whole blood aggregation, platelet contractile force, activity of glycoprotein (GP) IIb/IIIa, and P-selectin receptors in 100 consecutive outpatients with CHF. RESULTS: Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings as well. CT correlates well with whole blood aggregometry (r(2)=.587) and less with GP IIb/IIIa activity (r(2)=.326). No correlation has been observed for the CT with the platelet-bound P-selectin (r(2)=.041) and platelet contractile force measures (r(2)=.028). CONCLUSIONS: PFA-100 is indeed capable to serve as a platelet analyzer and may be successfully used as a screening device. However, patients with heart failure enrolled in the EPCOT trial exhibited a marginal, sometimes oppositely directed changes in the platelet function, challenging the diagnostic utility of PFA-100 to serve as a useful tool for the identification of platelet abnormalities, predicting clinical outcomes, or for the monitoring of antiplatelet strategies in this population.

Practical issues in the treatment of patients with heart failure.

The management of heart failure is complex. Initiating and maintaining drug therapy in patients with heart failure can be challenging. Many factors influence the heart failure syndrome and are important to account for when evaluating these patients. Concomitant diseases such as ischemic heart disease and hypertension may contribute to worsening heart failure, and treatment strategies addressing these conditions should be implemented in affected patients. Concomitant drugs also must be considered. The heart failure population is at risk for drug interactions, both pharmacokinetic and pharmacodynamic, because these patients often take many drugs at the same time. Proactively recognizing potential interactions and modifying a patient's regimen to minimize or avoid adverse effects are important. Many agents are contraindicated in heart failure; thus, avoiding such therapies may significantly affect a patient's outcome. The successful treatment of a patient with heart failure requires careful consideration of many factors, including other diseases, drugs, and social issues. Addressing these factors when treating patients translates into improved pharmaceutical care.

Metoprolol CR/XL in the treatment of chronic heart failure.

Metoprolol CR/XL (metoprolol succinate extended-release tablets) is a beta1-selective agent that improved survival and reduced hospitalization among patients with New York Heart Association class II-IV heart failure in a randomized trial. Metoprolol CR/XL differs from conventional metoprolol tartrate with respect to pharmacokinetic and pharmacodynamic properties that may be clinically important in patients with heart failure. A thorough patient evaluation should be performed to determine optimal dosage and titration of this drug, as with any beta-blocker, and to assess the potential for drug-drug or drug-disease interactions. By applying knowledge of drug-specific characteristics and designing therapy for each individual patient, improvement in patient outcomes can be realized with metoprolol CR/XL.

Therapeutic range of digoxin's efficacy in heart failure: what is the evidence?

Clinical studies have solidified the utility of digoxin in patients with left ventricular dysfunction and normal sinus rhythm. No definitive data have been published to clarify the range of serum digoxin concentrations associated with clinical benefit. The traditional therapeutic range of 0.8-2.0 ng/ml was developed originally to classify digoxin toxicity, not efficacy. In addition, this reference range was used before publication of the Digitalis Investigators Group trial. Clinical and neurohormonal studies have attempted to characterize serum concentrations that are associated with clinical efficacy.

A prospective, open-label study of single-dose ciprofloxacin absorption after chemotherapy in patients with malignancy.

The absorption of a single oral dose of ciprofloxacin 750 mg in patients with cancer who had chemotherapy-induced Cancer and Leukemia Group B grade I or II mucositis was evaluated. Ciprofloxacin was administered after an overnight fast. Plasma samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose. Drug concentrations were determined by reverse-phase high-performance liquid chromatography with fluorescence detection. Pharmacokinetic values were characterized by noncompartmental methods. The mean +/- SD for area under the curve, mean peak concentration (C(max)), and time to C(max) (T(max)) were 18.7 +/- 5.03 mg/L x hour, 4.41 +/- 1.74 mg/L, and 1.81 +/- 0.843 hours, respectively. The absorption of oral ciprofloxacin in patients with chemotherapy-induced grade I or II mucositis compares with that in healthy volunteers. These findings may call for further pharmacokinetic evaluation of the drug in a similar patient population.

Hemostatic abnormalities in patients with congestive heart failure: diagnostic significance and clinical challenge.

Knowledge of the pathogenesis of congestive heart failure (CHF) has improved greatly in recent years. However, this disease continues to cause one of the highest morbidities and mortalities in the Western world. The pathophysiology of heart failure is complex and much of our understanding revolves strictly around the neurohormonal mechanisms involved. Various pharmacologic interventions have significantly improved morbidity and include ACE inhibitors, beta-blockers, diuretics, and inotropic agents. Yet, no consensus has been reached regarding the use of anticoagulants or antiplatelet agents. It has been suggested that CHF is associated with altered hemostasis, but whether this prothrombotic state contributes to the pathogenesis and progression of the disease is unknown. The purpose of this review article is to discuss our current knowledge of platelet activation, thrombin generation, fibrinolysis, and endothelial dysfunction in CHF patients, and the potential role of anticoagulants and/or antiplatelet agents in preventing these hemostatic abnormalities.

Disease management of congestive heart failure.

AUDIENCE: This article is designed for primary care physicians, cardiovascular specialists, medical directors, and other managed care administrators responsible for heart failure patients. GOAL: To provide the reader with a basic understanding of heart failure epidemiology, heart failure management, and different strategies for the management of this particular patient population. OBJECTIVES: 1. To describe the impact of heart failure on the healthcare system in the United States. 2. To briefly describe the current practice for managing heart failure. 3. To describe the evidence for care by cardiologists of heart failure patients. 4. To describe the different disease management strategies being utilized in heart failure management.

Possible interaction involving phenytoin, dexamethasone, and antineoplastic agents: a case report and review.

OBJECTIVE: To describe a patient with subtherapeutic phenytoin concentrations and to review the literature regarding a possible interaction between phenytoin and chemotherapeutic agents as well as dexamethasone. CASE SUMMARY: A 29-year-old white man with brain metastases secondary to malignant melanoma consistently had suboptimal phenytoin concentrations while receiving chemotherapy consisting of cisplatin, carmustine, dacarbazine, and tamoxifen. In addition, this patient received dexamethasone, which may have influenced his phenytoin concentrations. DATA SOURCES AND STUDY SELECTION: Case reports were identified through a MEDLINE search and by cross referencing the articles identified. DISCUSSION: The available literature addressing suboptimal phenytoin concentrations in the setting of chemotherapy is reviewed. Aggressive dosing of phenytoin may be required to achieve therapeutic concentrations in patients who are concurrently receiving chemotherapy and/or dexamethasone, especially in patients who fall outside the predictive pharmacokinetic model for phenytoin. CONCLUSIONS: Subtherapeutic phenytoin concentrations may be decreased secondary to several proposed mechanisms: (1) the patient falls outside the predicted pharmacokinetic population parameters for phenytoin, (2) phenytoin absorption is decreased secondary to chemotherapy-induced gastrointestinal toxicity, and (3) metabolism of phenytoin is increased secondary to chemotherapy agents.

Is optimal angiotensin-converting enzyme inhibitor dosing neglected in elderly patients with heart failure?

BACKGROUND: The benefit of angiotensin-converting enzyme (ACE) inhibitors on mortality in heart failure has been proved in randomized controlled trials. METHODS: We prospectively evaluated the prescribing of ACE inhibitors and the prescribing of target ACE inhibitor doses in 43 ambulatory patients with heart failure to identify differences in ACE inhibitor utilization among elderly and nonelderly patients. The prescribed ACE inhibitor dose and other variables were assessed by direct patient interview and information contained in the medical record. Telephone calls were conducted at 3 months to identify the occurrence of clinical events. RESULTS: Fewer elderly patients were prescribed target ACE inhibitor doses compared with nonelderly patients (21.4% vs 68.8%; p = 0.0136). Elderly patients were more likely to experience an event than nonelderly patients (11 vs 4; p = 0.0074). Elderly patients not receiving target ACE inhibitor doses demonstrated a trend toward more events than elderly patients who were at target doses. CONCLUSION: The data suggest that this group of elderly patients with heart failure who received lower ACE inhibitor doses appeared to be at higher risk for clinical events.

Failure of thrombin generation markers to triage patients presenting with chest pain.

Thrombin generation (TG) is an important pathogenic factor in acute coronary syndromes including acute myocardial infarction (AMI). Since the diagnostic utility of TG remains uncertain we sought to determine whether markers of TG may triage patients presenting to the Emergency Department with chest pain. Soluble plasma levels of prothrombin fragment 1+2 (F(1+2)), and thrombin/antithrombin III complexes (TAT) were determined by ELISA in 80 patients presenting with chest pain to the Emergency Department and compared with 20 controls. There were no differences in TG markers between patients with non-cardiac chest pain and healthy controls. Patients with unstable angina (UA), and congestive heart failure (CHF) did not differ from controls with respect to F(1+2), and TAT was elevated in UA patients (6.05 +/- 1.15 ng/ml, p = 0.033) when compared with controls (3.34 +/- 0.20 ng/ml). Contrary to expectations, TAT levels at presentation with AMI were well below the concentrations observed in patiens with UA and CHF. Moreover, plasma F(1+2) levels were significantly lower than in healthy controls (0.84 +/- 0.10 ng/ml versus 1.22 +/- 0.11, p = 0.026). At the time of presentation to the Emergency Department, F(1+2) and TAT failed to suitably triage patients with chest pain. The surprisingly low levels of TG markers in AMI patients before applying intensive therapy and reperfusion strategies deserves further investigation.

Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST).

OBJECTIVE: To evaluate clinical characteristics and outcomes of patients with advanced heart failure receiving intravenous continuous dobutamine in the FIRST Trial (Flolan International Randomized Survival Trial). METHODS: Four hundred seventy-one patients with class IIIb to IV heart failure who were enrolled in the FIRST trial were included. Eighty patients treated with dobutamine at FIRST randomization were compared with 391 patients not treated with dobutamine at randomization. The occurrence of worsening heart failure, need for vasoactive medications, resuscitated cardiac arrest, myocardial infarction, and total mortality were compared between the 2 groups. RESULTS: The dobutamine group had a higher occurrence of first event (85.3% vs 64. 5%; P =.0006) and a higher mortality rate (70.5% vs 37.1%; P =.0001) compared with the no dobutamine group. Intravenous continuous dobutamine was an independent risk factor for death after adjusting for baseline differences. CONCLUSIONS: Dobutamine use at the time of randomization was associated with a higher 6-month mortality rate. This effect persisted after adjustment for baseline differences. This analysis challenges the concept that continuous intravenous dobutamine is beneficial to advanced heart failure patients with respect to survival.

A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: the U.S. ecadotril pilot safety study.

OBJECTIVE: To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction