The shortcomings of clinical practice guidelines.

Accumulation of medical knowledge related to diagnosis and management over the last 5-6 decades has altered the course of diseases, improved clinical outcomes and increased survival. Thus, it has become difficult for the practicing physician to evaluate the long-term effects of a particular therapy on survival of an individual patient. Further, the approach by each physician to an individual patient with the same disease is not always uniform. In an attempt to assist physicians in applying newly acquired knowledge to patients, clinical practice guidelines were introduced by various scientific societies. Guidelines assist in facilitating the translation of new research discoveries into clinical practice; however, despite the improvements over the years, there are still several issues related to guidelines that often appear 'lost in translation'. Guidelines are based on the results of randomized clinical trials, other nonrandomized studies, and expert opinion (i.e. the opinion of most members of the guideline committees). The merits and limitations of randomized clinical trials, guideline committees, and presentation of guidelines will be discussed. In addition, proposals to improve guidelines will be presented.

Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

BACKGROUND: Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. METHODS: The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. RESULTS AND CONCLUSIONS: The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.

Changes in plasma profiles of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in stress-induced cardiomyopathy.

BACKGROUND: Transient changes in the composition of the myocardial extracellular matrix may contribute to the ventricular systolic dysfunction in stress-induced cardiomyopathy (SIC). We examined the changes in plasma matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that occur early after the clinical presentation of SIC. METHODS AND RESULTS: Ten patients with SIC were enrolled. Plasma concentrations of the 6 major MMPs (1, 2, 3, 7, 8, and 9) and all 4 TIMPs (1, 2, 3, and 4) were analyzed and compared with data from 15 control subjects. Within 24 hours of the clinical presentation, SIC patients had lower MMP-1 levels (0.41 ± 0.13 vs 0.70 ± 0.13 pg/mL; P = .048) and MMP-8 levels (1.61 ± 0.34 vs 4.84 ± 1.38 pg/mL; P = .001) and higher TIMP-4 levels (3.06 ± 0.40 vs 2.16 ± 0.18 pg/mL; P = .05) compared with control. Seven of 9 SIC patients had elevated LV end-diastolic pressures, and all had normal LV end-diastolic dimensions and volumes. CONCLUSIONS: Patients afflicted with SIC had MMP and TIMP profiles similar to those described in hypertensive heart disease and diastolic heart failure and different from the profiles following myocardial infarction. Our findings uncovered a unique biomolecular profile in SIC during the first 24 hours of presentation.

Latent development of occlusive coronary atherosclerosis as a cause of decompensation of non-ischemic dilated cardiomyopathy.

Four patients with chronically well-compensated, non-ischemic dilated cardiomyopathy (NIDC) presented with occlusive atherosclerotic coronary artery disease as the cause of subacute decompensation (FC III-IV heart failure) 8-13 years following the diagnosis of NIDC. In addition to the atherogenic condition of heart failure, 3 of the patients acquired major atherosclerotic risk factors (dyslipidemia, diabetes mellitus) during the interval between the diagnoses of NIDC and problematic atherosclerotic coronary disease. For each patient, dyspnea on exertion was the primary symptom during the subacute decompensation. Only 1 patient noted precordial chest pain in the form of atypical angina during some of the dyspneic events. The diagnosis of occlusive coronary artery disease was made by coronary angiography, followed by angioplasty-stent deployment in 3 patients and coronary artery bypass surgery in 1; all improved to their baseline FC I-II status following these coronary interventions. As survival of patients with NIDC increases, occlusive coronary artery disease may enter an otherwise stable clinical course to provoke unanticipated decompensation (principally dyspnea), and can do so without causing angina pectoris as a heralding symptom.

Are hemodynamic parameters predictors of mortality?

This article addresses a question that the authors consider to be somewhat rhetorical: are hemodynamic parameters predictors of mortality? It reviews the specific hemodynamic abnormalities and pathophysiologic consequences distinctive to the patient who has decompensation and addresses the data that implicate abnormal hemodynamics as a treatment target associated with increased mortality. The focus is on patients who have decompensated heart failure, defined as left ventricular systolic dysfunction and an acute, subacute, or gradual worsening of symptoms while receiving optimal medical therapy.

Role of the pulmonary artery catheter in diagnosis and management of heart failure.

The pulmonary artery catheter will likely earn a place in the history of medicine as one of the most useful tools that shaped our understanding and management of various diseases. An intense assessment of its application in nonacute and nonshock decompensated heart failure has been provided by the ESCAPE trial, a landmark investigation that showed an overall neutral impact of pulmonary artery catheter-guided therapy over therapy guided by clinical evaluation and judgment alone. The current guidelines reserve the use of a pulmonary artery catheter for the management of refractory heart failure and select conditions. The pulmonary artery catheter remains a useful instrument in clinical situations when clinical and laboratory assessment alone is insufficient in establishing the diagnosis and pathophysiologic condition, and in guiding effective, safe therapy.

Recovery of normal ventricular function in patients with dilated cardiomyopathy: predictors of an increasingly prevalent clinical event.

BACKGROUND: This investigation was designed to identify clinical variables associated with recovery of normal ventricular function in patients with dilated cardiomyopathy treated with medical therapy. Recovery of normal ventricular function with medical treatment of patients with dilated cardiomyopathy is observed with increasing frequency. However, the clinical variables associated with such dramatic improvement of ventricular performance are poorly defined. METHODS: Fifty-three patients with dilated cardiomyopathy and reduced ejection fractions who achieved an increase in ejection fraction to > or = 40% with medical therapy were identified during follow-up in a dedicated heart failure clinic. A cohort of patients frequency-matched on baseline ejection fraction who did not recover ventricular systolic function to this magnitude constituted the control group. Clinical variables characterizing the 2 groups were compared by univariable analysis. Variables that significantly differed between the 2 groups were entered in a stepwise logistic regression analysis to identify factors independently associated with recovery of ejection fraction to > or = 40%. RESULTS: In the final logistic regression model, QRS duration, sex, etiology of cardiomyopathy, diabetes, and systolic blood pressure were significantly associated with improvement of ejection fraction to > or = 40%. CONCLUSIONS: Five clinical variables that are independently associated with improvement of left ventricular ejection fraction to normal or near-normal values with medical therapy alone were identified by this modeling process. These variables may be used to discriminate between patients in whom ventricular function will normalize with medical therapy alone and those who will require more aggressive pharmacologic or device therapy.

High mortality without ESCAPE: the registry of heart failure patients receiving pulmonary artery catheters without randomization.

BACKGROUND: In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), there was no difference in days alive and out of the hospital for patients with decompensated heart failure randomly assigned to therapy guided by pulmonary artery catheter (PAC) plus clinical assessment versus clinical assessment alone. The external validity of these findings is debated. METHODS AND RESULTS: ESCAPE sites enrolled 439 patients receiving PAC without randomization in a prospective registry. Baseline characteristics, pertinent trial exclusion criteria, reasons for PAC use, hemodynamics, and complications were collected. Survival was determined from the National Death Index and the Alberta Registry. On average, registry patients had lower blood pressure, worse renal function, less neurohormonal antagonist therapy, and higher use of intravenous inotropes compared with trial patients. Although clinical assessment anticipated less volume overload and greater hypoperfusion among the registry population, measured filling pressures were similarly elevated in the registry and trial patients, whereas measured perfusion was slightly higher among registry patients. Registry patients had longer hospitalization (13 vs 6 days, P < .001) and higher 6-month mortality (34% vs 20%, P < .001) than trial patients. CONCLUSIONS: The decision to use PAC without randomization identified a population with higher disease severity and risk of mortality. This prospective registry highlights the complex context of patient selection for randomized trials.

Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure.

BACKGROUND: Treatment of decompensated heart failure often includes the use of intravenous vasoactive medications, but the effect on outcome has not been clearly defined. METHODS: Data from 433 patients enrolled in the ESCAPE trial were analyzed to determine 6-month risks of all-cause mortality and all-cause mortality plus rehospitalization associated with the use of vasodilators, inotropes, and their combination. Patients had a mean left ventricular ejection fraction of 19%, 6-minute walk distance of 414 ft, and systolic blood pressure of 106 mm Hg. The main outcome measure was multivariable risk-adjusted 6-month hazard ratios (HRs). RESULTS: Overall 6-month mortality was 19%. Risk-adjusted HRs were not statistically significant for vasodilators (1.39, 95% CI 0.64-3.00), but were significant for inotropes (2.14, 95% CI 1.10-4.15) and the combination (4.81, 95% CI 2.34-9.90). Risk-adjusted 6-month mortality plus rehospitalization HRs were not significant for vasodilators (1.20, 95% CI 0.81-1.78, P = .37), but were significant for inotropes (1.96, 95% CI 1.37-2.82, P < .001) and their combination (2.90, 95% CI 1.88-4.48, P = .001). The decision to use vasodilators or inotropes was determined by hemodynamic parameters and renal function, but the main factor was treatment site. CONCLUSIONS: In ESCAPE, the choice of medications was mainly determined by the treatment site. Use of inotropic agents was associated with adverse outcomes, whereas the use of vasodilators was not. Inotropes in combination with vasodilators identified a group with the highest mortality. Prospective studies are needed to establish the appropriate use of vasoactive medications in this population.

Low-dose oral enoximone enhances the ability to wean patients with ultra-advanced heart failure from intravenous inotropic support: results of the oral enoximone in intravenous inotrope-dependent subjects trial.

BACKGROUND: We determined whether low-dose oral enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (i.v.) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value. METHODS: In this placebo-controlled study, 201 subjects with UA-HF requiring i.v. inotropic therapy were randomized to enoximone or placebo. Subjects receiving intermittent i.v. inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous i.v. inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days. RESULTS: Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the enoximone group were alive and free of i.v. inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of i.v. inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the enoximone group. CONCLUSIONS: Although there was no benefit over placebo in weaning patients from i.v. inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral enoximone can be used to wean a modest percentage of subjects from i.v. inotropic support for up to 90 days after initiation of therapy.

Prediction of rehospitalization and death in severe heart failure by physicians and nurses of the ESCAPE trial.

BACKGROUND: The predictive accuracy of physician investigators and nurse coordinators in estimating the risk of rehospitalization and death was determined for 373 hospitalized patients with severe advanced heart failure enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. METHODS AND RESULTS: Estimates were made at discharge, and patients were followed for 6 months after hospitalization. A statistical prognostic model was developed from clinical and laboratory data for the end points of rehospitalization and death. Both nurse and physician predictions of death were generally associated with the observed deaths (c-indices of 0.675 and 0.611), although the nurses' prediction was significantly better (chi-square = 4.75, P = .029). The prediction ability of the prognostic model was similar to the physicians' model (c-index = 0.603). The predictions of rehospitalization were much weaker for nurse, physician and prognostic models. CONCLUSIONS: Nurses' estimations of survival in discharged, advanced-stage heart failure patients were superior to either physicians' or model-based predictions. Not nurses, physicians, or the prognostic model provided useful predictions for rehospitalizations, but this may have resulted from the fact that the rehospitalization estimates did not include the death risk.

Invasive hemodynamic monitoring the aftermath of the ESCAPE trial.

The Swan-Ganz catheter was developed 35 to 40 years ago for intensive and cardiac care units to allow bedside placement and continuous monitoring and recording of right-sided heart, pulmonary artery, and wedge pressures and reasonably accurate determinations of cardiac output. Considerations for the clinical application of this balloon-tip, flow-directed, multilumen, thermodilution pulmonary artery catheter in the post-ESCAPE era are presented.

The physical examination in heart failure--Part I.

The major components and merits of the physical examination of patients with heart failure are presented. A staging of the physical examination practiced by most heart failure specialists is proposed based on the information needed at the time of the encounter. The challenges to our subspecialty regarding this diagnostic tool are the prevention of its extinction during an era of seemingly limitless comprehensive laboratory testing, the promotion of its widespread use, and, over the years, the subjection of its components to the rigors of blinded controlled studies. Part I addresses the staging of the physical examination in heart failure, general observation of the patient, vital signs, and assessment of arterial pulse and neck veins.

The physical examination in heart failure--Part II.

The major components of the physical examination of patients with heart failure are presented to allow practical application by physicians and nurses working in this arena. Part II contains the key elements of the chest, precordial-cardiac, hepatic, and peripheral examination in this specific clinical setting. Supplemental maneuvers are provided. Finally, the overall role and merits of the physical examination in managing the heart failure patient are discussed.

Stenotic aortic and mitral valves in three adult brothers with arthrogryposis multiplex congenita.

Three brothers with arthrogryposis multiplex congenita survived into adulthood. In their fourth decade, the clinical course for each brother became complicated by severe stenoses of their aortic and mitral valves. One brother died suddenly, and the remaining 2 developed heart failure. requiring valvular replacement.

Natural course of large spontaneous pneumothorax.

A large pneumothorax was detected on chest x-ray film in a 41-year-old woman. She declined recommendations for evacuation of the air trapped in her right chest. The condition spontaneously resolved during 3 months after being detected.

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.

CONTEXT: Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE: To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES: The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS: Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS: Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Time intervals of cardiac resynchronization therapy in heart failure.

Systolic and diastolic time intervals were measured in 11 patients with heart failure before and 1 and 3 months after the placement of atrial biventricular pacemakers for cardiac resynchronization therapy (CRT). CRT shortened the preejection period, principally by reducing left ventricular (LV) electromechanical delay with lesser reduction of isovolumic contraction time, and shortened the duration of LV systole, with a consequent trend of lengthening diastolic time.

Dobutamine-induced eosinophilia.

A man with dilated cardiomyopathy presented with decompensated heart failure and marked eosinophilia. After extensive clinical and laboratory evaluation for hypereosinophilic syndrome, including a myocardial biopsy, it was determined by means of rechallenge (second dobutamine infusion) that the patient was afflicted with dobutamine-induced eosinophilia. This report is important because of the high utilization rate of this drug in a sick population. Simply discontinuing it or switching to another agent can avert the high cost and risk of the evaluation for hypereosinophilic syndrome in this compromised group of patients.