Karen A. Hartman

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness

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.

Serial Biomarker Measurements in Ambulatory Patients With Chronic Heart Failure The Importance of Change Over Time

Background— Cardiac troponin T (cTnT) and B-type natriuretic peptide (BNP) have been used to estimate prognosis in heart failure; however, most studies have evaluated decompensated patients with single measurements. To determine if there are advantages to serial measurements, we evaluated stable chronic heart failure patients every 3 months for 2 years. Methods and Results— A cohort of 190 New York Heart Association class III–IV heart failure patients was prospectively enrolled from June 2001 to January 2004. Primary end points were death, cardiac transplantation, or hospitalization. At study enrollment cTnT was <0.01 ng/mL in 87 (45.8%) patients, 0.01 to 0.03 ng/mL in 50 (26.3%) patients, and >0.03 ng/mL in 53 (27.9%) patients. An increase in cTnT above normal (<0.01 ng/mL) carried a 3.4-fold increased risk (P=0.019). Further increases (≥20%) from an elevated level worsened the overall risk (hazard ratio, 5.09; P<0.001). BNP was elevated (>95th percentile for age and gender normal population) in 122 (64.2%) patients. An elevation of BNP from normal at any time during the study was associated with a poor outcome, but, once elevated, further changes in BNP (increases or decreases) remained associated with the same risk (hazard ratio, 5.09; P<0.001). Combined elevations of cTnT (>0.03 ng/mL) and BNP defined the highest risk group (hazard ratio, 8.58; P<0.001). Conclusions— Elevations of cTnT or BNP from normal detected at any time during clinical follow-up in ambulatory patients with chronic heart failure are highly associated with an increased risk of events. Further increases in cTnT contribute to additional risk. Combined elevations of cTnT and BNP contribute the highest risk. The ability to monitor changes by serial measurements adds substantially to the assessment of risk in this patient population.

Profiles of Serial Changes in Cardiac Troponin T Concentrations and Outcome in Ambulatory Patients With Chronic Heart Failure

OBJECTIVES The purpose of this study was to determine whether different profiles of cardiac troponin T (cTnT) values assessed over time would yield incremental prognostic information on clinically stable outpatients with heart failure (HF). BACKGROUND cTnT levels were used to estimate prognosis in HF; however, most studies evaluated hospitalized patients using single measurements. METHODS A cohort of 172 New York Heart Association functional class III to IV outpatients was prospectively studied with serial cTnT measurements collected every 3 months over a 2-year period. The primary end point was death or cardiac transplantation, and secondary end points included HF hospitalization. RESULTS Of the 172 patients, 22 (13%) died or underwent transplantation during the first year. Therefore, 150 patients were included in the second-year analysis of 3 pre-determined groups: 1) no serial cTnT elevations (defined as <0.01 ng/ml); 2) 1 or more, but not all cTnT values elevated > or =0.01 ng/ml; and 3) all cTnT values elevated during the first year. During the second year, 30 events occurred: 53 patients had persistently normal cTnT levels (<0.01 ng/ml) with 6 primary events (11%); 57 patients had 1 or more but not all cTnT levels elevated with 11 events (19%); 40 patients demonstrated persistently elevated cTnT levels with 13 (33%) primary events (odds ratio: 3.77; 95% confidence interval: 1.28 to 11.07, p = 0.02). CONCLUSIONS Elevations in cTnT, even using a low threshold of 0.01 ng/ml, detected during routine clinical follow-up of ambulatory patients with HF, are highly associated with an increased risk of events, particularly with frequent or persistent cTnT elevations of > or =0.01 ng/ml. Therefore, the ability to monitor clinical change through serial cTnT measurements may add to risk assessment in the ambulatory HF population.

Improvement in Health-related Quality of Life After Hospitalization Predicts Event-free Survival in Patients With Advanced Heart Failure

BACKGROUND Health-related quality of life (HRQOL) is a major clinical outcome for heart failure (HF) patients. We aimed to determine the frequency, durability, and prognostic significance of improved HRQOL after hospitalization for decompensated HF. METHODS AND RESULTS We analyzed HRQOL, measured serially using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), for 425 patients who survived to discharge in a multicenter randomized clinical trial of pulmonary artery catheter versus clinical assessment to guide therapy for patients with advanced HF. All patients enrolled had 1 or more prior HF hospitalizations or chronic high diuretic doses and 1 or more symptom and 1 sign of fluid overload at admission. Improvement, defined as a decrease of more than 5 points in MLHFQ total score, occurred in 68% of patients by 1 month and stabilized. The degree of 1-month improvement differed (P < .0001 group x time interaction) between 6-month survivors and non-survivors. In a Cox regression model, after adjustment for traditional risk factors for HF morbidity and mortality, improvement in HRQOL by 1 month compared to worsening at 1 month or no change predicted time to subsequent event-free survival (P=.013). CONCLUSIONS In patients hospitalized with severe HF decompensation, HRQOL is seriously impaired but improves substantially within 1 month for most patients and remains improved for 6 months. Patients for whom HRQOL does not improve by 1 month after hospital admission merit specific attention both to improve HRQOL and to address high risk for poor event-free survival.

Serial measurements of midregion proANP and copeptin in ambulatory patients with heart failure: incremental prognostic value of novel biomarkers in heart failure

Background Disease progression in heart failure (HF) reflects derangements in neurohormonal systems, and biomarkers of these systems can help to establish the diagnosis and assess the prognosis. Serial measurements of the precursor peptides of the natriuretic and vasopressin systems (midregional proatrial natriuretic peptide (MR-proANP) and C-terminal provasopressin (copeptin), respectively) should add incremental value to risk stratification in ambulatory patients with HF. Methods and results A cohort of 187 patients with class III–IV HF was prospectively enrolled, with biomarkers collected every 3 months over 2 years and analysed in relation to death/transplantation. Time-dependent analyses (dichotomous and continuous variables) showed that increases in MR-proANP (HR 7.6, 95% CI 1.85 to 31.15, p<0.01) and copeptin (HR 2.7, 95% CI 1.27 to 5.61, p=0.01) were associated with increased risk, but, in multivariate analysis adjusted for troponin T (cTnT) ≥0.01 ng/ml, only raised MR-proANP remained an independent predictor (HR 5.49, 95% CI 1.31 to 23.01, p=0.02). Combined increases in MR-proANP and copeptin (HR 9.01, 95% CI 1.24 to 65.26, p=0.03) with cTnT (HR 11.1, 95% CI 1.52 to 80.85, p=0.02), and increases ≥30% above already raised values identified the patients at greatest risk (MR-proANP: HR 10.1, 95% CI 2.34 to 43.38, p=0.002; copeptin: HR 11.5, 95% CI 2.74 to 48.08, p<0.001). Conclusions A strategy of serial monitoring of MR-proANP and, of lesser impact, copeptin, combined with cTnT, may be advantageous in detecting and managing the highest-risk outpatients with HF.

Relation of ADRB1, CYP2D6, and UGT1A1 Polymorphisms With Dose of, and Response to, Carvedilol or Metoprolol Therapy in Patients With Chronic Heart Failure

The response to beta blockers in patients with heart failure could be associated with the genotype of drug-metabolizing enzymes and/or drug targets. The purpose of the present study was to determine whether specific genetic polymorphisms in ADRB1 (encoding the beta1-adrenergic receptor), CYP2D6, and UGT1A1 correlated with dose of, or response to, metoprolol or carvedilol treatment in patients with heart failure. A cohort of patients with heart failure (n = 93), characterized as responders or nonresponders to metoprolol (n = 19) or carvedilol (n = 74) therapy, was retrospectively identified. Individual genotyping was performed for a panel of polymorphisms in the ADRB1, CYP2D6, and UGT1A1 genes. Univariate and multivariate analyses were performed to compare the genotype to the metoprolol or carvedilol response status and dose. A nonresponse was identified in 10 of 19 patients taking metoprolol and 32 of 74 patients taking carvedilol. None of the polymorphisms in ADRB1, CYP2D6, and UGT1A1 were associated with a response or nonresponse. However, a significant relation between the carvedilol (but not metoprolol) dose and the ADRB1 and CYP2D6 genotype was observed. Patients homozygous for the ADRB1 389Gly variant or who were CYP2D6 poor metabolizers achieved a significantly higher dose of carvedilol (p = 0.01 and p = 0.02, respectively). In conclusion, polymorphisms in ADRB1, CYP2D6, and UGT1A1 were not associated with a response to metoprolol or carvedilol therapy in our cohort of patients with heart failure. The ADRB1 and CYP2D6 genotype, alone and in haplotype, were significantly associated with the dose of carvedilol.

Only Large Reductions in Concentrations of Natriuretic Peptides (BNP and NT-proBNP) Are Associated with Improved Outcome in Ambulatory Patients with Chronic Heart Failure

BACKGROUND Concentrations of B-type natriuretic peptides (BNPs), including N-terminal pro-B-type natriuretic peptide (NT-proBNP), can be used to estimate prognosis in chronic heart failure. Large biologic variability, however, limits the usefulness of serial measurements in individual patients. As a result, the magnitude of change in peptide concentrations that is clinically meaningful remains to be established. METHODS We studied 172 New York Heart Association class III-IV outpatients. Primary endpoints were death/transplantation or heart failure hospitalization. The magnitude of peptide changes was categorized as no change (<20% increase or decrease from enrollment), > or =20% to < or =80% increase or decrease; and >80% increase or decrease. Changes were also assessed using cutpoints (500 ng/L for BNP and 1000 ng/L for NT-proBNP). RESULTS Fifty-two patients died or received transplants during the course of the study. Risk reduction for heart failure hospitalization was demonstrated only for BNP decreases of >80% from enrollment [hazard ratio (HR) 0.318, P = 0.0315]. BNP increases from less than to more than the prespecified cutpoint of 500 ng/L were associated with increased mortality risk (HR 2.101, P = 0.0069), whereas decreases from more than to less than the cutpoint did not reduce risk. NT-proBNP decreases from more than to less than the cutpoint of 1000 ng/L were associated with reduced risk of death/transplantation (HR 0.119, P = 0.0354). CONCLUSIONS BNP increases from less than to more than the cutpoint were associated with increased risk of events, whereas further increases did not add to risk. In contrast, only substantial natriuretic peptide decreases (>80%) reduced risk. These data suggest that only robust decreases in natriuretic peptide concentrations should be targeted to reduce mortality and heart failure-related hospitalizations.

Role for precursor Pro-B type natriuretic peptide in assessing response to therapy and prognosis in patients with decompensated heart failure treated with nesiritide.

BACKGROUND ProBNP, the precursor peptide to BNP and NT-proBNP (NP), circulates in patients with chronic heart failure (HF) and appears to be the predominant form of NP. This heterogeneity may confound interpretation of NP concentrations. The aim of this study was to evaluate the response to therapy and prognostic influence of proBNP in a cohort of patients admitted to hospital for decompensated HF. METHODS We prospectively evaluated 40 Class III-IV patients who received clinically-indicated nesiritide infusions as part of their care. Blood was drawn before, during, and post-infusion, and assayed for proBNP, BNP, and NT-proBNP. RESULTS All biomarkers were increased at baseline consistent with HF. ProBNP and NT-proBNP demonstrated significant reductions in response to therapy (42% and 18% post-infusion, respectively). In the patients who experienced post-hospital mortality (40% at 6 months), baseline proBNP and BNP concentrations were significantly lower than in survivors. This paradoxical finding may be explained by the end-stage nature of this patient cohort possibly experiencing exhaustion of their NP systems. CONCLUSIONS Circulating concentrations of proBNP are increased in decompensated HF and similar to NT-proBNP are reduced in response to acute therapy. Paradoxically and similar to BNP, baseline proBNP concentrations were lower in post-hospital non-survivors. While hypothesis generating, the results of this study support a role for proBNP in monitoring therapy and predicting short-term outcome. These findings need to be confirmed in a patient cohort without nesiritide therapy and more moderate HF.

Support for investigator-initiated clinical research involving investigational drugs or devices: the Clinical and Translational Science Award experience.

Purpose Investigator-initiated research involving investigational drugs and devices is key to improving health. However, this requires the investigator to serve as a “sponsor–investigator,” which can be complex and overwhelming. The Investigational New Drug/Investigational Device Exemption (IND/IDE) Taskforce of the Clinical and Translational Science Award (CTSA) consortium carried out a survey to examine how academic health centers (AHCs) assist sponsor–investigators with regulatory responsibilities. Method The 24 CTSA centers existing in 2008 were surveyed regarding regulatory oversight and support for sponsor–investigators. Responses were analyzed by descriptive statistics. The evaluation of survey responses yielded three models of institutional support/oversight. Results Nineteen centers and one affiliate responded. Eleven (55%) reported having an IND/IDE support office, increased from five (25%) prior to their CTSA award. The volume of investigator-initiated IND/IDE research was highly variable (measured by numbers of investigators, IND/IDE applications, and studies). Oversight, if done, was provided by either the IND/IDE office or elsewhere in the institution. Most IND/IDE offices assisted with IND/IDE submissions and preparation for external audits. Half reported advanced training for sponsor–investigators. Almost all reported a goal to increase IND/IDE research. Important issues include the need for robust training of investigator/staff, appropriate determination of IND-exempt research, and sufficient support for preparing IND/IDE applications. Conclusions Investigator-initiated research involving IND/IDEs is essential, but complex. AHCs should examine how they support sponsor–investigators in meeting the complex requirements. A model of either expert consultation/support or full service will minimize risks to participants and institutions, and regulatory noncompliance.

Response of novel biomarkers to BNP infusion in patients with decompensated heart failure: a multimarker paradigm.

Multibiomarker paradigms have been proposed to diagnose, define progression, and to monitor therapy of heart failure (HF) patients. The aim of this study was to evaluate the prognostic and therapy-monitoring potential of four novel biomarkers (copeptin, midregional proatrial natriuretic peptide (MR-proANP), neopterin, and procalcitonin) which have been shown to be elevated in the plasma of patients with HF and reported to have prognostic value. In a prospective study of 40 patients hospitalized for decompensated HF and who received nesiritide infusions as part of their care, blood was drawn before, during, and postinfusion and assayed for the novel biomarkers. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) which were previously measured and reported in this cohort were also included in the analyses. All biomarkers were elevated at baseline prior to nesiritide infusion, but copeptin, MR-proANP, and NT-proBNP demonstrated significant acute reductions in plasma levels in response to therapy. Copeptin levels were higher in posthospital nonsurvivors and by proportional hazards model were associated with an increased mortality risk (p = 0.04). Procalcitonin and neopterin added no incremental information on response to therapy or risk stratification. In contrast, copeptin and MR-proANP appear to have potential for monitoring acute responses to therapy. Only copeptin and BNP contributed to risk stratification in this cohort of advanced HF patients, but the conjoint use of BNP or NT-proBNP does not appear to impact the prognostic value of copeptin alone. These results are hypothesis generating to stimulate additional investigation.