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Heart Failure
Prognostic Impact of Plasma N-Terminal Pro–Brain
Natriuretic Peptide in Severe Chronic
Congestive Heart Failure
A Substudy of the Carvedilol Prospective Randomized Cumulative
Survival (COPERNICUS) Trial
Franz Hartmann, MD; Milton Packer, MD; Andrew J.S. Coats, MD; Michael B. Fowler, MD; Henry Krum, MB, BS, PhD; Paul Mohacsi, MD; Jean L. Rouleau, MD; Michal Tendera, MD; Alain Castaigne, MD; Stefan D. Anker, MD; Ildiko Amann-Zalan, MD, PhD; Background—The utility of N-terminal proBNP (NT-proBNP) to predict the occurrence of death and hospitalization was
prospectively evaluated in the COPERNICUS study, which enrolled patients with an ejection fraction Ͻ25% andsymptoms of chronic congestive heart failure at rest or on minimal exertion.
Methods and Results—Baseline plasma concentrations of NT-proBNP were measured in a subgroup of 814 men and 197
women with symptoms at rest or on minimal exertion who were enrolled in the COPERNICUS study and wererandomized to placebo (nϭ506) or carvedilol (nϭ505). Values of NT-proBNP were markedly increased despite therequirement that patients be euvolemic before the start of treatment (meanϮSD, 3235Ϯ4392 pg/mL; median, 1767pg/mL). By univariate Cox regression analysis, NT-proBNP was found to be a powerful predictor of subsequentall-cause mortality (relative risk [RR], 2.7; 95% CI, 1.7 to 4.3; Pϭ0.0001 for above versus below median) and all-causemortality or hospitalization for heart failure (RR, 2.4; 95% CI, 1.8 to 3.4; Pϭ0.0001 for above versus below median).
The predictive value of NT-proBNP was similar when both placebo and carvedilol patients were analyzed separately.
No significant interaction was found between NT-proBNP and treatment group (Pϭ0.93 for above- versus below-median NT-proBNP).
Conclusions—NT-proBNP was consistently associated with increased risk for all-cause mortality and for all-cause
mortality or hospitalization for heart failure in patients with severe congestive heart failure, even in those who were
clinically euvolemic. This marker therefore may be a useful tool in risk stratification of patients with severe congestive
heart failure. (Circulation. 2004;110:1780-1786.)
Key Words: heart failure Ⅲ natriuretic peptides Ⅲ prognosis
The association of neurohormonal activation with cardiac in patients with heart failure,7–9 indicating that NT-proBNP events in chronic congestive heart failure (CHF) is well might be a more sensitive cardiac marker than BNP.
established.1–4 Recently, natriuretic peptides, particularly NT-proBNP has been shown to be an independent indica- brain natriuretic peptide (BNP), were introduced as biochem- tor of survival in patients after myocardial infarction10,11 and ical indicators of impaired left ventricular function.5,6 Several in patients with established ischemic heart failure (NYHA assays measuring different peptides were developed and class II to III).12 So far, however, the predictive value of found to be suitable for risk stratification. Immunoreactive NT-proBNP plasma measurements has not been prospec- amino-terminal (NT) proBNP is present in human plasma tively evaluated in a large cohort of patients with symptoms with concentrations similar to that of BNP in subjects with normal left ventricular function. Compared with BNP, a higher The Carvedilol Prospective Randomized Cumulative Sur- absolute and relative increase in NT-proBNP has been observed vival (COPERNICUS) trial included the most severe heart Received June 26, 2002; de novo received October 25, 2003; revision received May 12, 2004; accepted May 21, 2004.
From Medizinische Klinik II, Universitaetsklinikum Schleswig-Holstein, Campus Luebeck, Luebeck (F.H.); Carvedilol Prospective Randomized Cumulative Survival Study Group (M.P., A.J.S.C., M.B.F., H.K., P.M., J.L.R., M.T., A.C.); Applied Cachexia Research, Department of Cardiology,Charite, Campus Virchow-Klinikum, Berlin (S.D.A.); Roche Diagnostics GmbH Mannheim (I.A.-Z.); Koehler GmbH, Freiburg (S.H.); and InnereMedizin III, Medizinische Universitätsklinik Heidelberg, Heidelberg (H.A.K.), Germany.
Correspondence to Dr F. Hartmann, Medizinische Klinik II, Universitaetsklinikum Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany. E-mail [email protected] 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000143059.68996.A7
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failure patients of all ␤-blocker trials conducted so far. This action between treatment and NT-proBNP, an interaction term was trial provided the unique opportunity to prospectively test the added to the multivariate model (interaction term is 1 for carvedilol predictive power of biochemical indexes of heart failure treatment and NT-proBNP above the median and 0 otherwise).
Statistical significance was defined as PϽ0.05 (2 tailed).
when clinical findings indicated severe disease. We hypoth-esized that plasma levels of NT-proBNP might identify patients at particularly high risk for an adverse outcome inindividuals with symptoms of severe chronic CHF. We Clinical Data
Treatment effects with carvedilol in the COPERNICUS study
further speculated that benefit from carvedilol treatment have been reported recently.13 In total, 2289 patients (1133 might be more pronounced in the patients with high NT- placebo, 1156 carvedilol) were analyzed. The Kaplan-Meier estimate of 1-year cumulative mortality rate was 14.9% (18.5% in the placebo group compared with 11.4% in the Methods and results of the COPERNICUS study have been reported carvedilol group). The risk of death was reduced by 35% elsewhere.13 The NT-proBNP substudy was approved by the CO- (relative risk [RR], 0.65, 95% CI, 0.52 to 0.81) for patients PERNICUS Steering Committee before the start of the main study treated with carvedilol. The corresponding annual hazard and was coordinated by the University Hospital of Luebeck in rates were 19.7% for placebo and 12.8% for carvedilol. In the cooperation with Roche Diagnostics GmbH. The institutional ethics NT-proBNP substudy, 1011 European patients (506 placebo, committees of the participating study sites approved the substudyprotocol. Written informed consent was obtained from all patients.
505 carvedilol) were analyzed. Patient characteristics indicate In COPERNICUS, 2289 patients with severe chronic CHF, left that the substudy population was comparable to the total ventricular ejection fraction Ͻ25%, and symptoms at rest or on COPERNICUS study population regarding age, sex, cause of minimal exertion despite appropriate conventional therapy for heart heart failure, left ventricular ejection fraction, heart rate, and failure were randomized to receive placebo or carvedilol. Patients other clinical findings (Table 1). In addition, overall survival had to be clinically euvolemic (defined as the absence of rales andascites and no more than minimal peripheral edema) and could not be distributions were similar in both the substudy and the main enrolled if they needed intensive care or treatment with intravenous COPERNICUS trial. In the NT-proBNP subpopulation, the inotropic agents or intravenous vasodilators within 4 days of screen- Kaplan-Meier estimate of 1-year cumulative mortality rate ing. Serum creatinine had to be Յ2.8 mg/dL or 250 ␮mol/L at was 13.4% (18.1% in the placebo group compared with 8.5% randomization and must not have increased Ͼ0.5 mg/dL or 44.2 ␮mol/L during the screening phase. Carvedilol/placebo doses were in the carvedilol group). The risk of death was reduced by uptitrated at 2-week intervals to a target dose of 25 mg twice daily 38% (RR, 0.625; 95% CI, 0.40 to 0.99) for patients treated or, if the patient was intolerant, to the highest tolerated dose. Patients with carvedilol. The corresponding annual hazard rates were then continued on the highest tolerated dose until the end of the trial.
18.1% for placebo and 11.3% for carvedilol.
Patients were followed up for up to 29 months. The Data and Safety The baseline NT-proBNP concentrations ranged from the Monitoring Board stopped the trial program early because of amarked effect of carvedilol on survival.
detection limit to 35830 pg/mL, with a median of 1767 (25th In a prospective protocol, 1011 of the 1387 European patients to 75th percentiles, 748 to 3927 pg/mL) and a meanϮSD of were included in the NT-proBNP substudy. Plasma samples for 3235Ϯ4392 pg/mL. In the substudy, a total of 78 patients baseline neurohormonal levels were obtained on the day of random- died (48 placebo versus 30 carvedilol) during follow-up ization (start of study medication; nϭ810) or, if not available, at the (median, 159 days; range, 1 to 488 days) (primary end point).
screening visit (3 to 14 days before randomization; nϭ201), with10-mL EDTA syringes used for sampling. Plasma was separated and We found that 180 patients died or were hospitalized for heart stored at Ϫ80°C until assays were performed. Plasma levels of failure (101 placebo versus 79 carvedilol), 205 patients died NT-proBNP were determined with Elecsys proBNP (Roche Diag- or were hospitalized for cardiovascular reasons (115 placebo nostics GmbH), a quantitative electrochemiluminescence immuno- versus 90 carvedilol), and 293 patients died or were hospi- assay.14 The analytical detection limit of the assay was 5 pg/mL. The talized for any reason (160 placebo versus 133 carvedilol) intra-assay coefficient of variation was 2.4% at 355 pg/mL and 1.8%at 4962 pg/mL; the interassay CVs were 2.9% at 355 pg/mL and 2.3% at 4962 pg/mL. Upper limits of normal of 100 pg/mL in menand 150 pg/mL in women are proposed by the manufacturer.
NT-proBNP and Clinical Events
Measurements were performed with the Elecsys 2010 immunoassay Table 2 indicates event rates of the primary and all secondary end points of the COPERNICUS trial according to baseline Statistical Analysis
NT-proBNP levels above or below the median of 1767 Myocardial marker levels were presented descriptively. Survival pg/mL, regardless of treatment. Baseline NT-proBNP levels distributions were compared by use of a 2-sided log-rank test. The above median were associated with an increased risk for effect of baseline NT-proBNP was characterized by hazard ratios all-cause mortality and all combined end points.
(and corresponding 95% CIs) on a Cox proportional-hazard model.
Kaplan-Meier analyses for all-cause mortality revealed Kaplan-Meier curves were generated, and 1-year mortality and 1-year mortality rates of 7.0% and 21.6% in patients with annual hazard rates were calculated by stratifying according tobaseline NT-proBNP levels above and below the median. Analyses NT-proBNP levels Յ1767 and Ͼ1767 pg/mL, respectively.
were conducted separately for groups receiving carvedilol or placebo Thus, the risk of death was 2.7-fold higher for the patients with baseline NT-proBNP values above the median (95% CI, Multivariate Cox proportional-hazards regression model was used 1.7 to 4.3; Pϭ0.0001, log-rank test; Figure 1).
to investigate the effect of NT-proBNP levels, taking into account The combined 1-year risk for all-cause mortality or hospi- the influence of other potentially prognostic factors (in particular,treatment group, left ventricular ejection fraction, age, sex, cause of talization for heart failure was 18.9% compared with 38.0% heart failure, creatinine, systolic blood pressure). To test for inter- in patients with below- or above-median NT-proBNP levels, 1782
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Pretreatment Characteristics of Patients in COPERNICUS and the
NT-proBNP Substudy
Hospitalized for heart failure within year, %* Patients receiving AT II receptor antagonists, % AT indicates angiotensin. All continuous data are expressed as meanϮSD.
*Only patients randomized after amendment III was initiated (nϭ1820 in COPERNICUS, nϭ1007 in the substudy) were asked about the number of hospitalizations for heart failure within the past yearbefore screening.
respectively. Thus, the combined risk of death or hospitaliza- Յ15%) were shown to have a statistically significant effect tion for heart failure was 2.5-fold higher for patients with on mortality (Pϭ0.05 level). Left ventricular ejection fraction baseline NT-proBNP values above the median (95% CI, 1.8 (continuous and categorized), cause of heart failure, and to 3.4; Pϭ0.0001, log-rank test) (Figure 2).
creatinine (categorized) were not significant on the Pϭ0.05 The impact of various baseline variables on the end points level. However, left ventricular ejection fraction predicted the of the study was investigated by univariate Cox regression combined end point of all-cause mortality and hospitaliza- analysis. Clinically relevant classes were defined for contin- tions for heart failure with Pϭ0.010 and Pϭ0.003 (continu- uous variables to further characterize their impact on out- ous and categorized) and all other combined end points.
come. Besides NT-proBNP (regardless of whether continuous Similarly, ischemic etiology predicted the combined end or categorized), systolic blood pressure (continuous and point of all-cause mortality and hospitalizations for heart categorized), age (continuous and categorized), creatinine failure with Pϭ0.008. No impact of treatment with amiod- (continuous), treatment group, hospitalization for heart fail- arone or angiotensin type II receptor antagonists on the end ure within the year before enrollment (recent hospitalization), points was observed. Predictive values of all other risk and any high-risk feature (any patient with ascites, rales, or indicators were similar for the primary and all secondary end edema at randomization, who was hospitalized at screening or points. Risk ratios and probability values are indicated in randomization, who was hospitalized Ͼ2 times within the past year or received intravenous positive inotropic agents or Investigation of the prognostic baseline parameters with a other intravenous drugs for heart failure within 14 days of stepwise-backward selection method in a multivariate Cox randomization, or whose baseline left ventricular ejection was proportional-hazards regression using the same categories as Event Rates According to Median Level of NT-proBNP (1767 pg/mL) Independent of
Treatment Group
All-cause mortality or hospitalization for All-cause mortality or protocol specified CV Hartmann et al
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NT-proBNP. In patients with plasma NT-proBNP levelsabove the median, those receiving placebo incurred a 1-yearmortality of 30.9%, whereas mortality was 13.8% in thosereceiving carvedilol (Pϭ0.068, log-rank test). In patientsentering the study with an NT-proBNP level below themedian, the 1-year mortality rates were 10.2% in thosereceiving placebo and 3.4% in those receiving carvedilol(Pϭ0.068, log-rank test). Therefore, administration of carve-dilol in high NT-proBNP patients resulted in 17.1 fewerdeaths per 100 patient-years compared with 6.8 fewer deathsper 100 patient-years in those receiving carvedilol who hadlower NT-proBNP levels (Figure 3).
Interaction between treatment group and NT-proBNP level was further investigated by including an interaction term inthe multivariate model. This analysis indicated that in the Figure 1. Kaplan-Meier curves indicating all-cause mortality for
COPERNICUS NT-proBNP substudy patients, the difference patients with prerandomization plasma NT-proBNP below (solid in risk reduction of carvedilol treatment in patients with line) and above (dashed line) group median of 1767 pg/mL.
above- versus below-median NT-proBNP levels was not Event rates and RRs are indicated in Table 2.
significant (Pϭ0.93; RR, 0.96).
for the univariate model revealed prognostic significance for Discussion
all-cause mortality in a model containing NT-proBNP, treat- The COPERNICUS NT-proBNP substudy is the first study to ment group, age, systolic blood pressure, recent hospitaliza- investigate the prognostic value of the newly developed tion, and high-risk combination. NT-proBNP was a highly cardiac marker NT-proBNP in a large number of patients significant risk indicator in the model with continuous vari- with severe CHF resulting from ischemic and nonischemic ables and in the model with categorized variables. Further cardiomyopathy. In these high-risk CHF patients who were relevant (PϽ0.05) prognostic variables for death in the mul- symptomatic at rest or on minimal exertion and had a left tivariate model were treatment group, systolic blood pressure ventricular ejection fraction Ͻ25%, high NT-proBNP plasma Ͻ100 mm Hg, age Ն65 years, recent hospitalization, and levels on admission were strongly associated with an in- high-risk combination. Significant independent prognostic creased risk of all-cause mortality and heart failure during variables for combined death and heart failure hospitaliza- follow-up. The association of NT-proBNP levels with cardiac tions were NT-proBNP classes, treatment group, systolic events was independent of treatment with placebo or carve- blood pressure Ͻ100 mm Hg, recent hospitalization, and dilol, cause of heart failure, systolic blood pressure, left high-risk combination (Table 4). Similar findings were ob- ventricular ejection fraction, age, and recent hospitalization.
served for the other combined end points.
The beneficial effect of carvedilol was independent of NT-proBNP levels. The combination of below-median pretreat- NT-proBNP and Treatment Effect
ment NT-proBNP levels and treatment with carvedilol was Subgroups were formed according to treatment with carve- associated with an extremely low mortality risk of 3.4% in the dilol or placebo and were again stratified according to median first year. This rate contrasted to the high mortality rate of30.9% in patients with above-median NT-proBNP and pla-cebo treatment. The substudy results indicate that risk strat-ification with NT-proBNP adds important information toclinical risk predictors in patients with very severe heartfailure, even those who were clinically euvolemic.
NT-proBNP as a Predictor of Prognosis in
Severe CHF
Risk prediction in heart failure patients is a prerequisite for
selecting treatment strategies, including cardiac transplanta-
tion. However, results from large trials have consistently
revealed the limitations of common indicators used either
singly or in combination.15 This relates also to left ventricular
ejection fraction, complex arrhythmias, and heart failure
symptoms. We anticipated that biochemical indexes and
circulating neurohormone concentrations may add precision
Figure 2. Kaplan-Meier curves indicating all-cause mortality or
to the generally less objective clinical indicators. Several heart failure hospitalizations in patients with prerandomization groups have demonstrated the usefulness but also the limita- plasma NT-proBNP below (solid line) and above (dashed line) tions of neurohormonal markers such as catecholamines and group median of 1767 pg/mL. Event rates and RRs are indi-cated in Table 2.
particularly natriuretic peptides, including atrial natriuretic 1784
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September 28, 2004
Univariate Cox Regression for Baseline Variables
Cause of heart failure (ischemic/nonischemic) Creatinine clearance (Cockroft, 1-unit decrease) LVEF indicates left ventricular ejection fraction; SBP, systolic blood pressure; LVH, left ventricular hypertrophy; recent hospitalization, at least 1 hospitalization within last year; and high-risk combination, any patient with ascites, rales, or edema atrandomization, who was hospitalized at screening or randomization, who was hospitalized more than twice within the past year, whoreceived intravenous positive inotropic agents or other intravenous drugs for heart failure within 14 days of randomization, or whosebaseline LVEF was Յ15%.
peptide and BNP.1–4,16,17 BNP is more predictive than atrial The COPERNICUS NT-proBNP substudy is the first natriuretic peptide for cardiac mortality in patients with study to extend this important finding to patients with chronic CHF and has provided prognostic information inde- severe CHF and left ventricular ejection fraction Ͻ25% pendently of other variables previously associated with poor resulting from ischemic or nonischemic cardiomyopathy.
The COPERNICUS patients represent a high-risk popula- In the Australia/New Zealand (ANZ) Heart Failure Study, tion with an overall 1-year placebo mortality rate of 18%.
the recently detected cardiac marker NT-proBNP was evalu- In the NT-proBNP substudy, the risk of dying was 2.7-fold ated for prediction of all-cause mortality and heart failure in higher in placebo patients with above-median baseline 297 patients with established ischemic left ventricular dys- NT-proBNP concentration compared with patients with function (NYHA class II to III; left ventricular ejection below-median NT-proBNP values. Thus, even in these fraction Ͻ45%) treated with carvedilol or placebo. Above- severely compromised patients who were symptomatic at median NT-proBNP levels conferred Ͼ4.5-fold-increased rest or on minimal exertion, NT-proBNP plasma concen- risk of mortality. NT-proBNP was superior to left ventricular trations could separate the population into subgroups with ejection fraction in predicting mortality and heart failure.12 more or less favorable outcomes. The prognostic signifi- Multivariate Cox Regression Using a Fixed Set of Baseline Variables
Cause of heart failure (ischemic/nonischemic) Hartmann et al
NT-proBNP in the COPERNICUS Study
1785
tions. However, our study was not primarily powered todetect a statistical significant difference of prognostic valuesof the marker in predefined subgroups. Thus, this finding is tobe interpreted with caution.
The reasons for this possible difference from the ANZ study findings are unknown but may be due, at least in part,to differences in patient population. Heart failure in the ANZstudy was less severe, and there was no overall survivalbenefit with carvedilol.
Thus, in COPERNICUS, NT-proBNP did not convincingly allow stratification into groups most likely to benefit fromcarvedilol therapy. Because it currently is not clear whichpatients will benefit most from such therapy, this medicationshould, according to the COPERNICUS data, be adminis-tered liberally in advanced CHF patients.
Figure 3. Kaplan-Meier curves indicating all-cause mortality for
Clinical Implications and Limitations of the
patients with prerandomization plasma NT-proBNP above COPERNICUS NT-proBNP Substudy
median receiving placebo (solid thick line) or carvedilol (dotted The short duration of the study may have limited the line) and below median receiving placebo (solid thin line) or statistical power of the prognostic findings. However, our carvedilol (dashed line). Treatment with carvedilol reduced riskof dying in patients with NT-proBNP levels above median by study shows for the first time a powerful association of 40% (RR, 0.60; 95% CI, 0.35 to 1.0; Pϭ0.07, log-rank test). In NT-proBNP with death and heart failure hospitalization in patients with below-median NT-proBNP levels, risk reduction patients with severe heart failure who suffer from shortness of was 46% (RR, 0.54; 95% CI, 0. 2 to 1.3; Pϭ0.07, log-rank test).
breath at rest or on minimal exertion. The combination of alow NT-proBNP level and treatment with carvedilol was cance of NT-proBNP was independent of the thresholds associated with a high probability of event-free survival.
used and was superior or similar to established risk Therefore, such patients appear to be appropriately treated indicators such as treatment modalities, cause of heart with medical therapy. Patients with high NT-proBNP levels failure, left ventricular ejection fraction, age, systolic who are not treated with carvedilol aggregate on the opposite blood pressure, and recent hospitalization.
extreme of the risk scale. Their 1-year mortality rate of 31% NT-proBNP as a Predictor of Response
could be halved by carvedilol treatment. Whether these to Treatment
patients with high levels of NT-proBNP may further benefit In an analysis of the Survival and Ventricular Enlargement from alternative treatment options such as cardiac transplan- (SAVE) data, neurohumoral activation at the time of hospital tation warrants further investigation.
discharge failed to identify those patients who would derive So far, the general application of NT-proBNP in heart benefit from treatment with ␤-blockers.18 In a previous report failure has been restricted by the fact that NT-proBNP blood of the ANZ Carvedilol Study Group, above-median BNP levels and the discriminator values related only to the specific concentrations combined with below-median norepinephrine assays used for the different trials. In the present study, levels predicted benefit from carvedilol treatment in ischemic NT-proBNP was measured by a newly developed, highly left ventricular dysfunction.19 Recently, similar findings were sensitive and standardized electrochemiluminescence immu- reported for NT-proBNP and adrenomedullin in the same noassay. The availability of such a standardized and easy-to- patient population. Carvedilol significantly halved the risk of use assay is prerequisite for general application of NT- heart failure hospitalization in patients with above-median proBNP as a biochemical marker in CHF patients. Under NT-proBNP levels, whereas treatment effect in the patients these conditions, it is anticipated that measurement of cardiac with below-median NT-proBNP did not reach significance. In hormones will become part of the routine workup of heart addition, the investigators reported statistically significant failure patients and will be a useful tool for risk stratification interactions of treatment with NT-proBNP for the prediction of all analyzed end points, indicating that the predictivepower of the marker is influenced by treatment with Acknowledgment
The study and substudy were supported by a grant from Roche Pharmaceuticals, and NT-proBNP plasma level measurements were In the present substudy, administration of carvedilol in performed in a core laboratory at Roche Diagnostics GmbH. We high–NT-proBNP patients resulted in 17.1 fewer deaths per gratefully appreciate the valuable and irreplaceable impact of Chris- 100 patient-years compared with 6.8 fewer deaths per 100 toph Staiger, Juergen Spinke, and Matthias Baumann during plan- patient-years in those with lower NT-proBNP levels receiv- ning, execution, and evaluation of the study.
ing carvedilol. Both differences did not reach statistical Disclosure
significance. However, the difference in impact of 10.3 lives Drs Packer, Coats, Fowler, Katus, Krum, Mohacsi, Rouleau, Ten- per 100 patient-years is at least noteworthy, even though dera, and Castaigne served as consultants to Roche Pharmaceuticals.
further statistical analyses failed to show significant interac- Drs Amann-Zalan and Hoersch are employees of or on committees tions between treatment group and NT-proBNP concentra- 1786
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September 28, 2004
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