Teaching Points::::CHF

Ace844 · July 5, 2006

Actually two questions:

hepatojugular reflex is this present in all CHF pt's or just in a acute crises?

Removed the other I found the answer.

Thanks

Hello Everyone,

For "Whit72," and everyone else who would like to know how to do a proper cardiovascualr exam and the specifics on JVD see below!!

[web:85180f8ea7]http://medicine.ucsd.edu/clinicalmed/heart.htm[/web:85180f8ea7]

http://medicine.ucsd.edu/Clinicalimg/head-ejdistension1.html

http://www.jcomjournal.com/pdf/hp_may02_veins.pdf.

http://depts.washington.edu/physdx/neck/index.html

Hope this Helps,

ACE844

whit72 · July 5, 2006

Thanks

Whit

Ace844 · July 22, 2006

(The American Journal of Emergency Medicine

Volume 24 @ Issue 4 , July 2006, Pages 451-454

doi:10.1016/j.ajem.2005.10.010

Brief Report

The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure

Oral presentation at the 73rd annual assembly of the Swiss Society of Internal Medicine (May 25-27, 2005) in Basel, Switzerland.

Alain Rudiger MDa, , , Oliver A. Burckhardt MDb, Paul Harpes MSc, S. Andreas Müller MDd and Ferenc Follath MDb

aBloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research, University College London, WC1E 6BT London, UK

bDepartment of Internal Medicine, University Hospital Zurich, 8091 Zurich, Switzerland

cDepartment of Biostatistics, University Zurich, 8001 Zurich, Switzerland

dDepartment of Cardiology, Triemlispital Zurich, 8065 Zurich, Switzerland

Received 4 September 2005; revised 7 October 2005; accepted 9 October 2005. Available online 17 June 2006)

1. Introduction

Acute heart failure (AHF) is a common but ill-defined clinical entity. Because of an aging population and improvement in survival rates after myocardial infarction, its prevalence is increasing [1] and [2]. In addition, the syndrome is associated with a high short- and long-term mortality [3], [4] and [5]. Recently, several effective but costly therapies have been developed [6] and [7]. The difficulty remains to choose the most adequate treatment for each single patient with AHF. Hence, risk stratification is essential and urgently needed for appropriate triage and therapeutic decision making.

Lymphocytopenia is common in hospitalized patients [8]. A decrease of the relative lymphocyte count in percentages (%L) has been observed in different cardiovascular disease states. It has been interpreted as a marker of the physiological stress response, mediated by an increased release of endogenous catecholamines [9] or cortisol [10]. Importantly, a decrease in the %L has been demonstrated to be predictive for mortality in patients with chronic heart failure [11], [12] and [13]. In patients with AHF though, the prognostic value of low %L is unknown. The aim of this study was to assess if the %L is a risk factor for long-term mortality in patients with AHF.

2. Methods

2.1. Study population

The present study is a subgroup analysis from a multicenter study, and the full results are published separately [5]. The study population included consecutive patients admitted to the medical intensive care unit, coronary care unit, and medical wards at the Department of Medicine of the University Hospital Zurich with a diagnosis of AHF. Diagnostic criteria for AHF were in accordance with the guidelines of the European Society of Cardiology [14] and included the following:

1. an underlying heart disease;

2. at least two symptoms and signs of AHF (dyspnea, orthopnea, rales, elevated jugular venous pressure) or cardiogenic shock;

3. a chest x-ray compatible with pulmonary congestion;

4. a new onset or rapid worsening of these clinical symptoms and signs within 7days.

Cardiogenic shock was defined by the presence of an impaired end-organ perfusion and a systolic blood pressure lower than 90 mm Hg despite adequate treatment with fluids or the need of inotropes or vasopressors. Baseline characteristics as well as routine laboratory values were collected from the patient's charts. Each patient was enrolled only once even when he was readmitted during the observation period. All patients had a follow-up after 12 months. Information regarding death was obtained from hospital records or telephone interviews with the patient's physician or a family member.

2.2. Laboratory

Blood samples for routine blood cell count analyses were taken on admission and in the mornings of the following days. Three milliliters of blood was collected in Vacutainer tubes (Plymouth, UK). All analyses were performed at the laboratory of the University Hospital Zurich. Complete blood cell counts were done with a commercial automated system (ADVIA 120 Hematology System, Bayer Diagnostics AG, Switzerland). This machine can analyze 120 blood samples per minute at only minor expenses. In addition, the analyzer can differentiate leukocytes by peroxidase staining, cytochemical light scatter, and light absorption measurements, without taking more time for the analysis. The %L was defined as (absolute number of lymphocytes / absolute number of leukocytes) × 100. The lower cutoff value for %L at our institution is 25.

2.3. Statistical analysis

All laboratory data were collected from the patient's electronic records. Mean, SDs, or percentages were calculated for the overall sample and subgroups. Comparisons were made with the use of the t test, Fisher exact test, or the χ2 test, as appropriate. The %L on admission and the minimum %L during the first 3 days were taken for the analysis. Logarithms of %L and renal dysfunction measurements were approximately normally distributed, so logarithms were taken whenever these variables were considered. Survival analysis for one or several risk factors was performed with a Cox proportional hazards regression. The null hypothesis was rejected for a 2-sided P value of less than .05. Confidence intervals (CIs) are given for the 95% level. All analyses were performed with SPSS 12 for Windows.

3. Results

3.1. General

The study population included 96 consecutive patients with AHF. Mean age was 71 (SD 13), and 58 (60%) were men. A de novo AHF (no previous history of heart failure) was present in 28 (29%) patients. The most frequent underlying cardiac diseases were coronary artery disease in 57 (59%) patients and valvular cardiopathy in 24 (25%) patients. A history existed for atrial fibrillation in 21 (22%) patients and for elevated blood pressure in 51 (53%) patients. Left ventricular ejection fraction (LVEF) was measured in 63 (66%) patients. Of them, 32 (51%) had an LVEF less than 35%, 10 (16%) between 35% and 50%, and 21 (33%) greater than 50%. Relative lymphocyte counts were available in 91 (95%), 55 (57%), and 58 (60%) patients on days 1, 2, and 3, respectively. Two patients had no %L measurement during the first 3 days.

3.2. Outcome

The baseline characteristics of our population are summarized in Table 1; the %L values on admission for different subgroups are shown in Table 2. After 1 year, 35 (36%) patients had died. In 1-year survivors and 1-year nonsurvivors, the mean %L on admission were 16.3 (SD 8.9) and 11.2 (SD 7.9), respectively (P = .04 with a t test for logarithms). A %L less than 25% on admission had a sensitivity and specificity for death at 1 year of 0.91 and 0.21, respectively, with an area under the curve of 0.680 (CI, 0.563-0.796) and a P value of .005 in the receiver operating characteristic analysis. This resulted in positive and negative likelihood ratios of 1.15 and 0.43. The according positive and negative predictive values for death at 1 year were 0.39 and 0.80, respectively. When we calculated with the minimum %L of the first 3 days of hospitalization, the mean values were 15.5 (SD 8.6) and 9.7 (SD 6.6) in 1-year survivors and 1-year nonsurvivors, respectively (P < .001 in a t test for logarithms). Only 11 (11%) patients had exclusively normal %L during the first 3 days of hospitalization, and they all survived 1 year. The minimum %L during the first 3 days of hospitalization was a stronger prognostic marker for long-term mortality than the %L on admission alone, although the difference was not statistically significant.

Table 1.

Baseline characteristics on admission of patients with AHF grouped depending on their outcome at 1 year Survivors (n = 61) Nonsurvivors (n = 35) P

Age (y), mean (SD)* 70 (13) 73 (13) NS

Male sex, n (%)* 38 (62) 20 (57) NS

History of heart failure, n (%)* 44 (72) 24 (69) NS

Coronary artery disease, n (%)* 36 (59) 21 (60) NS

Shock, n (%)* 3 (4.9) 5 (14) NS

LVEF (%), mean (SD)¶ 42 (17) 30 (16) .011

Troponin T (μg/L) (norm <0.1), mean (SD)§ 0.2 (0.6) 2.2 (8.5) NS

Creatinine clearance (mL/min), mean (SD)† 55 (26) 47 (24) NS

C-reactive protein (mg/L), mean (SD)† 32 (47) 71 (98) .031

Hemoglobin (g/L), mean (SD)* 122 (22) 117 (20) NS

Leukocytes/μL, mean (SD)‡ 9181 (3677) 10 522 (5316) NS

Lymphocytes/μL, mean (SD)§ 1458 (1024) 1015 (820) .006

%L, mean (SD)§ 16.3 (8.9) 11.2 (7.9) .004

Creatinine clearance was estimated by a modified Cockcroft and Gault formula. Results were available in *96, †94, ‡93, §91, and ¶63 patients. P values were calculated with Fisher exact test and t tests (for logarithms in creatinine clearances, lymphocytes, and %L).

Table 2.

Patients with AHF divided by different criteria, with the corresponding relative lymphocyte counts (%L) on admission No. of patients (%) %L, mean (SD)

Age (y) <65 29 (32) 16.4 (9.6)

≥65 62 (68) 13.6 (8.3)

Sex Female 37 (41) 15.6 (10.2)

Male 54 (59) 13.7 (7.7)

Coronary artery disease No 36 (40) 13.1 (7.4)

Yes 55 (60) 15.3 (9.6)

Shock No 83 (91) 14.6 (8.6)

Yes 8 (9) 13.3 (11.7)

LVEF (%) ≥35 29 (48) 16.6 (9.0)

<35 31 (52) 15.4 (8.8)

Troponin (μg/L) <0.1 61 (69) 15.4 (8.8)

≥0.1 28 (31) 13.0 (8.7)

Creatinine clearance (mL/min) ≥50 40 (45) 16.7 (8.4)*

<50 49 (55) 13.0 (8.9)*

Outcome at 1 y Survivors 58 (64) 16.3 (8.9)†

Nonsurvivors 33 (36) 11.2 (7.9)†

Creatinine clearance was estimated by a modified Cockcroft and Gault formula. The numbers (percentages) refer only to the patients who had a %L measured. Differences between %L were not significant within the grouping variables, except for renal dysfunction and outcome at 1 year (P values *.016 and †.004 in a t test for logarithms).

In a Cox regression analysis, %L and LVEF were both significant risks factors (P = .029 for log[%L] with a hazard ratio per unit change of 0.42 [CI, 0.19-0.91] and P = .018 for LVEF with a hazard ratio per unit change of 0.96 [CI, 0.93-0.99]). They were thus independent risks factors because %L was still significant after correcting for the effect of LVEF and conversely. The presence of shock was not a significant risk factor after adjusting for LVEF (P = .13, hazard ratio 0.43 [CI, 0.14-1.3]). Age, sex, underlying coronary artery disease, and renal dysfunction were not significant in the Cox regression analysis or log-rank test.

4. Discussion

The present study revealed that a low %L on hospital admission was significantly related to an increased long-term mortality in patients with AHF. A decreased %L remained an independent risk factor after adjusting for age, sex, renal dysfunction, LVEF, shock, and coronary artery disease. The test had a good sensitivity to predict long-term mortality in patients with AHF. However, clinicians must consider its low specificity and poor positive predictive value.

Our results correspond to published studies showing that %L is reduced in patients with severe cardiovascular disturbances. For instance, lymphocytopenia was observed in patients with acute myocardial infarction [15] and [16], and a study from our institution demonstrated that mechanical complications after myocardial infarction could be reliably predicted by lymphocytopenia in combination with the C-reactive protein level [17]. The present study included patients with AHF, but was not restricted to patients with myocardial infarction. Within our population, %L did neither differ between patients with coronary artery disease and patients without nor between patients with an elevated (>0.1 μg/L) and patients with a normal troponin T level. Prior studies indicated a predictive value of the relative lymphocyte concentration in patients with chronic heart failure [11], [12] and [13]. Cooper et al [12] limited their study population to patients who had an LVEF 35% or less, whereas Acanfora et al [13] included only patients who were older than 65 years. In contrast, our population was restricted neither by age nor by LVEF. Nevertheless, a low %L remained an independent risk factor for increased mortality, and %L was similar not only in patients with a reduced LVEF of 35% or less and in patients with an LVEF greater than 35%, but also in patients 65 years or younger and older than 65 years.

The precise underlying mechanisms for our results remain speculative. Lymphocytopenia may reflect neurohormonal activation in patients with AHF. Cortisol and catecholamines, which are both elevated in patients with heart failure [18], induce lymphocyte apoptosis [19] and [20], and catecholamines down-regulate lymphocyte proliferation and differentiation [9]. Homing of lymphocytes in the lymphoreticular structures has been proposed [21]. However, a histological study in critically ill patients showing extensive lymphocyte depletion in the white pulp of the spleen does not support this assumption [22]. In addition, a decrease in %L may reflect the severity of immunologic disturbances in AHF. Lymphocytopenia may be an anti-inflammatory response that accompanies severe illness [23]. Whether the decline in the %L only reflects the severity of both neurohormonal and immune system disturbances or whether lymphocytopenia truly contributes to mortality by favoring the development of nosocomial infections [24] awaits further investigations.

A limitation of the present study is the small sample size, which obviates an adjustment for all potential confounders. Hence, larger studies are needed to test the hypothesis that the %L is a truly independent risk factor. Other limitations are the lack of routinely measured B-type natriuretic peptide levels and the restricted use of echocardiography.

In conclusion, modern automated systems can count the %L fast and at only minor additional expenses. A low %L may reflect the severity of both neurohormonal and immune system disturbances. We demonstrate for the first time that a low %L in a single blood sample on hospital admission is a risk factor for long-term mortality in patients with AHF. Future prospective studies are needed to validate our results and to identify the prognostic value of different lymphocyte levels.

Acknowledgments

The authors thank Franco Salomon for his contribution to their understanding of the importance of the relative lymphocyte count.

References

[1] M.R. Cowie, D.A. Wood and A.J.S. Coats et al., Incidence and aetiology of heart failure, Eur Heart J 20 (1999), pp. 421–428. Abstract-MEDLINE | Abstract-EMBASE

[2] J.P. Hellermann, S.J. Jacobsen and M.M. Redfield et al., Heart failure after myocardial infarction: clinical presentation and survival, Eur J Heart Fail 7 (2005), pp. 119–125. Abstract

[3] J.M. Brophy, G. Deslauriers and B. Boucher et al., The hospital course and short term prognosis of patients presenting to the emergency room with decompensated congestive heart failure, Can J Cardiol 9 (1993), pp. 219–224. Abstract-MEDLINE | Abstract-EMBASE

[4] J.M. Brophy, G. Deslauriers and J.L. Rouleau, Long term prognosis of patients presenting to the emergency room with decompensated congestive heart failure, Can J Cardiol 10 (1994), pp. 543–547. Abstract-MEDLINE | Abstract-EMBASE

[5] A. Rudiger, V.-P. Harjola and A. Müller et al., Acute heart failure: clinical presentation, one-year mortality and prognostic factors, Eur J Heart Fail 7 (2005), pp. 662–670. Abstract

[6] J.B. Young and and the Publication Committee for the VMAC Investigators, Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure, JAMA 287 (2002), pp. 1531–1540. Abstract-EMBASE | Abstract-Elsevier BIOBASE

[7] F. Follath, J.G.F. Cleland and H. Just et al., Efficacy and safety of intravenous levosimendan compared to dobutamine in severe low-output heart failure (the LIDO-study): a randomised double-blind trial, Lancet 360 (2002), pp. 196–202. SummaryPlus | Full Text + Links | PDF (113 K)

[8] D.H. Castelino, P. McNair and T.W.H. Kay, Lymphocytopenia in a hospital population—what does it signify?, Aust N Z J Med 27 (1997), pp. 170–174. Abstract-MEDLINE | Abstract-EMBASE

[9] J. Bergquist, A. Tarkowski and A. Ewing et al., Catecholaminergic suppression of immunocompetent cells, Immunol Today 19 (1998), pp. 562–567. SummaryPlus | Full Text + Links | PDF (185 K)

[10] D.H. Nelson, A.A. Sandberg and J.G. Palmer et al., Blood levels of 17-hydroxycorticosteroids following the administration of adrenal steroids and their relation to levels of circulating leukocytes, J Clin Invest 31 (1952), pp. 843–849. Abstract-MEDLINE

[11] S.R. Ommen, D.O. Hodge and R.J. Rodeheffer et al., Predictive power of the relative lymphocyte concentration in patients with advanced heart failure, Circulation 97 (1998), pp. 19–22. Abstract-MEDLINE | Abstract-EMBASE

[12] H.A. Cooper, D.V. Exner and M.A. Woclawiw et al., White blood cell count and mortality in patients with ischemic and nonischemic left ventricular systolic dysfunction (an analysis of the studies of left ventricular dysfunction), Am J Cardiol 84 (1999), pp. 252–257. SummaryPlus | Full Text + Links | PDF (122 K)

[13] D. Acanfora, M. Gheorghiade and L. Trojano et al., Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure, Am Heart J 142 (2001), pp. 167–173. Abstract | PDF (106 K)

[14] M.S. Nieminen, M. Böhm and M.R. Cowie et al., Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. The Task Force on Acute Heart Failure of the European Society of Cardiology, Eur Heart J 26 (2005), pp. 384–416. Abstract-MEDLINE | Abstract-EMBASE

[15] S.P. Thomson, R.J. Gibbons and P.A. Smars et al., Incremental value of the leukocyte differential and the rapid creatine kinase–MB isoenzyme for the early diagnosis of myocardial infarction, Ann Intern Med 122 (1995), pp. 335–341. Abstract-MEDLINE | Abstract-EMBASE

[16] B. Annen, G. Mang and E. Schuiki et al., C-reactive protein and relative lymphocytopenia: early markers of myocardial infarction? (article in German), Schweiz Med Wochenschr 129 (1999), pp. 1931–1934. Abstract-MEDLINE | Abstract-EMBASE

[17] A. Widmer, A.Z. Linka and C.H. Attenhofer Jost et al., Mechanical complications after myocardial infarction reliably predicted using C-reactive protein levels and lymphocytopenia, Cardiology 99 (2003), pp. 25–31. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef

[18] C.K. Connolly and M.R. Wills, Plasma cortisol levels in heart failure, BMJ 2 (1967), pp. 25–27.

[19] F.C. Mooren, D. Blöming and A. Lechtermann et al., Lymphocyte apoptosis after exhaustive and moderate exercise, J Appl Physiol 93 (2002), pp. 147–153. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE

[20] D.P. Cioca, N. Watanabe and M. Isobe, Apoptosis of peripheral blood lymphocytes is induced by catecholamines, Jpn Heart J 41 (2000), pp. 385–398. Abstract-MEDLINE

[21] J. Westermann and U. Bode, Distribution of activated T cells migrating through the body: a matter of life and death, Immunol Today 20 (1999), pp. 302–306. Abstract | PDF (199 K)

[22] R.S. Hotchkiss, P.E. Swanson and B.D. Freeman et al., Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction, Crit Care Med 27 (1999), pp. 1230–1248.

[23] R.C. Bone, Sir Isaac Newton, sepsis, SIRS, and CARS, Crit Care Med 24 (1996), pp. 1125–1128. Abstract-MEDLINE | Full Text via CrossRef

[24] G. Rajan and J.W. Sleigh, Lymphocyte counts and the development of nosocomial sepsis, Intensive Care Med 23 (1997), p. 1187. Abstract-MEDLINE | Full Text via CrossRef

SEE RELATED ARTICLE, P. 66

[Ann Emerg Med. 2006;48:75-76.]

In this issue, Tung et al report their subanalysis of the 600-person PRIDE trial dataset focusing on the ability of amino-terminal pro-brain natriuretic peptide (NT-proBNP) to differentiate heart failure from other conditions in the 216 patients who arrived in the emergency department (ED) complaining of shortness of breath and had a history of chronic obstructive pulmonary disease or asthma.1 and 2 The authors do a good job of acknowledging their study’s limitations which include a potentially imprecise gold standard and the many forms of confounding that can occur in a retrospective subgroup analysis. Their paper is a straightforward account of what they did and they openly acknowledge its limitations.

Their conclusion, however, that “NT-proBNP may [emphasis added] be a useful adjunct to standard clinical evaluation of dyspneic subjects with previous obstructive airway disease” is not particularly helpful to clinicians since any claim can logically follow the word “may.” To ensure they are getting a balanced interpretation, readers may find it helpful to substitute “may or may not” for “may” every time they encounter it in a declarative statement. By doing so a reader can avoid being seduced by “may” into believing that the claim is true. A more helpful and precise conclusion for this study would have been “In this single-site retrospective study, elevated NT-proBNP levels were strongly associated with a clinical diagnosis of heart failure in dyspneic patients who have a history of chronic obstructive pulmonary disease or asthma; it remains to be seen whether the use of this test will improve patient outcomes.”

If my reservations about the article’s conclusion simply concerned semantic accuracy, then this issue would not be worthy of my time or yours. Unfortunately, overly broad or optimistic conclusions are routine in the medical literature and can have effects that echo long after an article’s publication.3 Such conclusions can be (and are) used by those with an interest in selling the product. It is a slippery slope from “this may be useful” to “since it correlates with diagnosis, it is useful.” Marketing directors are as skillful as Olympic bobsledders in negotiating that slide.

Just as I was wondering whether I was being overly paranoid about all of this, a 12 page glossy monograph on NT-proBNP funded by the test’s manufacturer arrived in the mail.4 It appears scholarly, comes from a prestigious medical center, offers continuing medical education, and cites 53 references to further enhance its credibility. Unfortunately, none of the cited studies compare outcomes in patients who receive this test to those who don’t, so there is no evidence to show that NT-proBNP or BNP improve patient care. Despite this, the monograph contains such statements as: “NT-proBNP provides an important diagnostic and prognostic test for these heart failure patients” and “whether they [the NP tests] will be integrated into the diagnostic workup of this latter group of patients [those with acute coronary syndrome or pulmonary embolism] will be determined by future studies that will evaluate their use as a guide to therapy.” The former quote offers as fact a statement that is unsubstantiated. The latter subtly implies that NP tests are already integrated into routine clinical practice for non-acute coronary syndrome dyspneic patients, despite no evidence to support this claim. It is just a matter of time before the Tung et al article is cited in similar fashion for a similar purpose.

Some may argue that I am being petty. They could argue that we don’t have outcome studies for many things we do in medicine, so why are they required here? In response, I argue that we ought to try to change that tradition, and I point to the many tests and treatments that have shown promise and theoretical appeal but ultimately were shown to provide no benefit. Invasive central venous with wedge pressure monitoring makes perfect sense: it allows us to tailor therapy to the patient’s intravascular volume and cardiac function. Despite the logic of this, when studied in randomized trials, there is no evidence that it improves outcomes and some concern that it harms patients.5, 6 and 7 Should we continually repeat history by introducing ever-more-expensive modalities into practice based on incomplete evidence only to discover years later that they offer no benefit to patients?

I am concerned that the following sequence has become routine in the research and marketing of new medical tests and treatments. Step 1 – perform research that suggests but, due to study design limitations and lack of patient-centered outcomes, fails to establish the utility of a test or treatment. Step 2 – perform additional research showing how the modality performs in subgroups. Step 3 – In the medical and marketing literature about the research on subgroups, make reference to the original study in a way that implies that the original research proved that the modality was effective, thereby creating a hegemonic belief that the test or treatment works. It is sequences like this that have led the editors of prominent medical journals to state “Medical journals are an extension of the marketing arm of pharmaceutical companies” and “Journals have devolved into information laundering operations for the pharmaceutical industry.”8 and 9 The damage goes way beyond the introduction of ineffective modalities into medical care. Ethicists have compellingly argued that these actions harm individuals and society at large by raising the cost of health care thereby depriving the less affluent of care.10

So my message to Annals readers is that it is your responsibility to protect our patients by interpreting original research papers very carefully and in proper context. We live in an age in which business interests fund the research and the continuing medical education activities that disseminate their message.8, 9, 10, 11 and 12 Research has shown that such relationships often shape the recommendations that are made.13 Journal peer review is an imperfect process for controlling the objectivity of conclusions, and journals have no control over how articles are cited and used after publication.14 The Tung et al article demonstrates some important characteristics of a potentially useful test. It does not measure patient outcomes and sheds no light on whether this test has a clinical role. Perhaps subsequent studies will establish that it is truly useful in these patients, perhaps not. Meanwhile, we should improve the soundness of our medical practice and the health of our society by introducing a new test or treatment only when there is solid evidence that it produces cost-effective improvement in patient outcome in relevant populations.

The author thanks Marshall T. Morgan, MD, for his insightful comments on the word “may.”

References

1 J.L. Januzzi, C.A. Camargo and S. Anwaruddin et al., N-terminal ProBNP for urgent investigation of shortness of breath the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study, Am J Cardiol 95 (2005), pp. 948–954. SummaryPlus | Full Text + Links | PDF (201 K)

2 Tung et al., Amino-Terminal pro-brain natriuretic peptide for the diagnosis of acute heart failure in patients with previous obstructive airway disease, Ann Emerg Med 48 (2006), pp. 66–74. SummaryPlus | Full Text + Links | PDF (388 K)

3 D.L. Schriger, Suggestions for improving the reporting of clinical research the role of narrative, Ann Emerg Med 45 (2005), pp. 437–443. SummaryPlus | Full Text + Links | PDF (296 K)

4 S.P. Collins, Use of NT-proBNP in the Emergency Department Evaluation of Shortness of Breath Implications for Clinical Practice, EMCREG, Cincinnati, OH (2005) 6.

5 A.F. Connors, T.S. Speroff and N.V. Dawson et al., The effectiveness of right heart catheterization in the initial care of critically ill patients, JAMA 276 (1996), pp. 889–897. Abstract-MEDLINE | Abstract-Elsevier BIOBASE

6 S. Harvey, D.A. Harrison and M. Singer et al., PAC-Man study collaboration: assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial, Lancet 366 (2005), pp. 472–477. SummaryPlus | Full Text + Links | PDF (106 K)

7 C. Binanay, R.M. Califf and V. Hasselblad et al., ESCAPE Investigators and ESCAPE Study Coordinators: evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial, JAMA 294 (2005), pp. 1625–1633. Abstract-MEDLINE

8 R. Smith, Medical journals are an extension of the marketing arm of pharmaceutical companies, PLoS Med 2 (2005), p. e138. Full Text via CrossRef

9 R. Horton, The dawn of McScience, New York Rev Books51 (2004), pp. 7–9.

10 M. Angell, The Truth about Drug Companies How They Deceive Us and What to Do about It, Random House, New York, NY (2005).

11 J.P. Kassirer, On the Take How Medicine’s Complicity with Big Business Can Endanger Your Health, Oxford University Press, New York, NY (2004).

12 B. Djulbegovic, M. Lacevic and A. Cantor et al., The uncertainty principle and industry-sponsored research, Lancet 356 (2000), pp. 635–638. SummaryPlus | Full Text + Links | PDF (77 K)

13 Abramson J. Drug profits infect medical studies. Los Angeles Times. January 7, 2006;sect B17:13.

Ace844 · July 22, 2006

(Annals of Emergency Medicine

Volume 48 @ Issue 1 , July 2006, Pages 66-74

doi:10.1016/j.annemergmed.2005.12.022

Cardiology/original research

Amino-Terminal Pro-Brain Natriuretic Peptide for the Diagnosis of Acute Heart Failure in Patients With Previous Obstructive Airway Disease

Roderick H. Tung MDa, Carlos A. Camargo, Jr MDb, Dan Krauser MDa, Saif Anwaruddin MDa, Aaron Baggish MDa, Annabel Chen MDa and James L. Januzzi, Jr MDa, ,

aDepartment of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA

bDepartment of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Received 12 July 2005; revised 13 September 2005, 18 November 2005; accepted 20 December 2005. Available online 17 February 2006.

Refers to: Getting the Right Message: Avoiding Overly Optimistic Interpretations of the Scientific Literature, Annals of Emergency Medicine, Volume 48, Issue 1, July 2006, Pages 75-76

David L. Schriger, a,

SummaryPlus | Full Text + Links | PDF (62 K)

Referred to by: Getting the Right Message: Avoiding Overly Optimistic Interpretations of the Scientific Literature, Annals of Emergency Medicine, Volume 48, Issue 1, July 2006, Pages 75-76

David L. Schriger, a,

SummaryPlus | Full Text + Links | PDF (62 K) )

Study objective

We evaluate results from amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing with or without those of clinical judgment for the evaluation of dyspneic patients with previous chronic obstructive pulmonary disease or asthma.

Methods

As a secondary analysis of previously collected observational data from a convenience sample of 599 breathless patients, 216 patients with previous chronic obstructive pulmonary disease or asthma who presented to the emergency department were analyzed according to results of NT-proBNP, clinical impression, and their final diagnosis. Test performance of NT-proBNP in these patients with chronic obstructive pulmonary disease or asthma was examined for the group as a whole, as well as in patients with and without previous heart failure. NT-proBNP results were compared to clinician-estimated likelihood for heart failure using receiver operating curves and as a function of NT-proBNP plus clinical evaluation. The final diagnosis was determined by 2 independent cardiologists blinded to NT-proBNP using all available data from the 60-day follow-up period.

Results

Overall, 55 patients (25%) had acute heart failure; the median value of NT-proBNP was higher in these patients compared with those without acute heart failure (2,238 vs 178 pg/mL); use of cut points of 450 pg/mL for patients younger than 50 years and 900 pg/mL for patients 50 years or older yielded a sensitivity of 87% (95% confidence interval [CI] 72% to 93%) and a specificity of 84% (95% CI 76% to 88%). In patients without previous heart failure (n=164), median NT-proBNP levels were also higher in patients with heart failure of new onset compared with those with chronic obstructive pulmonary disease or asthma exacerbation (1561 versus 168 pg/mL). High clinical suspicion for acute heart failure (probability >80%) detected only 23% of patients with new-onset heart failure, whereas 82% of these patients had elevated NT-proBNP levels. In patients who had both previous acute heart failure and chronic obstructive pulmonary disease or asthma (n=52), median NT-proBNP levels were significantly higher in those with acute heart failure (4,435 pg/mL) than patients with chronic obstructive pulmonary disease or asthma exacerbation (536 pg/mL). In patients with acute-on-chronic heart failure, NT-proBNP levels were elevated in 91%, whereas clinical impression considered only 39% of cases as high likelihood for acute heart failure.

Conclusion

NT-proBNP may be a useful adjunct to standard clinical evaluation of dyspneic patients with previous obstructive airway disease.

Article Outline

Introduction

Background

Importance

Goals of This Investigation

Materials and methods

Study Design and Setting

Selection of Participants

Methods of Measurement

Primary Data Analysis

Results

Characteristics of Study Subjects

Main Results

Limitations

Discussion

References

SEE EDITORIAL, P. 75.

Editor’s Capsule Summary

What is already known on this topic

Biomarkers B-type natriuretic peptide and its amino-terminal fragment (NT-proBNP) can aid in the detection of patients with acute decompensated heart failure in the emergency department.

What question this study addressed

This retrospective subanalysis of 216 patients from the ProBNP Investigation of Dyspnea in the Emergency Department study examined the discriminative capacity of NT-proBNP in patients with a history of asthma or chronic obstructive pulmonary disease.

What this study adds to our knowledge

These data suggest that NT-proBNP provided additional information to the clinician in patients with previous asthma or chronic obstructive pulmonary disease and possible acute heart failure. Patients with new heart failure were more often correctly identified with the cardiac biomarker than with clinical suspicion alone.

How this might change clinical practice

Because this was a retrospective subgroup analysis that used cut points determined from the data, these findings require replication before we can be certain that this test has diagnostic utility.

Introduction

Background

B-type natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP) have been demonstrated to be useful for diagnosing and excluding acute heart failure in the emergency department (ED).1 and 2 These markers may hold particular promise in elucidating the cause of dyspnea in patients with previous obstructive airways disease (including chronic obstructive pulmonary disease, chronic obstructive pulmonary disease, or asthma). However, NT-proBNP and B-type natriuretic peptide levels may rise in patients with pulmonary hypertension complicating chronic obstructive pulmonary disease or asthma,3, 4, 5, 6, 7 and 8 and data for NT-proBNP testing in those patients with previous lung disease are lacking. We recently reported the primary results of the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study,2 indicating the value of NT-proBNP testing for the identification or exclusion of acute heart failure in dyspneic patients.

Importance

Evaluation of dyspneic patients in the ED is challenging, particularly when detection of acute congestive heart failure is attempted among patients with a history of chronic obstructive pulmonary disease or asthma. Exacerbations of both obstructive airways disease and heart failure often have common symptoms, and there is often significant overlap in the findings from physical examination, laboratory tests, and chest radiographs for these patients.9 Diagnostic accuracy is further challenged when a dyspneic patient has a dual history of heart failure and chronic obstructive pulmonary disease or asthma. This scenario often leads to unnecessary administration of diuretics in patients with exacerbation of obstructive airway disease, as well as inappropriate treatment of heart failure patients with systemic steroids or inhalants for obstructive airway disease, the latter class of medications being particularly undesirable, given their cardiostimulant effects.10 Misdiagnosis with inappropriate therapeutic interventions in this setting may be associated with increased morbidity and mortality.11 Last, underrecognition of structural heart disease in patients with chronic obstructive pulmonary disease or asthma might also be accompanied by underuse of therapies such as angiotensin converting enzyme (ACE) inhibitors and β-blockers in such patients.

Goals of This Investigation

For the purposes of this analysis, we explored the performance of NT-proBNP testing for patients with history of chronic obstructive pulmonary disease or asthma in the PRIDE study to determine the test characteristics of NT-proBNP in these patients and to examine the value of NT-proBNP testing relative to standard clinical assessment for the evaluation of dyspneic patients with previous chronic obstructive pulmonary disease or asthma.

Materials and methods

Study Design and Setting

This is a secondary analysis of a single-center prospective cohort study. The Partners Institutional Review Board approved all study methods. The methods of the PRIDE study have been previously described.2 Briefly, 600 dyspneic patients were enrolled in a prospective study designed to examine the value of NT-proBNP testing compared to clinical judgment blinded to NT-proBNP results for the identification of acute heart failure.

For the current substudy, all patients with a history of emphysema, chronic bronchitis, chronic obstructive pulmonary disease, or asthma were analyzed and examined as a function of the final diagnoses of acute heart failure, chronic obstructive pulmonary disease or asthma exacerbation, or other causes. The history of asthma or chronic obstructive pulmonary disease was ascertained by patient self-report and review of the medical record at the ED visit.

Selection of Participants

The PRIDE study population was drawn from consenting patients aged 21 years or older and who presented with complaints of dyspnea to the ED of the Massachusetts General Hospital (Boston, MA), an urban ED with more than 80,000 visits a year. Enrollment extended between March and September 2003; a convenience sample of patients was enrolled 12 hours a day, 7 days per week. Exclusion criteria for the study were severe renal insufficiency (serum creatinine level >2.5 mg/dL), dyspnea after chest trauma, dyspnea as a result of severe coronary ischemia that was identified as greater than 0.1 mV ST-segment elevation or ST-segment depression on a 12-lead ECG if performed at presentation, greater than 2-hour delay after urgent intravenous loop diuretic administration (above any baseline maintenance dose), and unblinded natriuretic peptide level measurement. Of patients screened and found to be eligible for the PRIDE study as a whole, more than 95% agreed to enrollment, reflective of the low-risk nature of this diagnostic study. After enrollment, a 60-day follow-up was performed on every patient. Patients and their physicians were interviewed, and medical records, including inpatient and outpatient data, were reviewed for all clinical information available since enrollment. At the 60-day follow-up, 1 patient requested withdrawal from the trial, leaving a study sample of 599 patients for the PRIDE study as a whole.

Using all information available from the 60-day follow-up period, a clinical diagnosis (including acute heart failure or chronic obstructive pulmonary disease or asthma exacerbation) was assigned to each patient by 2 study physicians who were blinded to NT-proBNP results. In cases in which the diagnosis was unclear or in doubt, a third study cardiologist rendered an adjudicated diagnosis. In these 10% of cases in which the diagnosis was unclear or in doubt or when disagreement about the final diagnosis existed, an adjudicated diagnosis was rendered in accordance with Framingham Heart Study criteria for diagnosis of heart failure.

After adjudication of diagnoses, blood (collected into ethylenediamine tetraacetic acid tubes, processed, and frozen) samples from each patient were analyzed for NT-proBNP, using a validated, commercially available immunoassay (Elecsys ProBNP, Roche Diagnostics, Indianapolis, IN), using established methodology. Briefly, 20 μL of sample were incubated with biotinylated polyclonal capture antibodies and polyclonal ruthenium-complexed detection antibodies, both directed against NT-proBNP. After incubation, the captured NT-proBNP, bound to streptavidin-coated paramagnetic microparticles, was quantified by electrochemiluminescence. This assay has been reported to have less than 0.001% cross-reactivity with bioactive B-type natriuretic peptide, and in the PRIDE study, this assay had an interrun coefficient of variation of less than 1.0%.

As established in the main PRIDE study, the suggested NT-proBNP concentrations for identifying acute heart failure were greater than 450 pg/mL for patients younger than 50 years and greater than 900 pg/mL for patients 50 years or older, whereas 300 pg/mL was suggested as an optimal cut point for excluding heart failure.2

Methods of Measurement

Clinical data and a blinded NT-proBNP level were obtained prospectively for each study participant by clinical research assistants and enrolling physicians and entered on standardized case report forms.

All patients had complete medical histories taken and underwent physical examinations. All had CBC count and standard blood chemistry tests (including electrolytes and measures of renal function), but none had an unblinded natriuretic peptide test. A 12-lead ECG was obtained in all but 12 patients in the main study; all patients in this ancillary analysis had an ECG available. Of those in PRIDE, 573 (96%) patients had chest radiography performed at presentation; among those in this analysis, all 216 patients (100%) had a chest radiograph performed as part of their standard evaluation.

At the end of standard clinical assessment in the ED but before hospital admission or ED discharge, the attending physician in the ED, who could not be involved in enrollment, was asked to provide a professional estimate for the likelihood of the presence of acute heart failure in each patient, on a scale ranging from 0% to 100% using all available diagnostic testing, including chest radiography, laboratory tests, and previous or present echocardiography. “High” probability of the presence of heart failure was predetermined to be greater than or equal to 80%. The results of clinical estimated likelihood of the presence of heart failure, as well as the ED clinical diagnosis, were recorded for future correlation with NT-proBNP values.

Primary Data Analysis

In this observational ancillary study of the PRIDE study population, the primary endpoint was the examination of the performance of NT-proBNP in patients with chronic obstructive pulmonary disease or asthma, with a comparison of NT-proBNP and clinician-estimated likelihood of heart failure for the diagnosis of acute heart failure in patients with previous obstructive airway disease.

NT-proBNP results were compared to clinical judgment by comparing the area under the receiver operating characteristic curves (with 95% confidence intervals [CIs]). Receiver operating characteristic curves were also used to evaluate sensitivity and specificity of NT-proBNP at cut points suggested from the main PRIDE study. In addition, as previously described,2 a logistic model combining the elements of NT-proBNP and clinical judgment was then compared to each component.

This cohort of patients with previous obstructive airway disease was then analyzed in 2 subgroups, patients with heart failure history and patients without heart failure history, to test whether NT-proBNP would enhance the diagnostic yield of new-onset heart failure in the former group and correctly discern the cause of dyspnea in the latter. Receiver operating characteristic analyses were performed using Analyze-It software (Leeds, UK), whereas other statistics were performed using SPSS software (SPSS, Inc., Chicago, Ill.).

Results

Characteristics of Study Subjects

A study flow diagram in the format of Standards for Reporting Studies of Diagnostic Accuracy is shown in Figure 1. Of the original 599 dyspneic patients who completed follow-up in PRIDE, 216 (36%) patients had a history of chronic obstructive pulmonary disease or asthma. The baseline characteristics of all patients with previous obstructive airway disease are illustrated in Table 1. Fifty-two (24%) of these patients had a history of heart failure. Patients with a history of heart failure tended to be older and had a higher incidence of hypertension, coronary artery disease, and previous myocardial infarction. Overall, 25% of the 216 patients (n=55) were ultimately diagnosed by study physicians as having presented with acute heart failure, whereas 31% (n=68) of patients were diagnosed as having presented with acute exacerbation of chronic obstructive pulmonary disease or asthma, which is slightly less than the incidence of heart failure in the overall PRIDE study (35% of all patients). In all cases, diagnoses were made independent of NT-proBNP values.

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Figure 1. Flow diagram for the present study. HF, Heart failure; COPD, chronic obstructive pulmonary disease.

Table 1.

Baseline characteristics of 216 dyspneic patients with previous obstructive airway disease. Characteristic HF History (n=52) No HF History (n=164)

Demographics

Age (mean±SD) 69±11 59±16

Male 28 (54%) 69 (42%)

White 44 (85%) 148 (90%)

Symptoms (%)

Paroxysmal nocturnal dyspnea 11 (21) 14 (9)

Orthopnea 15 (29) 20 (12)

Lower-extremity edema 18 (35) 18 (11)

Chest pain 14 (27) 55 (34)

Cough 19 (37) 97 (59)

Fever 5 (10) 26 (16)

Increased sputum production 2 (4) 35 (21)

Change in sputum quality 4 (8) 19 (12)

Medical history (%)

Arrhythmia 17 (33) 18 (11)

Hypertension 32 (62) 69 (42)

Coronary artery disease 21 (40) 26 (16)

Previous myocardial infarction 8 (15) 10 (6)

Tobacco use (pack-year, mean) 58±38 53±34

Medications

β-Blocker 26 (50) 35 (21)

Loop diuretic 37 (71) 33 (20)

Hydrochlorothiazide 7 (13) 10 (6)

Digoxin 12 (23) 6 (4)

ACE inhibitor 23 (44) 23 (14)

Short-acting inhaled β-agonist 27 (52) 110 (67)

Inhaled anticholinergic 19 (37) 57 (35)

Long-acting inhaled β-agonist 15 (28) 50 (30)

Inhaled steroid 15 (28) 62 (38)

Systemic steroid 13 (25) 18 (11)

Leukotriene modifier 3 (6) 24 (15)

Physical signs (%)

Jugular venous distention 8 (15) 6 (4)

S3 Gallop 0 (0) 1 (0.1)

S4 Gallop 3 (6) 0 (0)

Lower-extremity edema 24 (46) 34 (21)

Rales 24 (46) 33 (20)

Wheezing 20 (38) 78 (48)

Main Results

Overall, median NT-proBNP values were higher among patients with a final diagnosis of acute heart failure (2,238 pg/mL; interquartile range 1154 to 7080) than in patients without acute heart failure (178 pg/mL; interquartile range 68 to 545; Figure 2) The area under the receiver operating characteristic curve using NT-proBNP to detect acute heart failure among patients with previous chronic obstructive pulmonary disease or asthma was 0.90 (95% CI 0.85 to 0.94; Figure 3), which compares favorably with the area under the receiver operating characteristic curve reported for the entire 599 patients as a whole of 0.94.2 When compared to the results of standard clinical assessment, NT-proBNP testing had greater area under the receiver operating characteristic compared to clinical estimation (with its area under the receiver operating characteristic curve of 0.83; 95% CI 0.76 to 0.89) for the diagnosis of acute heart failure among these 216 chronic obstructive pulmonary disease or asthma patients. The combination of NT-proBNP plus clinical judgment had a superior area under the receiver operating characteristic curve of 0.94 (95% CI 0.89 to 0.97) for evaluation of patients with previous obstructive airways disease.

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Figure 2. Median NT-proBNP levels of 216 dyspneic patients with previous obstructive airway disease, stratified by the presence or absence of acute congestive heart failure. Boxes refer to interquartile ranges, whereas whiskers refer to the fifth and 95th percentile of each group. Outliers are depicted as open circles, whereas extremes are depicted as stars. The cut points of 450 pg/mL (for ages <50 years, dashed line) or 900 pg/mL (for ages ≥50 years, solid line) are depicted.

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Figure 3. Receiver operating characteristic curves for all study patients with a history of obstructive airway disease. Clinical judgment had an area under the curve (AUC) of 0.83, whereas NT-proBNP had an AUC of 0.90; the combination of NT-proBNP plus clinical judgment had an AUC of 0.94.

Among all patients in this subanalysis, using the suggested age-adjusted cut points reported in the main PRIDE manuscript,2 NT-proBNP was 87% sensitive (95% CI 72% to 93%) and 84% specific (95% CI 76% to 88%). The results for all test characteristics of NT-proBNP are seen in Table 2 and Table 3. Using a cut point of 300 pg/mL as a “rule-out” threshold yielded an overall negative predictive value of 97%, with a sensitivity of 94% (95% CI 84% to 99%), specificity of 61% (95% CI 53% to 68%), positive predictive value of 44%, positive likelihood ratio of 2.4, and negative likelihood ratio of 0.09.

Table 2.

Test characteristics of NT-proBNP for the diagnosis of heart failure in the overall study population (N=216), patients without previous heart failure (N=164), and patients with previous heart failure (subgroup 2, N=52).⁎ Category Sensitivity, % (95% CI) Specificity, % (95% CI) PPV, % NPV, % Accuracy, % Likelihood Ratio + Likelihood Ratio −

All (n=216) 87 (72–93) 84 (76–88) 65 95 85 5.4 0.2

No previous heart failure (n=164) 82 (75–97) 90 (83–95) 53 97 88 7.5 0.2

Previous heart failure (n=52) 91 (76–98) 47 (24–71) 75 75 75 1.7 0.2

NPV, Negative predictive value; PPV, positive predictive value; +, positive; −, negative.

⁎ NT-proBNP was considered positive when >450 pg/mL for patients younger than 50 years and >900 pg/mL for those aged 50 years or older.

Table 3.

Specific performance of the NT-proBNP assay in subgroups studied. Category NT-proBNP Elevated NT-proBNP Not Elevated

All (n=216)

Acute HF 48 Of 55 7 Of 55

Not acute HF 26 Of 161 135 Of 161

No previous HF (n=164)

Acute HF 18 Of 22 4 Of 22

Not acute HF 16 Of 142 126 Of 142

Previous HF (n=52)

Acute HF 30 Of 33 3 Of 33

Not acute HF 10 Of 19 9 Of 19

There were 164 patients with a history of chronic obstructive pulmonary disease or asthma without previous heart failure. As depicted in Figure 4, the final diagnosis of acute heart failure accounted for 13% of the cases (n=22), and exacerbation of chronic obstructive pulmonary disease or asthma was the diagnosis in 35% (n=58) of the cases. Median NT-proBNP levels were significantly higher in patients with a diagnosis of acute heart failure (1,561 pg/mL; interquartile range 893 to 2,387 pg/mL) when compared to patients with chronic obstructive pulmonary disease or asthma exacerbation (168 pg/mL; 95% CI 64 to 411 pg/mL); 82% of patients with acute heart failure had an elevated NT pro-BNP level compared to 6% of patients with chronic obstructive pulmonary disease or asthma exacerbation. Of the remaining patients without acute heart failure or exacerbation of obstructive airways disease, the remaining diagnoses of note included pneumonia or bronchitis in 37% of patients, chest pain or acute coronary syndromes in 27% of patients, and atrial arrhythmias in 14% of patients.

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Figure 4. NT-proBNP results in 216 dyspneic patients with previous chronic obstructive pulmonary disease or asthma, categorized by the presence or absence of a history of heart failure and the final diagnosis assigned to the ED presentation. Final diagnoses were made independently of the NT-proBNP results. An elevated NT-proBNP was defined as an NT-proBNP >450 or 900 pg/mL for patients <50 years and ≥50 years, respectively.

Among patients with previous chronic obstructive pulmonary disease or asthma but without previous heart failure, NT-proBNP had an area under the receiver operating characteristic curve of 0.88 (95% CI 0.82 to 0.95); at the cut points used, NT pro-BNP had a sensitivity of 82% (95% CI 75% to 97%), a specificity of 90% (95% CI 83% to 95%), and an accuracy of 88% for detecting acute heart failure in patients with previous obstructive pulmonary diseases but without a history of heart failure. The negative predictive value of 300 pg/mL in this subgroup was 98%, with 90% sensitivity (95% CI 68% to 99%) and 66% specificity (95% CI 58% to 74%) and a positive likelihood ratio of 2.6 and a negative likelihood ratio of 0.15.

Clinical estimation of likelihood for acute heart failure had an area under the receiver operating characteristic curve of 0.86 (95% CI 0.76 to 0.95); however, in this subgroup of patients, only 16% of patients were given a “high” likelihood for acute heart failure. Accordingly, because of this low confidence of the clinicians to give a high clinical suspicion for heart failure in the ED, only 23% of the cases of new-onset heart failure would have been classified as high likelihood, and a large percentage of patients would have been classified falsely an having acute heart failure (36%).

In 52 patients with a dual history of heart failure and chronic obstructive pulmonary disease or asthma, 64% (n=33) of patients had a final diagnosis of acute heart failure, whereas 19% (n=10) of patients had exacerbation of chronic obstructive pulmonary disease or asthma (Figure 4). Of the remaining 9 patients, 4 patients had pneumonia, 3 patients had chest pain or acute coronary syndrome, and 2 patients had atrial arrhythmias. The median NT-proBNP levels were significantly higher in chronic obstructive pulmonary disease or asthma patients with acute-on-chronic heart failure (4,435 pg/mL; 95% CI 1,681 to 8,884 pg/mL) compared to chronic obstructive pulmonary disease or asthma patients with exacerbation of chronic obstructive pulmonary disease or asthma (535 pg/mL; interquartile range 188 to 1,256 pg/mL). Of patients with acute-on-chronic heart failure, most (91%) had an elevated NT-proBNP level compared to 30% of patients with a final diagnosis of chronic obstructive pulmonary disease or asthma exacerbation. Among the patients with acute-on-chronic heart failure with superimposed chronic obstructive pulmonary disease or asthma, the area under the receiver operating characteristic curve of NT-proBNP for the detection of acute heart failure was 0.85 (95% CI 0.73 to 0.95); at the cut points used, NT-proBNP had a sensitivity of 91% (95% CI 76% to 98%), a specificity of 47% (95% CI 24% to 71%), and an accuracy of 75% for detecting acute-on-chronic heart failure in this subgroup of patients. Also, in this subgroup, the “rule-out” cut point of 300 pg/mL had a negative predictive value of 80%, sensitivity of 97% (95% CI 84% to 100%), specificity of 21% (95% CI 6% to 46%), positive likelihood ratio of 1.2, and negative likelihood ratio of 0.14.

Clinical impression for detection of acute-on-chronic heart failure in these patients had an area under the receiver operating characteristic curve of 0.78 (95% CI 0.66 to 0.92); however, with great infrequency of strong clinical suspicion (only 2% of cases were given a probability of heart failure ≥80%), only 39% of the cases of acute-on-chronic heart failure were detected using this approach, with a majority of the difference actually being incorrectly diagnosed as chronic obstructive pulmonary disease or asthma exacerbation. Considering the combination of NT-proBNP plus clinical judgment, 100% of patients presenting with acute heart failure would have been identified.

Limitations

Our study has the potential limitations that pertain to all previous studies in this area, in which establishing a criterion standard for the diagnosis of heart failure is difficult. Although this verification bias is possible, we attempted to minimize this risk by rendering a final diagnosis based on all available data from presentation through a 60-day follow-up period, which is considerably longer than most other studies of this kind,1 and 13 allowing for clearer assessment of the medical status of patients in the study. However, because of lack of uniformity in the evaluation of dyspnea among patients admitted to the hospital, evaluation bias cannot be eliminated and is inherent in studies of this nature.

Because exacerbation of heart failure in a patient with previous obstructive airway disease may actually trigger acute bronchospasm, the possibility exists that some patients may actually have had acute exacerbations of both diagnoses at enrollment. Study physicians in PRIDE were instructed to identify the diagnosis most likely to have triggered presentation to the ED. Thus, it is possible that the methods of 2 mutually exclusive diagnostic classifications of heart failure or chronic obstructive pulmonary disease or asthma led to underdiagnosis or misdiagnosis of both presentations. The PRIDE study occurred in a single center from a large urban teaching hospital, which may influence the generalizability of our results. However, the prevalence of heart failure in our patient population and the clinical characteristics of our patients are similar to those in other multicenter trials of B-type natriuretic peptide testing.1 and 14 Our analysis of patients with histories of obstructive airway disease has the limitations of most substudies. The small sample size compromises the statistical power to make conclusions. In addition, the cut points for NT-proBNP used were derived from the original data set, which inherently biases the data. Further studies to confirm the cut points established in PRIDE are ongoing. Ideally, all patients should have had objective evidence corroborating their diagnosis of chronic obstructive pulmonary disease or asthma, including peak flow measurements and pulmonary function testing. However, there is precedent in the published literature for this method based primarily on self-report and available data at enrollment.1 and 14 Considering that the combination of NT-proBNP plus clinical judgment was based on a logistic model, as described,2 and 15 it may have inherent weaknesses in terms of reproducibility in actual situations.

Discussion

Routine natriuretic peptide testing of dyspneic patients in the ED setting has been demonstrated to be a useful adjunct to clinical diagnosis and radiographic studies because NT-proBNP and B-type natriuretic peptide can distinguish heart failure from other causes of dyspnea with high sensitivity, specificity, and accuracy.1, 2, 15, 16 and 17 However, there are few studies that investigate the test characteristics of B-type natriuretic peptide in patients with a history of obstructive airway disease,7 and 14 and no study to date has directly evaluated NT-proBNP in such patients. Optimal diagnosis and treatment of this patient population is a particular challenge in the ED setting because the symptoms and signs of chronic obstructive pulmonary disease or asthma exacerbation may frequently be difficult to differentiate from those of acute heart failure, and when the 2 diagnoses coexist, treatment decisions become incrementally more complex.18, 19 and 20

We found that NT-proBNP testing was useful for identifying and excluding acute heart failure in patients with previous obstructive airway diseases, even in patients with a history of heart failure, a subgroup of patients not previously assessed in studies of natriuretic peptides. In addition, we demonstrate the potential value of NT-proBNP relative to clinical assessment, demonstrating the superiority of a combined strategy of NT-proBNP testing and clinical assessment, which improved the diagnostic accuracy of the latter approach. We suggest that NT-proBNP testing is useful for the evaluation of the dyspneic patient with previous obstructive airway disease because it more often correctly identifies the presence of acute heart failure in such patients and thus potentially would allow earlier application of optimal therapies for heart failure, including the correct administration of diuretics, ACE inhibitors, or β-blockers, while minimizing the unnecessary use of steroids and cardiotonic medications such as β-agonists. NT-proBNP testing would also be valuable for correctly excluding a diagnosis of heart failure, which would allow for the avoidance of unnecessary diuresis, as well as use of drugs such as β-blockers, which may be associated with risk for bronchospasm in patients with hyperreactive airway disease.

Because a patient’s medical history may be a major factor influencing a physician’s assessment when such a patient presents with dyspnea, we considered the value of NT-proBNP testing for 2 important subgroups: patients with chronic obstructive pulmonary disease or asthma only and patients with an overlapping history of chronic obstructive pulmonary disease or asthma plus heart failure in order to determine whether NT-proBNP testing may increase the detection of new-onset heart failure in the former, as well as correctly identify the cause of dyspnea in the latter. In addition, we examined what the effect would be of adding NT-proBNP testing to standard clinical assessment in the ED.

In the group with a history of chronic obstructive pulmonary disease or asthma without a history of heart failure, 77% of the cases of new-onset heart failure would have been missed if the diagnosis had been based solely on clinical judgment. Our data suggest that for every 100 dyspneic patients with previous obstructive airway disease but without known heart failure tested with NT-proBNP that up to 8 cases of previously unrecognized heart failure might be diagnosed. Our data confirm the prevalence of structural heart disease among dyspneic patients with obstructive airway disease, as suggested by Bayes-Genis and colleagues,12 who also demonstrated the value of NT-proBNP for the detection of “masked” heart failure in similar patients. For such patients with comorbid obstructive airway disease and heart failure, more frequent application of therapies such as ACE inhibitors or β-blockers might be expected to reduce the risk of mortality.20, 21, 22 and 23 Such changes in patient treatment could have important mortality benefits because β-blockers are particularly underused among patients with obstructive airway diseases because of concern about exacerbating underlying lung disease.

In the group of patients with overlapping histories of heart failure and chronic obstructive pulmonary disease or asthma, 61% of cases of heart failure exacerbation would have been missed based on clinical judgment alone. Among these patients, NT-proBNP testing was exceptionally sensitive; the addition of NT-proBNP testing to clinical judgment would correctly identify 3.3 additional patients for every 10 patients tested. Of note, the specificity of elevated NT-proBNP levels was lower, likely because of ongoing B-type natriuretic peptide release in these patients with chronically elevated left ventricular end diastolic pressures at baseline. However, the NT-proBNP values in patients with acute heart failure in this group were considerably higher than those without acute-on-chronic heart failure (4,435 vs 535 pg/mL). In this situation, nonetheless, the specificity of NT-proBNP testing may be less helpful than the enhanced sensitivity for clinical decisionmaking.

In summary, we demonstrate that routine NT-proBNP measurement adds significantly to clinical evaluation in the diagnosis of acute heart failure in patients with previous chronic obstructive pulmonary disease or asthma presenting to the ED with dyspnea, a frequently encountered population that can be a challenge to evaluate and treat. Improved diagnosis or exclusion of acute heart failure in this population may aid clinicians in correctly initiating and titrating medical therapies, avoid potentially incorrect therapeutic interventions, and thus potentially improve patient care. Larger, prospective studies of natriuretic peptide testing for the evaluation of patients with obstructive airways disease are now warranted to confirm the role natriuretic peptide tests play in the standard evaluation of this clinically challenging patient subgroup.

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11 R.C. Wuerz and S.A. Meador, Effects of prehospital medications on mortality and length of stay in congestive heart failure, Ann Emerg Med 21 (1992), pp. 669–674. Abstract

12 W.B. Kannel, R.B. S’Agostino and H. Silbershatz et al., Profile for establishing risk of heart failure, Arch Intern Med 159 (1999), pp. 1197–1204. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef

13 A. Bayes-Genis, M. Santalo-Bel and E. Zapico-Muniz et al., N-terminal pro-brain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction, Eur J Heart Fail 6 (2004), pp. 301–308. Abstract

14 P.A. McCullough, J.E. Hollander and R.M. Nowak et al., Uncovering heart failure in patients with a history of pulmonary disease rationale for the early use of B-type natriuretic peptide in the emergency department, Acad Emerg Med 10 (2003), pp. 198–204. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef

15 P.A. McCullough, R.M. Nowak and J. McCord et al., B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure analysis from Breathing Not Properly (BNP) Multinational Study, Circulation 106 (2002), pp. 416–422. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef

16 J.G. Lainchbury, E. Campbell and C.M. Frampton et al., Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath, J Am Coll Cardiol 42 (2003), pp. 728–735. SummaryPlus | Full Text + Links | PDF (184 K)

17 P.A. McCullough, E.F. Philbin and J.A. Spertus et al., Confirmation of a heart failure epidemic findings from the Resource Utilization Among Congestive Heart Failure (REACH) study, J Am Coll Cardiol 39 (2002), pp. 60–69. SummaryPlus | Full Text + Links | PDF (215 K)

18 S.T. Weiss, Epidemiology and heterogeneity of asthma, Ann Allergy Asthma Immunol 87 (2001), pp. 5–8. Abstract-MEDLINE | Abstract-EMBASE

19 P.M. Yurchak, Cardiac problems in the pulmonary patient. In: A.P. Fishman, Editor, Pulmonary Diseases and Disorders (2nd ed.), McGraw-Hill, New York, NY (1988).

20 The SOLVD Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure, N Engl J Med 325 (1991), pp. 293–302.

21 The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), N Engl J Med 316 (1987), pp. 1429–1435.

22 Merit-HF Study Group, Effect of metoprolol CR/XL in chronic heart failure Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-heart failure), Lancet 353 (1999), pp. 2001–2007.

23 M. Packer, M.R. Bristow and J. Cohn et al., The effect of carvedilol on morbidity and mortality in patients with chronic heart failure U.S. Carvedilol Heart Failure Study Group, N Engl J Med 334 (1996), pp. 1349–1355. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef

Supervising editor: W. Brian Gibler, MD

Author contributions: JJ conceived the study, designed the trial, and obtained research funding. JJ supervised the conduct of the trial and data collection and analysis. RT, CC, DK, SA, AB, and AC undertook recruitment of patients and managed the data. RT drafted the manuscript, and all authors contributed substantially to its revision. RT and JJ take responsibility for the paper as a whole.

Funding and support: Supported by a grant from Roche Diagnostics, Indianapolis, IN.

Address for reprints: James L. Januzzi, Jr, MD, Massachusetts General Hospital, Yawkey 5800, 55 Fruit Street, Boston, MA 02114; 617-726-3443, fax 617-643-1620

Ace844 · July 24, 2006

(NEJM: Volume 355:308-310 July 20 @ 2006 Number 3

Diastolic Heart Failure — A Common and Lethal Condition by Any Name

Gerard P. Aurigemma, M.D.)

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This issue of the Journal contains two provocative contributions to the literature on heart failure. Owan et al.1 describe the epidemiologic outcomes and survival rates among patients with heart failure who were admitted to the Mayo Clinic Hospitals for the disease from 1987 through 2001, extending results published in 19982; Bhatia et al.3 review the shorter-term outcomes among patients hospitalized for heart failure in the province of Ontario over a two-year period, beginning in April 1999. Both groups of investigators subdivided their patients according to the level of ejection fraction. They then compared the characteristics and clinical courses of the patients with a preserved ejection fraction of 50 percent or greater (Owan et al.) or more than 50 percent (Bhatia et al.) to those with a reduced ejection fraction.

Owan et al. and Bhatia et al. use the term "heart failure with preserved ejection fraction," as opposed to the term "diastolic heart failure." Strictly speaking, "heart failure with preserved (or normal) ejection fraction" is not incorrect and appears to be preferred by the American College of Cardiology and the American Heart Association.4 However, "diastolic heart failure" describes the dominant underlying pathophysiological features5,6 and has connotations familiar to the clinician. Furthermore, virtually all patients with heart failure and preserved ejection fraction who are studied carefully will show abnormalities in diastolic function and elevated left-ventricular filling pressures.7 The two current studies remind us that ejection fraction is not a good predictor of clinical disability and suggest that congestive symptoms are more closely related to the filling (diastolic) properties of the ventricle than to the ejection (systolic) properties. Accordingly, the terms "diastolic" and "systolic" heart failure are used here instead of heart failure with "preserved" or "reduced" ejection fractions, respectively.

A principal conclusion of these studies may come as a surprise: patients with diastolic heart failure have the same or only slightly better rates of survival than those with systolic heart failure at one year1,3 and at five years.1 These data challenge the widely held perception that the survival rate among patients with most forms of heart disease is inversely related to the ejection fraction, at least for ejection fractions below 45 percent.8,9,10 How do we reconcile the findings of Owan et al. and Bhatia et al. with the apparently contradictory results from previous studies, such as the Cardiovascular Health Study (a large, multicenter community-based study)9 or the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study (to our knowledge, the only large, randomized clinical trial of the treatment of diastolic heart failure published to date)?10

One may start by asking whether the patients in the two current studies could have been misclassified according to ejection fraction. Although there is not complete unanimity on what is the lower limit of normal, 50 percent is reasonable.5 In the study by Owan et al., the mean (±SD) ejection fraction was 29±10 percent among patients with systolic heart failure and 61±7 percent among patients with diastolic heart failure; this difference suggests that substantial overlap between the two subgroups was unlikely. (The data of Bhatia et al. are even more clear-cut on this point, since patients with an intermediate ejection fraction [40 to 50 percent] were a separate subgroup.) Furthermore, thanks to studies that involve serial echocardiography, we now know that the ejection fraction does not typically change appreciably between hospital admission and hospital discharge, despite dramatic changes in patients' clinical status.11 Therefore, the incorrect classification of patients according to their ejection fraction is unlikely.

In my judgment, the difference between the current results and those of previously published studies relates both to patient characteristics and to the growing recognition of diastolic heart failure. It may be important that Owan et al. studied only patients who survived long enough to be discharged from the hospital. As a result, a higher rate of in-hospital mortality among patients with systolic heart failure than among those with diastolic heart failure may have been overlooked in this study. Furthermore, in both studies, the mean age was higher among patients with diastolic heart failure than among those with systolic heart failure. An older population is more likely to have important coexisting medical conditions, such as cerebrovascular disease or renal insufficiency. Since the primary outcome was death from any cause rather than death from cardiac causes, it seems reasonable to postulate that older patients with diastolic heart failure would have been more likely to have complications from these coexisting medical conditions, despite the authors' attempts at statistical adjustment. Unfortunately, the comparison of these results with those of the CHARM study is bedeviled by what are undoubtedly significant differences in the mean age (which was likely to have been higher in the current studies) and the prevalence of severe coronary artery disease (which was likely to have been higher in the CHARM study).

Although the current analyses were carefully performed, one must be cautious in extrapolating the results. First, the population studied by Owan et al. is more than 97 percent white, and no data on ethnic background were given by Bhatia et al. Second, the authors studied the first or only hospitalization for heart failure. The study populations therefore may not reflect the patients who are hospitalized for heart failure in clinical practice, many of whom are admitted repeatedly for exacerbations of the disease or even for procedure-related heart failure. Finally, the study data may not be applicable to outpatients with heart failure.

Another principal conclusion of Owan et al. is that diastolic heart failure has increased in prevalence over time.1 The authors estimate that, in their study, more than half of the patients discharged with heart failure had diastolic heart failure, and they enumerate the probable explanations. One is the increasing percentage of older patients in the population, coupled with the fact that the prevalence of diastolic heart failure varies directly with the mean age of the population.6 I concur with the authors' observation that, owing to increasing awareness, clinicians were more likely to admit a patient to the hospital for diastolic heart failure in 2001 than previously. In fact, a systematic search of the literature for "diastolic heart failure" (and related terms) shows an increase in the number of publications by a factor of 20 between 1986 and 2002, which includes the study period of Owan et al. There was similar growth during that period in the number of publications with "diastolic dysfunction" in the title, a relative rarity in 1986. Although not mentioned by Owan et al., the growing availability of echocardiography, as well as point-of-care biomarkers such as brain natriuretic peptide, probably increases the likelihood that patients with dyspnea will be diagnosed as having diastolic heart failure, whether or not they are admitted to the hospital.

The nosology of heart failure has been the subject of much current debate, and some extreme positions have been taken. The observation that 22 to 29 percent of patients with diastolic heart failure die within one year of hospital discharge, and 65 percent die within five years, is a reminder that we are facing a lethal condition, regardless of its name. Owan et al. also show that, in recent years, there has been little improvement in survival rate among patients with diastolic heart failure, in contrast to the improvement in survival rate over time among patients with systolic heart failure.

The news is not all bad, however. The noted improvement in the survival rate of patients with systolic heart failure1 provides encouragement that emerging treatment strategies for diastolic heart failure, such as the use of angiotensin-receptor blockers,12,13 might eventually have a clinical effect. We should also not neglect preventive measures with proven efficacy (such as antihypertensive therapy),14 given that there is no effective cure for aging. The prevention of a first or recurrent myocardial infarction is likely to be the best means we have to keep the ejection fraction "preserved." However, the development of specific, effective management approaches for diastolic heart failure must also become a high priority.

Dr. Aurigemma reports having received grant support and consulting fees from Novartis and grant support from Biosite. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester.

References

Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251-259. [Abstract/Full Text]

Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282-2289. [Abstract/Full Text]

Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260-269. [Abstract/Full Text]

Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46:e1-e82. [Full Text]

Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118-2121. [Full Text]

Aurigemma GP, Gaasch WH. Diastolic heart failure. N Engl J Med 2004;351:1097-1105. [Full Text]

Zile MR, Gaasch WH, Carroll JD, et al. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779-782. [Abstract/Full Text]

Aurigemma GP, Gaasch WH, Villegas B, Meyer TE. Noninvasive assessment of left ventricular mass, chamber volume, and contractile function. Curr Probl Cardiol 1995;20:361-440. [Medline]

Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. Ann Intern Med 2002;137:631-639. [Abstract/Full Text]

Solomon SD, Anavekar N, Skali H, et al. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 2005;112:3738-3744. [Abstract/Full Text]

Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17-22. [Abstract/Full Text]

Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-781. [CrossRef][iSI][Medline]

Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure. Part II: causal mechanisms and treatment. Circulation 2002;105:1503-1508. [Full Text]

Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997;278:212-216. [Abstract]

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