David Eccleston

B-Type Natriuretic Peptide Testing, Clinical Outcomes, and Health Services Use in Emergency Department Patients With Dyspnea: A Randomized Trial

Context Serum levels of B-type natriuretic peptide (BNP) increase in patients with decompensated heart failure, and BNP testing is commonly done to distinguish cardiac from noncardiac causes of dyspnea. Contribution In this randomized trial, BNP testing did not reduce health services use or improve health outcomes for dyspneic patients who visited emergency departments. Caution Patients were sick enough that the test itself was unlikely to change treatment decisions or outcomes. Implication The practice of measuring BNP in all dyspneic patients to see if heart failure is a cause of their symptoms may not be justified. The Editors A total of 10% to 15% of all emergency department presentations are due to shortness of breath, secondary to heart failure or lung disease. Approximately 80% of patients with acute heart failure syndromes present through the emergency department (1), with dyspnea as the chief symptom (2). The incidence of heart failure is reaching epidemic proportions in the Western world (3). In Europe, up to 2% of the population has symptomatic heart failure (4) (1.5% to 2% in Australia [5]). The incidence of heart failure increases with age; approximately 10% of persons older than 65 years and more than 50% of those older than 85 years have heart failure (6, 7). With an aging population and greater survival from disease processes leading to heart failure, the burden of this disease on the health care system will only increase. Plasma B-type natriuretic peptide (BNP) measurement in patients who present with shortness of breath could improve diagnosis and management. B-type natriuretic peptide is a 32 AA peptide hormone released from the cardiac muscle cells in response to increased ventricular filling pressure and volume expansion (8). Some observational studies have suggested excellent sensitivity and specificity for this test in diagnosing heart failure (915). However, only 1 trial of moderate size (450 patients) has randomly assigned patients to undergo BNP testing or not (16). In the study, investigators in Switzerland reported that the use of the BNP test reduced hospital and intensive care unit (ICU) admissions by 10% and further reduced the median time to discharge. Death and readmissions of these patients were not altered. B-type natriuretic peptide testing markedly reduced costs (

Five-minute heart rate variability can predict obstructive angiographic coronary disease

1800 per patient), mainly because of the reduction in hospital and ICU admissions. The U.S. Food and Drug Administration approved the BNP test, and it is widely marketed throughout the United States and Europe. Swiss emergency care systems differ from Anglo-American health systems, and it is not known whether this influences the extent to which BNP testing may affect the decision to admit patients. It is not known how the test will affect patient management and admission rates when it is done in the central laboratory and patients are assessed with results of chest radiography, electrocardiography, and laboratory testing, which are all available to the treating emergency physician. We investigated whether patients who presented with shortness of breath would be managed differently and hospitalization rates would be altered if BNP was measured. We did a randomized, controlled trial of BNP testing in 2 busy, university-based, teaching hospital emergency departments. Methods Design Overview This study on BNP in shortness of breath was a randomized, controlled, single-blind trial investigating the effect of BNP testing on admission rates, length of hospital stay, and management of patients who presented to the emergency department with shortness of breath as the main symptom. We blinded patients to the intervention but did not blind clinicians or those who assessed trial outcomes. Setting and Participants We conducted the study in the emergency departments of The Alfred (Prahan, Victoria, Australia; a tertiary referral center with 45000 patient attendances per year), and The Northern Hospital (Epping, Victoria, Australia; a metropolitan hospital with 70000 patient attendances per year). We enrolled patients who presented with severe shortness of breath as the main symptom from August 2005 to March 2007. We included only patients who presented with the primary symptom of shortness of breath and were triaged to category 1 to 3 (severe illness acuity requiring assessment by a physician immediately to within 30 minutes after arrival). Exclusion criteria were age younger than 40 years, dyspnea secondary to trauma, cardiogenic shock, and a creatinine level greater than 250 mol/L (>2.82 mg/dL). We further excluded patients who were transferred to another hospital within 24 hours of presentation because of difficulty with follow-up. A registrar or consultant clinically assessed all patients in the emergency department. Routine investigations included blood tests, chest radiography, and electrocardiography. We ordered transthoracic echocardiography and pulmonary function tests within 30 days of presentation when possible. Randomization and Interventions Emergency department staff enrolled patients in the study at presentation. Patients were randomly assigned to have BNP tested (BNP group) or not tested (control group) before consent. Consent for use of patient data and follow-up and further involvement in the trial was obtained within 24 hours. We blinded patients to the intervention. Allocation to the BNP and control group was by random numbers (from computer-generated, random-number tables) in a sealed envelope. The randomization was stratified by site. We collected 10 mL of the patients blood in tubes containing EDTA and sent it to the hospital laboratory. Patients randomly assigned to the BNP group had BNP analyzed, and the result was provided with other blood test results within 60 minutes. We measured BNP by using the Abbott AxSYM MEIA Automated Immunoassay (Abbott, Chicago, Illinois). The measurable range of the BNP assay is 15 to 4000 ng/L. The assay has a functional sensitivity of 20 ng/L (coefficient of variation, 20%) and is calibrated against the Triage B-Type Natriuretic Peptide test (Biosite, San Diego, California) (9). The diagnostic value of detecting heart failure by using this BNP assay has been documented (17). Four education sessions during the study period familiarized emergency department staff with BNP, its role in the diagnosis of heart failure, and the current literature in the field. The BNP test had been done at the main study hospital for 5 years if requested from the cardiology department; but if other physicians requested the test, a chemical pathologist needed to approve it. Each physician who treated an enrolled patient received a written guideline on the treatment of acute heart failure and chronic obstructive pulmonary disease, as well as the BNP nomogram published by McCullough and coworkers (10). We advised physicians that a BNP level less than 100 ng/L made the diagnosis of heart failure unlikely, whereas a BNP level greater than 500 ng/L made heart failure likely. Outcomes and Follow-up Primary outcomes were hospital admission rate, length of stay, and change in patient management. Secondary outcomes were 30-day mortality and readmission rates. We contacted all patients or next of kin after 30 days about readmission and death. We achieved complete follow-up of all study participants. Trained research assistants, who were not blinded to the group assignment, collected baseline demographic characteristics, admission rates, length of hospital stay, and clinical information from hospital records. Two physicians made the final diagnosis of heart failure; one was a cardiologist. The physicians had access to additional information, including case notes; results of blood tests; electrocardiography and chest radiography reports; and clinical course during inpatient stay, including response to treatment, transthoracic echocardiography results, and pulmonary function test results. We did not blind physicians to the group assignment, but we did blind them to the BNP results. Reviewers defined heart failure on the basis of the definition from the European Society of Cardiology working group on heart failure diagnostic criteria (18), as well as an algorithm for the diagnosis of heart failure. The reviewers determined whether heart failure caused the presentation to the emergency department with dyspnea or not. If the 2 independent reviewers agreed, their diagnoses were taken as the final diagnosis. When they disagreed, a third physician reviewed all available data and made the final diagnosis. The degree of agreement between the 2 reviewers was substantial in both the BNP and control groups (= 0.79 [95% CI, 0.78 to 0.83] and 0.82 [CI, 0.78 to 0.86], respectively). Statistical Analysis Prespecified outcomes were the hospital admission rate, the length of hospital stay, and any change in management in the 2 groups. With a sample size of 300 patients in each group, we calculated an 80% power to detect an absolute reduction of 10 percentage points (80% to 70%) in hospital admission rates and a relative reduction of 20% (8.0 to 6.4 days) in hospital length of stay, assuming tests were 2-sided and P values were 0.05. Statistical analysis was done by intention to treat in all patients who consented after randomization. Demographic characteristics, clinical characteristics, and baseline vital signs in the BNP and control groups are reported in counts and percentages or means (SDs), as appropriate. We compared admission rates by using Pearson chi-square and Fisher exact tests. We used the MantelHaenszel test to compare admission rates with and without the BNP test and stratified by hospital site. We compared length of admission between the 2 groups by using the 2-sample Wilcoxon rank-sum (MannWhitney) test. In addition, we did multivariate logistic regression to investigate the probability of hospital admission and length of stay. Covariates included a history of hypertension, history of heart failure, and hos

The effect of intended duration of clopidogrel use on early and late mortality and major adverse cardiac events in patients with drug-eluting stents.

Objective Obstructive coronary artery disease (CAD) is evident in only half of patients referred for diagnostic angiography. Five-minute heart rate variability (HRV) is a non-invasive marker for autonomic control of the vasculature, which this study hypothesised could risk-stratify cardiac patients and reduce unnecessary angiograms. Design A prospective observational study (the Alternative Risk Markers in Coronary Artery Disease (ARM–CAD) study). Setting Three cardiac centres in Melbourne, Australia. Patients 470 consecutive patients undergoing elective angiography (with predominantly normal cardiac rhythm), regardless of co-morbidity. Main outcome measures The presence of obstructive CAD (≥50% stenosis) on angiography. Results Patients with obstructive CAD had significantly reduced HRV, particularly in the low frequency (LF) range (median 180 vs 267 ms2 without CAD; p<0.001). There was a linear trend with the severity of CAD; median LF power (IQR) in patients with normal coronaries was 275 (612), with minor coronary irregularities 255 (400), single-vessel CAD 212 (396) and more severe disease 170 (327) ms2; p value for trend 0.003. There was a similar reduction in LF power regardless of the anatomical location of coronary stenoses. Comparing patients with LF less than 250 and 250 ms2 or greater, the adjusted OR for obstructive CAD using multivariate regression was 2.42, 95% CI 1.33 to 4.38 (p=0.004). No interactions were noted in subgroup analysis and HRV added to risk prediction irrespective of the baseline Framingham risk (p<0.0001). Conclusion Low HRV is strongly predictive of angiographic coronary disease regardless of other co-morbidities and is clinically useful as a risk predictor in patients with sinus rhythm. Clinical trial registration information http://clinicaltrials.gov/ct2/show/NCT00403351 www.armcad.com

A pilot study of resistance to aspirin in stroke patients

BACKGROUND The optimal duration of clopidogrel use for prevention of stent thrombosis with drug-eluting stent (DES) use is uncertain. Our objective was to determine whether the planned duration of clopidogrel at the time of percutaneous coronary intervention affected patient outcomes. METHODS We analyzed data from 2,980 patients who underwent percutaneous coronary intervention in the Melbourne Interventional Group registry who had 12-month follow-up. We compared outcomes at 30 days and 12 months according to planned duration of clopidogrel use. RESULTS Twelve-month mortality was significantly lower in patients with a DES with a longer (>or=12 months) planned duration of clopidogrel when compared with a shorter (<or=6 months) planned duration (2.8% vs 5.3%, P = .012). However, myocardial infarction, target-vessel revascularization, and overall major adverse cardiac events were similar in the longer- and shorter-duration clopidogrel strategies. In contrast, in patients receiving a bare-metal stent, mortality at 12 months was similar among the clopidogrel-duration strategies. Kaplan-Meier analysis demonstrated improved cumulative survival with planned clopidogrel use of >or=12 months (log rank P = .017), and the propensity score-adjusted odds ratio was 0.59 (95% confidence interval 0.35-0.99, P = .04). Premature cessation of clopidogrel in DES patients was documented in 5.2% of patients alive at 30-day follow-up, and these patients had increased 12-month mortality (10.6% vs 1.4%, P < .0001) and major adverse cardiac events (22.4% vs 12.0%, P = .005). CONCLUSIONS These data suggest that in patients treated with DES, longer (>or=12 months) planned duration of clopidogrel results in reduced 12-month mortality and that premature cessation of clopidogrel results in significantly higher event rates. Randomized studies are urgently needed to address this issue.

B-Type Natriuretic Peptide Testing and the Accuracy of Heart Failure Diagnosis in the Emergency Department

Aspirin resistance has been shown to be a significant risk factor for recurrent cardiovascular ischaemic events. However, there are a lack of data correlating aspirin resistance and risk of cerebrovascular ischaemic events. This pilot study aimed to determine the prevalence of aspirin resistance in an Australian stroke population and to correlate aspirin resistance with an increased risk of ischaemic stroke. Fifty patients treated with aspirin for 2 years were tested for aspirin resistance using the Ultegra Rapid Platelet Function Assay (Accumetrics, San Diego, CA, USA) on admission to Royal Melbourne Hospital for ischaemic stroke. The 2-year history of ischaemic stroke and transient ischaemic attack (TIA) were assessed. Prevalence of aspirin resistance among our patients was 30%. Univariate analysis suggested a non-significant trend towards increased rate of previous ischaemic stroke or TIA and aspirin resistance (odds ratio, OR=3.88; 95% confidence interval 0.54-29.87; p=0.18). This study shows that aspirin resistance is prevalent within the Australian ischaemic stroke population.

BNP Testing and the Accuracy of Heart Failure Diagnosis in the Emergency Department

Background—It is often difficult to diagnose heart failure (HF) accurately in patients presenting with dyspnea to the emergency department (ED). This study assessed whether B-type natriuretic peptide (BNP) testing in these patients improved the accuracy of HF diagnosis. Methods and Results—Patients presenting to the Alfred and the Northern Hospital EDs with a chief complaint of dyspnea were enrolled prospectively from August 2005 to April 2007. Patients were randomly allocated to have BNP levels tested or not. The diagnostic gold standard for HF was determined by 1 cardiologist and 1 emergency or respiratory physician who, blinded to the BNP result, independently reviewed all available information. The ED diagnosis of HF in the non-BNP group showed a sensitivity, specificity, and accuracy of 65%, 92%, and 81%, respectively. The BNP group had a similar sensitivity, specificity, and accuracy of 66%, 90%, and 78%, respectively, for the diagnosis of HF in the ED. There was no significant difference between the BNP and non-BNP groups in any of the measures of diagnostic accuracy for HF. Conclusion—In the clinical setting of EDs, availability of BNP levels did not significantly improve the accuracy of a diagnosis of HF. Clinical Trial Registration—clinicaltrials.gov. Identifier: NCT00163709.

Randomized trial comparing 600- with 300-mg loading dose of clopidogrel in patients with non–ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: Results of the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial

Background—It is often difficult to diagnose heart failure (HF) accurately in patients presenting with dyspnea to the emergency department (ED). This study assessed whether B-type natriuretic peptide (BNP) testing in these patients improved the accuracy of HF diagnosis. Methods and Results—Patients presenting to the Alfred and the Northern Hospital EDs with a chief complaint of dyspnea were enrolled prospectively from August 2005 to April 2007. Patients were randomly allocated to have BNP levels tested or not. The diagnostic gold standard for HF was determined by 1 cardiologist and 1 emergency or respiratory physician who, blinded to the BNP result, independently reviewed all available information. The ED diagnosis of HF in the non-BNP group showed a sensitivity, specificity, and accuracy of 65%, 92%, and 81%, respectively. The BNP group had a similar sensitivity, specificity, and accuracy of 66%, 90%, and 78%, respectively, for the diagnosis of HF in the ED. There was no significant difference between the BNP and non-BNP groups in any of the measures of diagnostic accuracy for HF. Conclusion—In the clinical setting of EDs, availability of BNP levels did not significantly improve the accuracy of a diagnosis of HF. Clinical Trial Registration—clinicaltrials.gov. Identifier: NCT00163709.

Impact of early percutaneous coronary intervention on short- and long-term outcomes in patients with cardiogenic shock after acute myocardial infarction

BACKGROUND There is uncertainty about the benefit of a higher loading dose (LD) of clopidogrel in patients with non-ST elevation acute coronary syndrome (NSTEACS) undergoing early percutaneous coronary intervention (PCI). METHODS We compared the effects of a 600- versus a 300-mg LD of clopidogrel on inhibition of platelet aggregation, myonecrosis, and clinical outcomes in patients with NSTEACS undergoing an early invasive management strategy. Patients with NSTEACS (n = 256, mean age 63 years, 81.6% elevated troponin) without thienopyridine for at least 7 days were randomized to receive 600- or 300-mg LD of clopidogrel. Percutaneous coronary intervention was performed in 140 patients, with glycoprotein IIb/IIIa inhibitor use in 68.6%. Adenosine diphosphate (ADP)-induced platelet aggregation was measured by optical platelet aggregometry immediately before coronary angiography. RESULTS Post-PCI myonecrosis was defined as a next-day troponin I greater than 5 times the upper limit of reference range and greater than baseline levels. Clopidogrel 600-mg LD compared with 300-mg LD was associated with significantly reduced ADP-induced platelet aggregation (49.7% vs 55.7% with ADP 20 micromol/L) but did not reduce post-PCI myonecrosis or adverse clinical outcomes to 6 months. There was no association between preprocedural platelet aggregation and outcome. CONCLUSIONS These data confirm a modest incremental antiplatelet effect of a 600-mg clopidogrel LD compared with 300-mg LD but provide no support for a clinical benefit in patients with NSTEACS managed with an early invasive strategy including a high rate (69%) of glycoprotein IIb/IIIa inhibitor use during PCI.

Improving the quality of percutaneous revascularisation in patients with multivessel disease in Australia: cost-effectiveness, public health implications, and budget impact of FFR-guided PCI.

This study assesses the impact of early percutaneous coronary intervention in patients presenting with cardiogenic shock after acute myocardial infarction. Predictors of in-hospital death include the need for intubation, cardiopulmonary resuscitation, and angiographic failure; long-term outcomes at 2 years in hospital survivors are favorable.

Clopidogrel, Prasugrel or Ticagrelor in Patients with Acute Coronary Syndromes undergoing Percutaneous Coronary Intervention.

PURPOSE The international multicentre FAME Study (n=1,005) demonstrated significant health benefits for patients undergoing multivessel percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) measurement compared with angiography guidance alone (ANGIO). We determined the cost-effectiveness and the public health/budget impact for Australia. METHODS We performed a prospective economic evaluation comparing FFR vs. ANGIO in patients with multivessel disease based on original patient-level FAME data. We used Australian utilities (EQ-5D) and costs to calculate quality-adjusted life years (QALYs) and incremental cost-effectiveness adopting the societal perspective. The public health and budget impact from the payers perspective was based on Australian PCI registries. Uncertainty was explored using deterministic sensitivity analyses and the bootstrap method (n=5,000 samples). RESULTS The cost-effectiveness analysis showed that FFR was cost-saving and reduces costs by 1,776 AUD per patient during one year. Over a two-year time horizon, the public health impact ranged from 7.8 to 73.9 QALYs gained and the budget impact from 1.8 to 14.5 million AUD total cost savings. Sensitivity analyses demonstrated that FFR was cost-saving over a wide range of assumptions. CONCLUSIONS FFR-guided PCI in patients with multivessel coronary disease substantially reduces cardiac events, improves QALYs and is cost-saving in the Australian health care system.