Acute Decompensated Heart Failure and the Use of Vasodilator Therapy in Canada

1. Acute Decompensated Heart Failure and the Use of Vasodilator Therapy in Canada

2. Session Objectives By the end of this session, participants will be able to: Understand how to diagnose acute decompensated heart failure (ADHF) Identify current treatment goals and options

3. Challenges in CHF Management in Multi-system Disease Recognition of heart failure Co-morbidities or complications? Barriers to “appropriate heart failure therapy” Goals of therapy

4. Case Study 1 – Mr. B† Presentation: 65 year-old male smoker >10 years history of hypertension, COPD and previous MI Chronic cough, minimally productive Presents to ER reporting acute onset of shortness of breath that awakened him from sleep Physical exam: – BP 160/100 mm Hg – HR 96 beats/min regular Normal heart sounds – RR 30 breaths/min – Room air O2 sat % = 92%

5. Case Study – Mr. B Jugular Venous Pressure (JVP) = 6 cm Rales, S3 and S4 heart sounds Lab values: – Troponin: negative – Serum creatinine: 132.6 µmol/L – Lipid levels: HDL <45 mg/dL; LDL 189 mg/dL; TG 212 mg/dL – Na = 1.1 mmol/L: K = 4.7 mmol/L – Blood urea nitrogen: 13.56 mmol/L No peripheral edema; x-ray suggests acute pulmonary edema

6. CXR Shows Cardiomegaly Without Evidence of Venous Congestion Q1. What diagnosis would you give this patient? COPD End-stage emphysema Reactive airway disease ADHF

7. Q 2: Which of the Historical Features is Most Suggestive of CHF as a Cause of his Dyspnea? Remote MI Cough Nocturnal cough PND Smoking He does not have heart failure

8. Q 3: Which Physical Exam Feature Best Supports a Diagnosis of CHF? High JVP Presence of AF S3 Holosystolic murmur Quiet heart sounds He does not have heart failure

9. Positive Likelihood Ratios for Heart Failure (in ER) Past history CHF 5.8 PND 2.6 S3 11 CXR venous congestion 12 EKG AF 3.8

10. Negative Likelihood Ratios for Heart Failure (in ER) No rales (crackles) 0.51 No past CHF 0.45 No SOBOE 0.48 CXR without cardiomegaly 0.33 EKG normal 0.64

11. Clinical Presentation of AHF Dyspnea in 89% of patients at presentation Rales in 68% Peripheral edema in 66% SBP <90 mm Hg in <3%

17. How Good are Existing Tools for Diagnosing Heart Failure? 

19. ADHF: Clinical Presentation in US HF with SBP >140 mm Hg (~50%) HF with SBP 90 – 140 mm Hg (~47%) HF with SBP <90 mm Hg (~3%) Cardiogenic shock (<1%) Pulmonary edema(<3%) *CXR in 90%: Radiographic pulmonary congestion in 76% Isolated right-sided HF (?) ACS with HF ~30% of ACS have HF, 10% of AHFS have ACS

20. Clinical Assessment and Outcomes of Patient with Severe CHF

21. What are the Guidelines and Recommendations for Treating Patients with ADHF?

22. Current Guidelines for ADHF

23. Erratum describes NTG dose 5-10 mcg/min Erratum describes NTG dose 5-10 mcg/min

25. Mr. B’s Diuretic Treatment Was Increased. How Did He Respond? Remains dyspneic – minimal relief of symptoms Moderate increase in SCr Mr. B is, therefore, still wet BP remains elevated

26. Day 1 – 15 to 30 Minutes AfterInitiation of Vasodilator Therapy Patient characteristics indicate Mr. B is an appropriate candidate for nesiritide BP decreases by 20% Symptom relief – Mr. B appears more comfortable, breathes better, less volume overload He went on to recover and was ultimately discharged on day 5 to follow up with family MD and with HF clinic

27. Day 2 Mr. B is asymptomatic at rest No S3, no rales JVP = 3 cm Diuretic dose is changed to oral form Chronic meds are optimized Mr. B is assessed to be euvolemic: IV nesiritide discontinued

28. Case Study 2 : Old and SOB† 85 year old female with SOBOE for 3 months Flu 12/03 (cough, SOB, fever, mild leg edema L>R) Dx “viral pneumonia” in ER – antibiotics CXR in ER ? nodule with subsequent CT 03/04 “fine interstitial pattern” 3 days ago: ER with progressive dyspnea NYD (seen and discharged with antibiotic and puffer) Return to ER complaining of dyspnea

29. Case 2: Old SOB PMH Longstanding depression/ anxiety disorder ? MI 1973 (never hospitalized) Medication Elavil and Clonazepam

30. Examination (off service resident) BP=162/96 mm Hg HR=102 beats/min; T=36.2 C; RR=26 breaths/min Mild respiratory distress JVP “not sure” Chest a “few creps” Normal heart sounds Mild asymmetric edema R>L

31. Q4: Does Old SOB Have CHF? Definitely yes Possibly Probably not Definitely not

32. Elderly: Clinical Features CHF Delirium Falls Functional decline Sleep disturbance Nocturia/incontinence Dyspnea uncommon if sedentary Ankle edema Other causes Sacral edema Pulmonary findings non-specific

33. Investigations O2 sat 90% on RA WBC 12 left shift, HB =110 NCNC Cr 140 µmol/L CK and Tn I normal D-dimer “positive”

35. EKG

36. Further Investigations pH: 7.50 pCO2: 28 pO2: 82 Bicarb.: 22 Saturation: 3 litres Leg dopplers negative Spirometry: “poor effort”

37. Q5: What is the Next Most Appropriate  Investigation? Await response to clinical treatment (lasix, O2, antibiotics, heparin, steroids)? Obtain more history? Spiral CT to R/O PE? Echocardiogram? BNP?

38. Diagnosis of HF Best clinician diagnosis is about 80%1 Average time in ER before diuretic is 3 hours Most common drugs in ER: Salbutamol, antibiotics, furosemide Worsening renal function in hospital is associated with poor prognosis2 So we wish to avoid inappropriate diuretic while maximizing use when indicated Better diagnostic methods needed2 – BNP, NT- pro-BNP IMPROVE- CHF CANADA Study3

39. B-Type Natriuretic Peptide (BNP) 32-amino acid peptide secreted primarily from the ventricles of the heart Released in response to stretch and increased volume in the ventricles BNP levels correlate with: Left ventricular end-diastolic pressure and volume New York Heart Association (NYHA) functional classification Extent of reversible ischemia Rapid, point-of-care assay for BNP now available to facilitate diagnosis of CHF and use as a prognostic marker Natriuretic Peptides (NP) are hormones that are manufactured and released by the heart muscle cells, in response to extra fluid volume, which causes an increased stretch on the heart muscle and its chambers. B-type natriuretic peptide (BNP) is produced by the heart ventricles in response to ventricular volume expansion and pressure overload. BNP is not secreted under normal circumstances, nor in response to routine activities of daily living, such as hydration status and physical activity. BNP is only generated and secreted in response to excess ventricular stretch and pressure as occurs in HF. In addition, it is not stored but is generated and secreted in direct response to the severity of the HF as it progresses or improves. Therefore, elevated levels are diagnostic for HF, under all circumstances and levels of severity of HF, for which a patient might present to a health care facility. There is a positive relationship between disease severity and BNP levels. In addition, blood BNP levels correlate positively with left ventricular end diastolic pressure, and there is an inverse correlation to left ventricular function and BNP following acute myocardial infarction. History: It was demonstrated in 1979 that the density of secretory granules in the atria (“atrial granularity”) correlates to changes in water and electrolyte balance (de Bold et al. 1979) It was later shown that atrial extracts injected into rats elicited an immediate natriuretic and diuretic effect (de Bold, et al 1981). In the early Early 1980s ANP was characterized by amino acid sequence and cDNA clones. (Atlas, et al. 1984 and Greenberg et al. 1984) BNP was then characterized by amino acid sequence and DNA clones (Maekawa, et al. 1988 and Seilhamer, et al. 1989). Endogenous BNP levels were shown to be elevated in patients with heart failure and that BNP is the natural hormonal response of the heart to heart disease (Mukoyama, et al. 1990) Atrial stretch receptors link blood volume to renal function Distension of a balloon catheter in atria of dogs resulted in diuresis Henry et al (1956) Secretory granules discovered in the atria Kisch (1956) Jamieson and Palade (1964) BNP was characterized by amino acid sequence and DNA clones Maekawa, et al. (1988) Seilhamer, et al. (1989) Natriuretic Peptides (NP) are hormones that are manufactured and released by the heart muscle cells, in response to extra fluid volume, which causes an increased stretch on the heart muscle and its chambers. B-type natriuretic peptide (BNP) is produced by the heart ventricles in response to ventricular volume expansion and pressure overload. BNP is not secreted under normal circumstances, nor in response to routine activities of daily living, such as hydration status and physical activity. BNP is only generated and secreted in response to excess ventricular stretch and pressure as occurs in HF. In addition, it is not stored but is generated and secreted in direct response to the severity of the HF as it progresses or improves. Therefore, elevated levels are diagnostic for HF, under all circumstances and levels of severity of HF, for which a patient might present to a health care facility. There is a positive relationship between disease severity and BNP levels. In addition, blood BNP levels correlate positively with left ventricular end diastolic pressure, and there is an inverse correlation to left ventricular function and BNP following acute myocardial infarction. History: It was demonstrated in 1979 that the density of secretory granules in the atria (“atrial granularity”) correlates to changes in water and electrolyte balance (de Bold et al. 1979) It was later shown that atrial extracts injected into rats elicited an immediate natriuretic and diuretic effect (de Bold, et al 1981). In the early Early 1980s ANP was characterized by amino acid sequence and cDNA clones. (Atlas, et al. 1984 and Greenberg et al. 1984) BNP was then characterized by amino acid sequence and DNA clones (Maekawa, et al. 1988 and Seilhamer, et al. 1989). Endogenous BNP levels were shown to be elevated in patients with heart failure and that BNP is the natural hormonal response of the heart to heart disease (Mukoyama, et al. 1990) Atrial stretch receptors link blood volume to renal function Distension of a balloon catheter in atria of dogs resulted in diuresis Henry et al (1956) Secretory granules discovered in the atria Kisch (1956) Jamieson and Palade (1964) BNP was characterized by amino acid sequence and DNA clones Maekawa, et al. (1988) Seilhamer, et al. (1989)

40. Processing of the Human BNP Gene The coding sequences for proBNP is contained in three exons. separated by two introns. The introns are spliced from the pro BNP primary transcript to generate the mature mRNA which serves as the template for proBNP synthesis. The first exon contains the 5’-untranslated end and the signal peptide, and a portion of the HN2-fragment. Exon 2 contains the remainder of the NH2-region, and then most of the sequence encoding the mature protein. Exon 3 encodes the remainder of the mature protein, and a 3’-untranslated end which contains a polyadenylated tail which confers instability to the message. The mRNA encodes a large pre-BNP whose signal peptide important for localization of the protein to secretory granules is cleaved in the formation of the immediate precursor for hBNP (proBNP, or g-BNP. The g-BNP is 108 amino acids is length. Processing of this precursor between Arg76 and Ser-77 releases a mature BNP molecule containing 32 amino acids. NOTES: The coding sequences for proBNP is contained in three exons. separated by two introns. The introns are spliced from the pro BNP primary transcript to generate the mature mRNA which serves as the template for proBNP synthesis. The first exon contains the 5’-untranslated end and the signal peptide, and a portion of the HN2-fragment. Exon 2 contains the remainder of the NH2-region, and then most of the sequence encoding the mature protein. Exon 3 encodes the remainder of the mature protein, and a 3’-untranslated end which contains a polyadenylated tail which confers instability to the message. The mRNA encodes a large pre-BNP whose signal peptide important for localization of the protein to secretory granules is cleaved in the formation of the immediate precursor for hBNP (proBNP, or g-BNP. The g-BNP is 108 amino acids is length. Processing of this precursor between Arg76 and Ser-77 releases a mature BNP molecule containing 32 amino acids. NOTES:

41. Physiology of BNP Slide 36 B-type natriuretic peptide (BNP) has several biologic effects that are beneficial in patients with heart failure. Human BNP has been shown to increase excretion of sodium and fluids and, at the same time, increase vasodilation in blood vessels thus improving the cardiac performance for patients with decompensated heart failure. The use of nesiritide (hBNP) is pharmacologic doses produces favorable clinical and hemodynamic effects. Slide 36 B-type natriuretic peptide (BNP) has several biologic effects that are beneficial in patients with heart failure. Human BNP has been shown to increase excretion of sodium and fluids and, at the same time, increase vasodilation in blood vessels thus improving the cardiac performance for patients with decompensated heart failure. The use of nesiritide (hBNP) is pharmacologic doses produces favorable clinical and hemodynamic effects.

42. Causes of Increased BNP LV systolic dysfunction LVH with diastolic abnormalities Significant pulmonary embolism Cor pulmonale Pulmonary HTN Aging (modest increases) Renal insufficiency

43. BNP Concentration for the Prediction of Clinical Events Slide 18 In 325 patients presenting to the ED with dyspnea, BNP levels were determined. Patients were then followed for 6 months looking for the following endpoints: death (cardiac and non-cardiac), hospital admissions (cardiac), and repeat ED visits for CHF. Using Kaplan-Meyer plots for all CHF events, patients who left the emergency department with BNP levels >480 pg/ml had a 6-month cumulative probability of a CHF event of (43%). On the other hand, patients who left the emergency department with BNP levels <230 pg/ml had an excellent prognosis with only 2.5% incidence of CHF end-points. The odds ratio for 6-month CHF death in patients with BNP levels > 230 was 46. BNP levels measured in patients presenting with dyspnea to the ED are highly predictive of future cardiac events. Utilization of BNP levels in patients presenting with symptoms of CHF should prove to be a cost-effective way to risk-stratify patients with HF.  Slide 18 In 325 patients presenting to the ED with dyspnea, BNP levels were determined. Patients were then followed for 6 months looking for the following endpoints: death (cardiac and non-cardiac), hospital admissions (cardiac), and repeat ED visits for CHF. Using Kaplan-Meyer plots for all CHF events, patients who left the emergency department with BNP levels >480 pg/ml had a 6-month cumulative probability of a CHF event of (43%). On the other hand, patients who left the emergency department with BNP levels <230 pg/ml had an excellent prognosis with only 2.5% incidence of CHF end-points. The odds ratio for 6-month CHF death in patients with BNP levels > 230 was 46. BNP levels measured in patients presenting with dyspnea to the ED are highly predictive of future cardiac events. Utilization of BNP levels in patients presenting with symptoms of CHF should prove to be a cost-effective way to risk-stratify patients with HF.

44. The BNP Study: First Evidence that Adding BNP to Testing Improves Diagnostic Accuracy

45. Earlier BNP Studies Breathing Not Properly Study1 US sites with BNP >1000 patients Improved diagnostic accuracy and AUC BASEL study2 Single centre Swiss study of BNP with 500 patients Improved accuracy, shorter ER times, less cost PRIDE3 Single city Boston (US) study with NT-pro-BNP and approximately 1,000 patients Improved diagnostic accuracy, age-related cutpoints

46. Do BNP Levels Help Diagnose Those with Acute Dyspnea?

47. The IMPROVE-CHF Study

50. NT-proBNP Complements Clinical Judgment This graph from the Canadian IMPROVE-CHF trial indicates that combining BNP measurement with clinical judgment gives significantly better diagnostic accuracy. References: 1. Arnold JMO, Howlett JG et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Can J Cardiol 2007;23(1):21-45. 2. Moe GW et al. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study.Circulation 2007;115(24):3103-10. This graph from the Canadian IMPROVE-CHF trial indicates that combining BNP measurement with clinical judgment gives significantly better diagnostic accuracy. References: 1. Arnold JMO, Howlett JG et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Can J Cardiol 2007;23(1):21-45. 2. Moe GW et al. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study.Circulation 2007;115(24):3103-10.

51. Clinical Outcomes, Evaluation With and Without Natriuretic-Peptide-Test Guidance

52. Average Direct Medical Costs (in $US) Through 60 Days, Evaluation With and Without BNP Guidance

53. What Does the CCS Say about BNP Testing? Recommendations: BNP or NT-proBNP should be measured to help confirm or rule out a diagnosis of HF in the acute or ambulatory care setting in patients in whom the clinical diagnosis is in doubt (Class I, Level A) Measurement may also be considered in patients with known HF for prognostic stratification (Class IIa, Level A) Sequential measurement of BNP/NT-proBNP levels may be considered to guide therapy in HF patients (Class IIb, Level B)

54. BNP/NT-proBNP in Heart Failure Practical Tips Biomarkers such as BNP and NT-proBNP are complementary to, but do not replace, good clinical evaluation No compelling factors favor the use of BNP versus NT-proBNP The choice of assay is dictated by availability clinician’s familiarity and ability to interpret the results

55. BNP and NT-proBNP In HF

56. First Medications Used in the ED V = ventolin; A= Atrovent Edm = Edmonton FMC= Foothills Medical Centre TO= Toronto, St Michaels Hospital N&N = Nitro and Nesiritide V = ventolin; A= Atrovent Edm = Edmonton FMC= Foothills Medical Centre TO= Toronto, St Michaels Hospital N&N = Nitro and Nesiritide

57. Hospital Course Admitted Treated with O2, lasix (40 mg IV) No heparin No antibiotics Bronchodilators Morning diuresed 2.5 litres “feel better than in months”

58. Case Study 3: Mr. S† Is this Heart Failure? 57 year old obese, type 2 DM, hypertensive, ex-smoker (30 packs/year) Biopsy proven stage 3 sarcoid Jan 02 Prednisone with good effect, tapered off Nov 02 Dec 02 increasing cough, SOBOE, wheeze, orthopnea

59. Case 3 1/52 PTA (Mar 03) increasing dyspnea Respirology “may need to restart prednisone… but little change in CXR” Presents to the ER complaining of increased SOB Meds Adalat XL 60 HCTZ Flovent 2 puffs BID

60. BP=140/80 mm Hg; HR=112 beats/min; T=37.6 C; RR=28 breaths/min – in moderate distress O2 78% increased to 90% with FiO2 0.4 JVP 7-8 cm, cool extremities Crackles at both bases ? Increased P2 Mild edema Cr= 155 µmol/L (was normal) WBC 15K pH=7.45 PCO2= 39 PO2= 59 Bicarb= 27 on Sat 40% (A-a 177)

61. EKG

62. Mar 03

63. Aug 02

64. Case 3 Reviewed by attending respirologist who notes acute decline change in exam and feels she “must be in CHF” due to rapidity of decline and physical findings

65. Q6: Is this CHF? Definitely yes Possibly Probably not Definitely no

66. Q7: What Test Should be Done Next? Serum ACE Bronchoscopy High resolution CT chest Echocardiogram BNP

67. Results BNP was 20 pg/mL Echo revealed normal LV function and moderate pulmonary hypertension (RVSP 55) CT angiogram showed no evidence of PE

68. What Features Suggested This was Not CHF? Degree of hypoxia in a “stable” patient? Extent of CXR abnormality discordant with clinical assessment? Course of clinical worsening?

69. Conclusions Diagnosis of CHF in multi-system disease is challenging Co-morbidities are common, mask the diagnosis of CHF, limit therapeutic options, and negatively impact prognosis BNP may aid in the diagnosis of CHF in this patient population