HOST W. Frank “Peek-a-Boo” Peacock IV, MD Vice Chief of Research Department of Emergency...
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![Page 1: HOST W. Frank “Peek-a-Boo” Peacock IV, MD Vice Chief of Research Department of Emergency Medicine The Cleveland Clinic Cleveland, OH.](https://reader035.fdocuments.us/reader035/viewer/2022081603/56649f1e5503460f94c35663/html5/thumbnails/1.jpg)
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HOST
W. Frank “Peek-a-Boo” Peacock IV, MD
Vice Chief of ResearchDepartment of Emergency Medicine
The Cleveland ClinicCleveland, OH
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Debate Format
• Introduction from moderator
• 7 minute presentation from each side of the debate
• 2 minutes rebuttal from each side
• 4 minutes for questions from the audience
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Questions from the Audience
• 4 minutes for questions
• Question cards were given to you during registration and will be collected during and after the debate
• May also use floor microphones
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Registration
• The audio files and the PPT slide decks for these debates will be available on checourse website in a few weeks.
• You will be notified via email when these files become available.
• You must fill out and turn in the evaluation form to receive CME credit
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Please Turn Cell Phones and Pagers to Silent Mode
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Pro: “Cleveland Assassin
Emerman”
Vasoactive Agents in ADHF
Con: “Southpaw Storrow”
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Charles L. “Cleveland Assassin”
Emerman, MD
BADASS
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Vasoactive Agentsin Heart Failure:
You Aren’t Going to Use These?
Charles L. Emerman, MD
Professor and Chairman of Emergency Medicine
Case Western Reserve University
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My Opponent: Dr. Storrow
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Perhaps He’d Like You to Use…
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Or, Perhaps He’d Like Us to Use…
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We Aren’t Talking About Vasoconstrictors / Inotropes Here
Cuffe MS, et al. JAMA. 2002;287:1541–1547.
Ev
ent
Ra
te (
%)
Treatment Failure From Adverse
Event (48 h)
Sustained Hypotension
Acute MyocardiaI Infarction
Mortality
MilrinoneMilrinone
PlaceboPlacebo
Atrial Fibrillation
P < 0.001 P < 0.001
P = 0.18
P = 0.004P = 0.19
12.6
2.1
10.7
3.21.5
0.4
4.6
1.5
3.82.3
0
5
10
15
20
OPTIME-CHF: In-hospital Adverse Events
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Dobutamine (n = 141)
Nes 0.015 g/kg/min (n = 187)
Cu
mu
lati
ve M
ort
alit
y R
ate
(%)
Time From Start of Treatment (days)
Nes 0.030 g/kg/min (n = 179)
Effect of Short-term Nesiritide or Dobutamine on 6-Month Survival
05
10
15
20
25
30
35
0 30 60 90 120 150 180
Log-rank test:Dobutamine vs nesiritide 0.015 g/kg/min P = 0.041Dobutamine vs nesiritide 0.030 g/kg/min P = 0.445Nes 0.015 g/kg/min vs nes 0.030 g/kg/min P = 0.187
Elkayam U, et al. J Cardiac Fail. 2000;6(Suppl 2):169.
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But If You Add Vasodilators to Inotropes, You Improve Your Results
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The Debate Here Isn’t Between NTG and Nesiritide: It is Vasodilators Versus Usual Care with Diuretics
Ch
ange
fro
m B
asel
ine
in P
CW
P (
mm
Hg)
End of Placebo-Controlled Period
Time on Study Drug (Hours)
During 3-hour Placebo PeriodPlacebo, n = 62 IV NTG, n = 60Nesiritide, n = 124
After 3-hour PeriodIV NTG, n = 92Nesiritide, n = 154
†P < 0.05 vs IV NTG*P < 0.05 vs placebo
*
†*
0 0.25 0.5 1 2 3 6 9 12 24 36 48
-9
-8
-7
-6
-5
-4
-3
-2
-1
0PCWP - Placebo
PCWP - IV NTG
PCWP - Nesiritide
†*
†* †
** †
* †
†††
*
NTG, nitroglycerin; PCWP, pulmonary capillary wedge pressure; IV, intravenous.
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Effects of Non-PSDs
Favors Non-PSD
HF hospitalization
Cardiovascular death
Arrhythmic death
Any death
Adverse Effect of Non-PSD
0 1 2Hazard Ratio
Data from the SOLVD trial.J Am Coll Cardiol. 2003;42:705––708. Circulation. 1999;100:1311––
1315.
PSD, potassium-sparing diuretic; HF, heart failure.
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Nesiritide Blocks Adverse Actions of Furosemide
• Experimental study of paced induced HF in dogs
• Nesiritide improved urine sodium excretion, glomerular filtration rate (GFR), and urinary output
Circulation. 2004;109:1680––1685.
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The More You Use,the More You Lose
• 1,354 patients divided into furosemide dose quartiles
• Highest quartile had lowest ejection fraction, sodium level, and hemoglobin level and highest creatinine (Cr)and blood urea nitrogen (BUN) levels
• Even after adjustment, significant difference in outcome
Am J Cardiol. 2006;97:1759––1764.
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Chronic Diuretic Use and Hospital Mortality
0
1
2
3
4
5
6
7
8
Mortality
Nodiuretics
Diuretics
Nodiuretics
Diuretics
• Data from 45,000 in the ADHERE registry
• Effect of diuretics in past 90 days
• Also found increase in length of stay (LOS)
• Patients previously on diuretics less likely to be discharged to home asymptomatic
Costanza MR. 2004 ACC meeting.CR <2 CR >2
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Impairment in Renal Function
• Administration of furosemide associated with drop in GFR and plasma flow and rise in mean arterial pressure
• Effect blunted by losartan
Chen HH. Am J Physiol Renal Physiol. 2003;284:F1115––F1119.
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High-Dose vs Low-Dose Diuretics and Vasodilators
• 110 patients with acute decompensated heart failure (ADHF)
• Randomized to low-dose furosemide + high-dose IV NTG or repeated high doses of furosemide and low dose of IV NTG
• More rapid improvement of pulse oximetry in group A
0%
5%
10%
15%
20%
25%
30%
35%
40%
A B
Intubate
Any AE
Lancet. 1998;351:9100.
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In Other Words:Vasodilators — GoodDiuretics — Not So Good
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Alan B. “Southpaw” Storrow, MD
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Nitro Is Being Bullied…and you should be mad about it
Alan B. Storrow, MD
Vice Chairman for Research
Department of Emergency Medicine
Vanderbilt University
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The Life Story of “Nitro”
• NTG grew up poor– (i.e. no industry backing)
• Worked hard and worked well, despite growing up around the stuck-up rich kids – (milrinone, nesiritide, levosimendan)
• Remains a hard-working blue collarHF drug
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NTG in a Nutshell
• Low dose: venous vasodilation
• High dose: arterial vasodilation
• Vasodilatation leads to decreased PCWP, preload and afterload
• Improves epicardial coronary blood flow and CO
• Little or no change in heart rate
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NTG Studies in ADHF
Does it work?
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Sublingual NTG in ADHF
• Hemodynamic effects• Sublingual captopril vs NTG in ADHF• 24 ICU patients: PCWP >20 mm Hg and CI <2.5 L/min/m2
• Baseline diuretics and digoxin: no inotropes/vasodilators• Systolic blood pressure 110–130 mm Hg• Randomized to either
– Captopril 25 mg sublingual (pill chewed)– NTG 0.8 mg sublingual
Haude M, et al. Int J Cardiol. 1990;27:351–359.
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Does Topical NTG Work in ADHF?
• The “chili dog” effect
• Application of NTG paste to 13 patients with PCWP >18 mm Hg
• 2.5–5 cm of NTG paste
• Hemodynamic response over 6 hours
Kawai C, et al. Clin Ther. 1984;6:677–688.
Before NTG
After NTG
PCWP(mm Hg)
26.3 16.8*
CI(L/min/m2)
2.7 2.9
SVR(dynes.s/cm-5)
1,920 1,520*
*P < 0.005.*P < 0.005.
SVR, systemic vascular resistance.
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High-Dose IV NTG in ADHF• 104 patients with ADHF
– Chest x-ray + O2 saturation <90%, blood pressure >110/70 mm Hg
• Randomized to– A: 3 mg isosorbide dinitrate IV q 5 minutes + furosemide 40 mg IV– B: isosorbide dinitrate 1 mg/h (titrated 1mg/h every 10 minutes) +
furosemide 80 mg IV every 15 minutes• Continued until
– O2 saturation >96%
– Mean arterial pressure decreased 30% or to <90 mm Hg• Primary end point
– In-hospital death– Intubation within 12 hours (criteria)– Acute myocardial infarction within 24 hours
Cotter G, et al. Lancet. 1998;351:389–393.
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High-Dose IV NTG in AHF
Cotter G, et al. Lancet. 1998;351:389–393.
P = 0.006P = 0.006
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High-Dose IV NTG in AHF
Cotter G, et al. Lancet. 1998;351:389–393.
Conclusion: High-dose NTG after low-dose furosemideis safe and effective in controlling pulmonary edemaConclusion: High-dose NTG after low-dose furosemideis safe and effective in controlling pulmonary edema
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• Retrospective analysis of ADHERE• Comparison of >15,000 patients who received IV
– NTG– Nesiritide– Dobutamine– Milrinone
• 1st - univariable predictors of mortality• 2nd - propensity scores for each • 3rd - logistic regression to predict mortality adjusting
for steps 1 and 2
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Is Little NTG Colicky(Nitrate Tolerance)?
• Theoretical decreased hemodynamic and clinical effect after prolonged use of NTG
• *Three possible mechanisms: – 1) Plasma volume expansion– 2) Neurohormonal – 3) Free radicals
• Conflicting data except free radical idea: supported well in rats and isolated blood vessels
* Elkayam O. J Cardiol Pharm Ther. 2004;9:227–241.
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Colic, or Just Gas?
• Tolerance prevention – 12 hours on and 12 hours off– Oral hydralazine
• Take-home point: in the first 6–12 hours, with aggressive up-titration — not an issue — VMAC an example
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Guidelines for Little NTG
• American College of Cardiology/American Heart Association (ACC/AHA): Helpful for chronic heart failure — nothing about acute
• European Society of Cardiology (ESC): Helpful in ADHF — Class I, level B evidence
• Heart Failure Society of America (HFSA): NTG used to improve congestion in those patients not hypotensive — Strength = C
• American College of Emergency Physicians (ACEP): Level B — “administer IV nitrates to patients with acute heart failure and dyspnea”
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VMAC: A Closer Look at the Data
• NTG was NOT titrated aggressively
• Mean dose of NTG at 3 hours in catheterized and noncatheterized?
• 42 and 29 mcg/min
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Result of Poor Titration
Placebo
Nesiritide
NitroChanges from baselinein PCWPChanges from baselinein PCWP
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.
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Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.
Outcomes at 3 and 24 Hours for All Treated Patients by Randomization Group
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“High-Dose NTG” Subgroup
• Subgroup comparison of patients who received high-dose NTG (n = 12) and nesiritide (n = 15)at one center
• Maximum mean dose of NTG was 161 mcg/min
• Maximum mean infusion of nesiritide was0.012 mcg/kg/min
Elkayam U, et al. Am J Cardiol. 2004;93:237–240.
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“High-Dose NTG” Subgroup
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“High-Dose NTG” Subgroup
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2007 High-DoseOutcome Analysis
• Nonrandomized• 29 hypertensive,
refractory patients• 2-mg boluses every
3 minutes up to10 doses
• Mean = 6.5 mg• Compared with non–
high-dose group
• Less intubation– 14% vs 27%
• Less bilevel positive airway pressure– 7% vs 20%
• Less ICU admission– 37% vs 80%
• Adverse events uncommon
Levy P. Ann Emerg Med. 2007;50:144–152.
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As If I Really Need One
Dr. Storrow
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Predictors of Worsening Renal Function
Butler J, et al. Am Heart J. 2004;147:331––338.OR, odds ratio; CI, confidence interval.
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Impact of Diuretic Dosing on Outcomes in Decompensated HF
• Data derived from ADHERE database • ~80,000 patients who received
diuretics but no inotropes or vasodilators
• Divided patients based on diuretic dose in first 24 hours <160 mg vs 160 mg
J Cardiac Fail. 2004;10:S114––S368.
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Groups Reasonably Matched for Concomitant Medications
Medications Dose <160 mg(%)
Dose 160mg (%)
ß-blockers 38,370 (61.0) 12,049 (61.2)
ACE inhibitors 36,771 (58.5) 10,971 (55.8)‡
ARBs 8,760 (13.9) 3,012 (15.3)‡
Calcium channel blocker
16,009 (25.5) 5,408 (27.5)‡
Peripheral vasodilator
3,359 (5.3) 1,695 (8.6)‡
J Cardiac Fail. 2004;10:S114––S368.
‡‡P P < 0.05.< 0.05.
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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Prior Medications
Dose <160 mg (%) Dose 160 mg (%)
Diuretics 67.1 82.3‡
ß-blockers 47.6 50.7‡
ACE inhibitors 39.8 41.8‡
ARBs 11.9 13.3‡
J Cardiac Fail. 2004;10:S114––S368.‡P < 0.05.
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Laboratory DataDose <160 mg Dose 160 mg
Elevated troponin (μg/L)
5.2 5.7‡
BNP, median (pg/mL)
704 782‡
Cr (mg/dL) 1.2 1.4‡
LVEF <40% 44.7 46.9‡
BUN, median (mg/dL)
16.0 18.0‡
J Cardiac Fail. 2004;10:S114––S368.
‡P < 0.05.
BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction.
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Renal Outcomes
0
5
10
15
20
25
30
? Cr>.5 Newdialysis
<160 mg
=>160 mg
J Cardiac Fail. 2004;10:S114––S368.
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Clinical Outcomes
0123456789
10
Mortality ICU admit Hosp LOS
<160 mg
=>160 mg
J Cardiac Fail. 2004;10:S114––S368.
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Multivariate Adjusted Results
J Cardiac Fail. 2004;10:S114––S368.ICU, intensive care unit.
In-hospital MortalityICU AdmissionsLength of Stay Total > 4 days ICU > 3 daysRenal Function SCr increase > 0.5 mg/dl ≥ 10 mL/min decrease in GFR Initiation of dialysis
Adjusted Odds Ratio (95% CI) P-value
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
High Dose vs Low-Moderate Dose IV DiureticBetter Worse
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You Don’t Want This Unhappy Kidney, Do You?
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Of Course Not – You WantMr. Happy Kidney
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Nesiritide: Another Trust Fund Kid?
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Guideline Recommendations for Nesiritide
• ACC/AHA: No comment on ADHF• HFSA: In the absence of hypotension,
nesiritide (or NTG) can be considered as an addition to diuretics for improvement in congestion (Strength = C)
• ESC: Discuss its potential use, but no recommendation
• ACEP:
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A Visionary?
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Is Chuck Really Harry?
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0 30 60 90 120 150 1800
10
20
30
40
50
60
70
80
90
100
Time Observed from the Start of Treatment (days)
NTG (n = 216)
Nesiritide 0.01 µg/kg/min (n = 211)
All nesiritide (n = 273)
Stratified log-rank test:
NTG vs nesiritide 0.01 µg/kg/min P = 0.616
NTG vs all nesiritide doses P = 0.319
Mortality Rates: VMAC Over 6 MonthsC
um
ula
tive
Mo
rtal
ity
Rat
e (%
)
Young JB, et al. AHA Meeting 2000 Late Breaking Trials Session.
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Circulation Meta-analysis
• Pooled analysis of 5 trials– VMAC, PRECEDENT, Mills, Colucci x 2
• Relative risk = 1.52 (1.16–2.00) for worsening renal function
• Relative risk = 2.29 (1.07–4.89) forrenal failure
• No difference in need for dialysis
Sackner-Bernstein JD, et al. Circulation. 2005;111:1487–1491.
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JAMA Meta-analysis• 3 trials pooled
– NSGET, VMAC, PROACTION
• Relative risk of death at 30 days for those on nesiritide = 1.74 (0.97–3.12)
Sackner-Bernstein JD, et al. JAMA 2005;293:1900–1905.
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Food and Drug Administration Interim Report• Scios submits interim report to the Food and Drug
Administration on NATRECOR® (nesiritide)• January 3, 2006• Scios Inc today announced it is submitting an interim
report to the U.S. Food and Drug Administration…
• The interim report contains two additional deaths that had occurred within 30 days after treatment with NATRECOR but had not been initially reported to the company.
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Aaronson KD, et al. JAMA. 2006;296:1465–1466.
Mortality within 30 Days of TreatmentAssociated with Nesiritide or Control Therapy
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The Real Chuck?
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