host w. frank “peek-a-boo” peacock iv, md vice chief of research department of emergency...
TRANSCRIPT
HOST
W. Frank “Peek-a-Boo” Peacock IV, MD
Vice Chief of ResearchDepartment of Emergency Medicine
The Cleveland ClinicCleveland, OH
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
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
Registration
• The audio files and the PPT slide decks for these debates will be available on checourse website in a few weeks.
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Please Turn Cell Phones and Pagers to Silent Mode
Pro: “Cleveland Assassin
Emerman”
Vasoactive Agents in ADHF
Con: “Southpaw Storrow”
Charles L. “Cleveland Assassin”
Emerman, MD
BADASS
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
My Opponent: Dr. Storrow
Perhaps He’d Like You to Use…
Or, Perhaps He’d Like Us to Use…
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
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.
But If You Add Vasodilators to Inotropes, You Improve Your Results
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.
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.
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.
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.
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
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.
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.
In Other Words:Vasodilators — GoodDiuretics — Not So Good
Alan B. “Southpaw” Storrow, MD
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
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
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
NTG Studies in ADHF
Does it work?
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.
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.
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.
High-Dose IV NTG in AHF
Cotter G, et al. Lancet. 1998;351:389–393.
P = 0.006P = 0.006
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
• 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
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.
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
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”
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
Result of Poor Titration
Placebo
Nesiritide
NitroChanges from baselinein PCWPChanges from baselinein PCWP
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.
Outcomes at 3 and 24 Hours for All Treated Patients by Randomization Group
“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.
“High-Dose NTG” Subgroup
“High-Dose NTG” Subgroup
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.
As If I Really Need One
Dr. Storrow
Predictors of Worsening Renal Function
Butler J, et al. Am Heart J. 2004;147:331––338.OR, odds ratio; CI, confidence interval.
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.
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.
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.
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.
Renal Outcomes
0
5
10
15
20
25
30
? Cr>.5 Newdialysis
<160 mg
=>160 mg
J Cardiac Fail. 2004;10:S114––S368.
Clinical Outcomes
0123456789
10
Mortality ICU admit Hosp LOS
<160 mg
=>160 mg
J Cardiac Fail. 2004;10:S114––S368.
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
You Don’t Want This Unhappy Kidney, Do You?
Of Course Not – You WantMr. Happy Kidney
Nesiritide: Another Trust Fund Kid?
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:
A Visionary?
Is Chuck Really Harry?
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.
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.
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.
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.
Aaronson KD, et al. JAMA. 2006;296:1465–1466.
Mortality within 30 Days of TreatmentAssociated with Nesiritide or Control Therapy
The Real Chuck?