Transcript “High-Dose NTG” Subgroup

HOST
W. Frank “Peek-a-Boo” Peacock IV, MD
Vice Chief of Research
Department of Emergency Medicine
The Cleveland Clinic
Cleveland, 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
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Vasoactive Agents in ADHF
Pro:
“Cleveland Assassin
Emerman”
Con:
“Southpaw Storrow”
Charles L.
“Cleveland
Assassin”
Emerman, MD
Vasoactive Agents
in 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
OPTIME-CHF: In-hospital Adverse Events
20
P < 0.001
15
Milrinone
P < 0.001
Placebo
12.6
10.7
10
P = 0.004
P = 0.18
5
2.1
Treatment Failure
From Adverse
Event (48 h)
3.8
3.2
1.5
0.4
0
4.6
Sustained
Hypotension
Acute
MyocardiaI
Infarction
P = 0.19
1.5
Atrial
Fibrillation
2.3
Mortality
Cuffe MS, et al. JAMA. 2002;287:1541–1547.
Effect of Short-term Nesiritide or
Dobutamine on 6-Month Survival
Log-rank test:
Dobutamine vs nesiritide 0.015 g/kg/min P = 0.041
Dobutamine vs nesiritide 0.030 g/kg/min P = 0.445
Nes 0.015 g/kg/min vs nes 0.030 g/kg/min P = 0.187
Dobutamine (n = 141)
Cumulative Mortality Rate (%)
Nes 0.030 g/kg/min (n = 179)
Nes 0.015 g/kg/min (n = 187)
35
30
25
20
15
10
5
0
0
30
60
90
120
150
180
Time From Start of Treatment (days)
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
Time on Study Drug (Hours)
0 0.25 0.5
1
2
3
*
6
9
12 24 36 48
0
PCWP - Placebo
-1
PCWP - IV NTG
-2
PCWP - Nesiritide
-3
-4
-5
-6
-7
-8
-9
†
†*
* †
* †
*
*
*
†
*
During 3-hour Placebo Period
Placebo, n = 62
IV NTG, n = 60
Nesiritide, n = 124
†
†
†
†
End of Placebo-Controlled Period
After 3-hour Period
IV NTG, n = 92
Nesiritide, n = 154
†P < 0.05 vs IV NTG
*P < 0.05 vs placebo
NTG, nitroglycerin; PCWP, pulmonary capillary wedge pressure; IV, intravenous.
Effects of Non-PSDs
Favors Non-PSD
Adverse Effect of Non-PSD
HF hospitalization
Cardiovascular
death
Arrhythmic death
Any death
0
PSD, potassium-sparing diuretic;
HF, heart failure.
1
Hazard Ratio
2
Data from the SOLVD trial.
J Am Coll Cardiol. 2003;42:705–708. Circulation. 1999;100:1311–1315.
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
8
• Data from 45,000 in the
ADHERE registry
7
6
No
diuretics
Diuretics
5
4
No
diuretics
Diuretics
3
2
1
0
Mortality
CR <2
CR >2
• 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.
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)
40%
35%
30%
• 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
25%
Intubate
Any AE
20%
15%
10%
5%
0%
A
B
Lancet. 1998;351:9100.
In Other Words:
Vasodilators — Good
Diuretics — 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 collar
HF 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?
Before
NTG
• The “chili dog” effect
• Application of NTG
paste to 13 patients with
PCWP >18 mm Hg
PCWP
After
NTG
26.3
16.8*
2.7
2.9
1,920
1,520*
(mm Hg)
• 2.5–5 cm of NTG paste
• Hemodynamic response
over 6 hours
CI
(L/min/m2)
SVR
(dynes.s/cm-5)
*P < 0.005.
SVR, systemic vascular resistance.
Kawai C, et al. Clin Ther. 1984;6:677–688.
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
P = 0.006
Cotter G, et al. Lancet. 1998;351:389–393.
High-Dose IV NTG in AHF
Conclusion: High-dose NTG after low-dose furosemide
is safe and effective in controlling pulmonary edema
Cotter G, et al. Lancet. 1998;351:389–393.
• 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
Nitro
Changes from baseline
in PCWP
Nesiritide
Publication Committee for the VMAC
Investigators. JAMA. 2002;287:1531–1540.
Outcomes at 3 and 24 Hours for All Treated Patients by Randomization Group
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.
“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 was
0.012 mcg/kg/min
Elkayam U, et al. Am J Cardiol. 2004;93:237–240.
“High-Dose NTG” Subgroup
“High-Dose NTG” Subgroup
2007 High-Dose
Outcome Analysis
• Nonrandomized
• 29 hypertensive,
refractory patients
• 2-mg boluses every
3 minutes up to
10 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
OR, odds ratio; CI, confidence interval.
Butler J, et al. Am Heart J. 2004;147:331–338.
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
ß-blockers
ACE inhibitors
ARBs
Calcium channel
blocker
Peripheral
vasodilator
‡P
Dose <160 mg
(%)
38,370 (61.0)
36,771 (58.5)
Dose 160
mg (%)
12,049 (61.2)
10,971 (55.8)‡
8,760 (13.9)
16,009 (25.5)
3,012 (15.3)‡
5,408 (27.5)‡
3,359 (5.3)
1,695 (8.6)‡
< 0.05.
ACE, angiotensin-converting enzyme; ARB,
angiotensin receptor blocker.
J Cardiac Fail. 2004;10:S114–S368.
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‡
‡P
< 0.05.
J Cardiac Fail. 2004;10:S114–S368.
Laboratory Data
Dose <160 mg
‡P
Dose 160 mg
Elevated troponin
(μg/L)
BNP, median
(pg/mL)
Cr (mg/dL)
5.2
5.7‡
704
782‡
1.2
1.4‡
LVEF <40%
44.7
BUN, median
(mg/dL)
16.0
46.9‡
18.0‡
< 0.05.
BNP, B-type natriuretic peptide; LVEF, left
ventricular ejection fraction.
J Cardiac Fail. 2004;10:S114–S368.
Renal Outcomes
30
25
20
15
<160 mg
=>160 mg
10
5
0
? Cr>.5
New
dialysis
J Cardiac Fail. 2004;10:S114–S368.
Clinical Outcomes
10
9
8
7
6
5
4
3
2
1
0
<160 mg
=>160 mg
Mortality ICU admit Hosp LOS
J Cardiac Fail. 2004;10:S114–S368.
Multivariate Adjusted Results
High Dose vs Low-Moderate Dose IV Diuretic
Better
Worse
In-hospital Mortality
ICU Admissions
Length of Stay
Total > 4 days
ICU > 3 days
Renal Function
SCr increase > 0.5 mg/dl
≥ 10 mL/min decrease in GFR
Initiation of dialysis
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Adjusted Odds Ratio (95% CI) P-value
ICU, intensive care unit.
J Cardiac Fail. 2004;10:S114–S368.
You Don’t Want This Unhappy
Kidney, Do You?
Of Course Not – You Want
Mr. 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?
Mortality Rates: VMAC Over 6 Months
100
Stratified log-rank test:
Cumulative Mortality Rate (%)
90
NTG vs nesiritide 0.01 µg/kg/min
80
P = 0.616
NTG vs all nesiritide doses P = 0.319
NTG (n = 216)
70
Nesiritide 0.01 µg/kg/min (n = 211)
60
All nesiritide (n = 273)
50
40
30
20
10
0
0
30
60
90
120
150
180
Time Observed from the Start of Treatment (days)
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) for
renal 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.
Mortality within 30 Days of Treatment
Associated with Nesiritide or Control Therapy
Aaronson KD, et al. JAMA. 2006;296:1465–1466.
The Real Chuck?