Download Risk Factors for Drug-Induced TdP

IATROGENIC SUDDEN DEATH
11th International Symposium Heart Failure & Co
Reggia di Caserta; April 30, 2011; 12:05 P.M.
Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.A
Medical Director, Midwest Heart Specialists Heart Failure and
Pulmonary Arterial Hypertension Programs
Medical Director, Edward Hospital Center for Advanced Heart Failure
Naperville, Illinois, U.S.A.
Prolonged QT Interval
The corrected QT interval (QTc) is calculated by
dividing the QT interval (0.60 seconds) by the
square root of the RR interval (0.84 seconds). In
this case, the QTc is 0.65 seconds.
Torsades des Pointes
This is an atypical, rapid, and bizarre
form of ventricular tachycardia that is
characterized by a continuously
changing axis of polymorphic QRS
morphologies.
The electrocardiographic rhythm strip
shows torsades de pointes, a
polymorphic ventricular tachycardia
associated with QT prolongation. There
is a short, preinitiating RR interval due
to a ventricular couplet which is
followed by a long, initiating cycle
resulting from the compensatory pause
after the couplet.
The Ionic Basis of Ventricular Repolarization
James AF et al.
Prog Biophysics
Molecular Biol
2007; 94: 265-319
Proposed Cellular Mechanism for
the Development of TdP in the LQTS
LQTS
Intrinsic Heterogeneity
Net Repolarizing Current
↓IKr, ↓IKs, ↑ICa, ↑late INa
QT Prolonging drugs
and ion channel mutations
Prolongation of APD,
Preferentially in M cells
EAD-induced
triggered beat
Long QT
↑ Dispersion of
refractoriness
Torsade de Pointes
(Reentry)
Harvekamp W et al. EHJ 2000; 21: 1216-31
Terfenadine-Induced Brugada-Like Phenotype
Di Diego JM et al.
Circulation
2002; 106: 2004-11
Risk Stratification for ACA or SCD in LQTS Patients
14%
Very High
Risk
(Secondary
Prevention):
Post-CPR or Spontaneous TdP
High Risk
3%
(Primary Prevention):
Either one or more:
QTc > 500msec
Prior Syncope
Low Risk:
0.5%
QTc ≤ 500 msec
and
No Prior Syncope
Moss AJ et al. Circulation 2000:101:616-23
QT Prolonging Drugs and Sex-Related Differences in TdP (http://www.torsades.org)
Drug
Drug Class
Sex/Incidence of Tdp
hERG/Ikr Blocker
F>M
Yes, mixed reaction
Amiodarone
Anti-Arrhythmic
Arsenic trio-oxide
Anti -cancer
Bepridil
Anti-anginal
Cloroquine
Anti-malarial
Chlorpromazine
Anti-psychotic/Anti-emetic
F>M
Yes
Cisapride
Gi stimulant
F>M
Yes
Clarithromycin
Antibiotic
F>M
Yes
Disopyramide
Anti-Arrhythmic
F>M
Yes
Dofelitide
Anti-Arrhythmic
F>M
Yes
Domperidone
Anti-nausea
Yes
Dropedirol
Sedative/Anti-nausea
Yes
Erythromycin
Antibiotic
F>M
Yes
Halofantrine
Anti-malarial
F>M
Yes
Haloperidol
Anti-psychotic
F>M
Yes, mixed reaction
Ibutilide
Anti-Arrhythmic
F>M
Yes
Levomethadyl
Opiate antagonist
Mesoridazine
Anti-psychotic
Methadone
Opiate agonist
F>M
Yes
Pentamidine
Anti-infective
F>M
Yes, trafficking
Pimozide
Anti-psychotic
F>M
Yes
Procainamide
Anti-Arrhythmic
Quinidine
Anti-Arrhythmic
F>M
Yes
Sotalol
Anti-Arrhythmic
F>M
Yes
Sparfloxacin
Antibiotic
Yes
Thioridazine
Anti-psychotic
Yes
Yes, trafficking
F>M
Yes
Yes
?
Yes
Yes
Association between Effective Free Therapeutic Plasma Concentration
and the Composite End Point of CA, SD, TdP, VT or VF
9.60
10
9
8
5.97
7
6
OR
5
4
)
3
1.00
1.23
0.90
2
1
0
< 1/1000
1/1000-1/100
1/100-1/10
De Bruin ML et al. EHJ 2005; 26: 590-7
1/10/2001
>1
ETCP/IC50
Prolongation of the QT Interval, APD, and Transmural Gradient
After Exposure to Representative Drugs in an
Arterially Perfused Rabbit LV Wedge Preparation
Liu T et al. Heart Rhythm 2006; 3: 948-56
Conditions Predisposing to TdP
Cardiac Abnormalities
– Ventricular Hypertrophy
– Heart Failure
– Previous anti-arrhythmic therapy
Electrolytes and Metabolic Disorders
–
–
–
–
–
–
Hypokalemia
Hypmagnesemia
Hypocalcemia
Severe hypothyroidism
Anorexia nervosa
Hypo-/Hyperglycemia
Bradyarrhythmias
Sympathetic activity
Female gender
Transmural Action Potentials in the Rabbit LVH Renovascular Model
Yan GX et al. Am J Physiol Circ Physiol 2001; 281: H1968-75
Risk Factors for Drug-Induced TdP
Drug regimen
– High drug doses or concentrations (except
quinidine
– Rapid IV infusion
– Concurrent use of other drugs that can
prolong the QT interval or that slow drug
metabolism due to inhibition of hepatic
cytochrome P450 enzymes (erythromycin,
cimetidine, grapefruit juice
Risk Factors for Drug-Induced TdP
ECG abnormalities
– Baseline QT prolongation or T wave lability
– Development of marked QT prolongation, T
wave lability , or T wave morphologic changes
during therapy
– Bradycardia which may be related to a fall in
local extracellular [K], leading to enhanced
drug-induced inhibition of Ikr
– Congenital long QT syndrome or “silent”
mutations in LQTS genes
Risk Factors for Drug-Induced TdP
Metabolic Factors
– Electrolyte disturbances, such as
hypokalemia, hypomagnesemia,
hypocalcemia
– Impaired hepatic and/or renal function
Other
– Underlying heart disease, particularly heart
failure and LV hypertrophy
– Recent conversion from AF
– Female sex
ESC-Proposed Algorithm for Evaluating QT Effects of Drugs in Development
Critical Evaluation of the Expected Clinical Value of New Compound
MOLECULE STRUCTURE
Any similarities to compounds known to prolong ADP/QT?
IN VITRO TESTS
Cloned Channels
Isolated cells/tissue
Isolated heart
Use model with which you have greatest experience
Use reference compounds known to affect ADP/Qt
Use appropriate experimental conditions (long cycle length, ↓K
Include “major” metabolites
ADP/QT↑
No Effect
Reevaluate
Abandon
IN VIVO TESTS
Proceed
Use models applied in toxicology/safety pharmacology
Perform serial ECG measurements
QT↑
Reevaluate
Abandon
No Effect
PHASE I/II CLINICAL TRIALS
Proceed
Use appropriate study design, adjust ECG recordings with plasma levels. timing
should include “active metabolites, assess gender-related effects
Schematic of Representative Design of Thorough QT Study
Link M G et al. Circ Heart Fail 2010;3:547-555
Management of LQTS
Acquired LQTS
– Pharmachologic
Magnesium Sulfate
Isoproterenol
Lidocaine
Phenytoin
Sodium bicarbonate (for
quinidine-mediated
arrhythmias)
– Non-Pharmachologic
Temporary Pacing (atrial
or ventricular)
Congenital LQTS
– Pharmacologic
Beta blockers
Mexiletine
– Nonpharmacologic
Permanent dual chamber
pacemaker
Left cardiac sympathetic
denervation (cardiothoracic
sympathectomy)
ICD
Magnesium Sulfate
First Line Therapy
Effective for both treatment and prevention of LQTrelated ventricular ectopic beats or TdP
Benefit occurs without QT shortening
Benefit occurs in pts. with normal serum [Mg] at
baseline
Standard regimen:
– 2 g IV bolus of 50% MgSo4 over 1-2 min followed in 15
min by another such bolus if required.
– Some pts. receive 3-20 mg/min continuous infusion
– Bolus dose in children 25-50 mg/Kg
– No data on IV maintenance dosing in children
Temporary Transvenous Overdrive Pacing
Generally reserved for pts. with LQTrelated TdP unresponsive to IV Mg
Pacing rates of ≈ 100 bpm ↓ dispersion of
refractoriness and EADs development and
may shorten surface QT, especially with
bradycardia
Many class IA and III antiarrhythmic drugs
that cause TdP have “reverse use
dependency” mediated in part by changes
in the extracellular [K] changes
Isoproterenol
Initial dose 0.05-0.1 mcg/Kg/min in
children and 2mcg/min in adults, then
titrated to achieve HR of 100 bpm
Can be used to ↑ sinus rate and ↓ QT
Can be used as temporizing measure
before pacing
Other Acute Therapy
Alkalinization of the Plasma:
– Sodium bicarbonate
– Useful when TdP is due to quinidine
– Qud +OH- <-> QudOH
IV K
– May be useful in pts. with nl. [K]
– 0.5 meq/Kg to a maximum of 40 meq ↑ plasma [K]
by 0.7 meq/L, reverses QT prolongation and QT
morphologic changes and ↓ QT dispersion
– Effectiveness in preventing or reversing Tdp
uncertain
Chronic Management of Acquired LQTS
Treatment of underlying cause
– Discontinuation of offending drug
– Correction of metabolic abnormalities
Avoidance of drugs that prolong QT interval
Nutritional rehabilitation in pts. with eating
disorders
PPM in pts. with chronic bradycardia or pausedependent TdP
Thorough history and ECG screening of
immediate family members because of
occasional association with congenital LQTS
Cumulative Probability of Death in Patients
with LQTS with ACA or Recurrent Syncope
Zareba W et al. J Cardiovasc Electrophysiol 2003; 14: 337-41
Diuretic Use and the Risk of Mortality in
Patients with Left Ventricular Dysfunction
Mortality Risk by Diuretic Use at Baseline
Diuretic (n=2901) No Diuretic (n=3896)
N
Incidence
N
Incidence
P value
Death: all cause 1013
12.8
586
5.3
0.001
CV Death
903
11.4
510
4.6
0.001
Sudden Death
241
3.1
183
1.7
0.001
SOLVD database
Cooper HA et al. Circulation. 1999; 100(12): 1311
Side Effects of Aldactone
25
Aldactone
complications more
frequent vs. trials
VA (TX)
20
RALES
15
Dosing tends to be
higher in the community
10
– RALES dose 12.5-25
mg/d
D/C Rates
G-Mastia
0
K > 6.0
5
Bozkurt et. al., JACC 2003;41:211
after RALES: RX
Juurlink et al. NEJM 2004;351:543
after RALES:Death
Juurlink et al. NEJM 2004;351:543
In-Hospital Outcomes
Abraham WT etal. JACC 2005;46(1):57-64
Mortality Odd Ratios
Pair-Wise Treatment Comparisons
NES (n=4663)
Vs
MIL (n=1534)
NES (n=4270)
Vs
DOB (n=3301)
NES (n=4402)
Vs
NTG(n=5668)
Unadjusted
0.53 (0.44–0.64)†
0.37 (0.32–0.44)†
1.64 (1.38–1.94)†
Adjusted for
covariatesa
0.59 (0.48–0.73)†
0.47 (0.39–0.56)†
0.95 (0.78–1.16)‡
Adjusted for
covariates &
propensity scoreb
0.59 (0.48–0.73)†
0.47 (0.39–0.56)†
0.94 (0.77–1.16)‡
Analysis*
Hosmer-Lemeshow goodness-of-fit test not significant at 5% levels for the models adjusted for risk factors and/or propensity, except for covariateadjusted NTG vs. DOB comparison, where p 0.04. Area under the receiver operator curve 0.70 or higher. Because of multiple pair-wise
comparisons, only p values 0.008 were considered significant using Bonferroni correction. *Patients taking both medications were excluded from
†-p 0.005. ‡-p 0.58. §-p 0.021 for covariate adjustment and 0.027 for covariate
and propensity score adjustment. aCovariates include age, gender, SBP, DBP, BUN, creatinine, sodium, heart rate, and dyspnea.
each pair-wise analysis.
bCovariates
included in the propensity score by treatment comparison are: NES vs. DOB: SBP, sodium, BUN, creatinine, age, weight, LVEF,
edema; NES vs. MIL: SBP, age, LVEF, dyspnea, weight; NTG vs. DOB: SBP, sodium, BUN, heart rate, LVEF, symptom duration; NTG vs. MIL:
SBP, BUN, LVEF, symptom duration, dyspnea, QRS 120 ms, previous revascularization; NES vs. NTG: SBP, BUN, creatinine, LVEF, symptom
duration, edema, previous HF, QRS 120 ms; DOB vs. MIL: SBP, age, hemoglobin, heart rate, dyspnea, VTF.
Abraham WT etal. JACC 2005;46(1):57-64
Survival
OPTIME-CHF: Etiology and Mortality
;
Felker GM et al. J Am Coll Cardiol. 2003
Effect of Levosimendan on Mortality
Days Following Randomization
5
14
31
90
Placebo
Levosimendan
Placebo
Levosimendan
1
5
0
0
5
14
1
1
REVIVE II
12
35
20
45
REVIVE I
4
5
1
4
REVIVE I + II
Circ.in press
Placebo
1
6
16
40
Levosimendan
5
15
21
49
Use of Inotropes in HF Therapy
Dobutamine is know to be associated with an increase in
myocardial oxygen consumption, heart rate and risk of
arrhythmias1,2
Milrinone produces tachycardia and other arrhythmias, and is
limited by hypotension in many patients2,3
Stimulation of the B-adrenergic pathway has been linked to HF
disease progression4
– MOA on heart for both Milrinone and Dobutamine
– Rationale for use of B-blockers in chronic HF therapy
Other observations, including RCTs, have shown worse
outcomes with positive inotropic agents in the treatment of
ADHF2,5,6
1. Burger AJ, etal. Am Heart J 2002;144:1102– 8
2. Monrad ES etal. Circulation 1986;73 Suppl III:III168 –74.
3. Cuffe ES etal. JAMA 2002;287:1541–7.
4. Sackner-Bernstein J, Mancini DM. JAMA1995;274:1462–7
5. Felker GM etal. J Am Coll Cardiol 2003;41:997–1003.
6. Felker GM, Oconner CM. Am Heart J 2001;142:393– 401.
Conclusions
The majority of iatrogenic sudden deaths are
due to the effects of drugs on cardiac
repolarization
Drugs-induced QT prolongation is more
common in women than in men
The occurrence of iatrogenic sudden death is
influenced by drug regimen, ECG abnormalities,
cardiac and metabolic abnormalities
The risk of individual patients must be carefully
assessed
Knowledge of the acute and chronic treatment of
iatrogenic sudden death is lifesaving