Presentation on theme: "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,"— Presentation transcript:
1 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.AMedical Director, Midwest Heart Specialists Heart Failure andPulmonary Arterial Hypertension ProgramsMedical Director, Edward Hospital Center for Advanced Heart FailureNaperville, Illinois, U.S.A.
2 Prolonged QT IntervalThe 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.
3 Torsades des PointesThe 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.This is an atypical, rapid, and bizarreform of ventricular tachycardia that is characterized by a continuouslychanging axis of polymorphic QRS morphologies.
4 The Ionic Basis of Ventricular Repolarization James AF et al.Prog Biophysics Molecular Biol2007; 94:
5 Proposed Cellular Mechanism for the Development of TdP in the LQTS Intrinsic HeterogeneityQT Prolonging drugsand ion channel mutationsNet Repolarizing Current↓IKr, ↓IKs, ↑ICa, ↑late INaProlongation of APD,Preferentially in M cellsEAD-inducedtriggered beatLong QT↑ Dispersion of refractorinessTorsade de Pointes(Reentry)Harvekamp W et al. EHJ 2000; 21:
6 Terfenadine-Induced Brugada-Like Phenotype Di Diego JM et al.Circulation2002; 106:
7 Risk Stratification for ACA or SCD in LQTS Patients Very HighRisk(SecondaryPrevention):Post-CPR or Spontaneous TdP14%5 year K-M Rates of ACA or SCDHigh Risk(Primary Prevention):Either one or more:QTc > 500msecPrior Syncope3%Low Risk:QTc ≤ 500 msecandNo Prior Syncope0.5%Moss AJ et al. Circulation 2000:101:616-23
8 QT Prolonging Drugs and Sex-Related Differences in TdP (http://www Drug ClassSex/Incidence of TdphERG/Ikr BlockerAmiodaroneAnti-ArrhythmicF > MYes, mixed reactionArsenic trio-oxideAnti -cancerYes, traffickingBepridilAnti-anginalYesCloroquineAnti-malarialChlorpromazineAnti-psychotic/Anti-emeticCisaprideGi stimulantClarithromycinAntibioticDisopyramideDofelitideDomperidoneAnti-nauseaDropedirolSedative/Anti-nauseaErythromycinHalofantrineHaloperidolAnti-psychoticIbutilideLevomethadylOpiate antagonist?MesoridazineMethadoneOpiate agonistPentamidineAnti-infectivePimozideProcainamideQuinidineSotalolSparfloxacinThioridazine
9 Association between Effective Free Therapeutic Plasma Concentration and the Composite End Point of CA, SD, TdP, VT or VFOR1.00ETCP/IC50De Bruin ML et al. EHJ 2005; 26: 590-7
10 Arterially Perfused Rabbit LV Wedge Preparation Prolongation of the QT Interval, APD, and Transmural Gradient After Exposure to Representative Drugs in anArterially Perfused Rabbit LV Wedge PreparationA, Arterially perfused rabbit left ventricular wedge preparation demonstrating prolongation of the QT interval, APD, and transmural gradient when exposed to representative drugs. B, Effect on the QT interval by a panel of known QT-prolonging drugs in increasing concentrations. Reprinted with permission from Elsevier.30Liu T et al. Heart Rhythm 2006; 3:
11 Conditions Predisposing to TdP Cardiac AbnormalitiesVentricular HypertrophyHeart FailurePrevious anti-arrhythmic therapyElectrolytes and Metabolic DisordersHypokalemiaHypmagnesemiaHypocalcemiaSevere hypothyroidismAnorexia nervosaHypo-/HyperglycemiaBradyarrhythmiasSympathetic activityFemale gender
12 Transmural Action Potentials in the Rabbit LVH Renovascular Model Transmural action potentials in the rabbit left ventricular hypertrophy renovascular model. A, Left ventricular hypertrophy (LVH) led to APD, along with EAD genesis in the subendocardium and endocardium. B, Graphic representation. Note that APD90 is longer at all transmural distances in the LVH model. Reprinted with permission.17Yan GX et al. Am J Physiol Circ Physiol 2001; 281: H
13 Risk Factors for Drug-Induced TdP Drug regimenHigh drug doses or concentrations (except quinidineRapid IV infusionConcurrent 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
14 Risk Factors for Drug-Induced TdP ECG abnormalitiesBaseline QT prolongation or T wave labilityDevelopment of marked QT prolongation, T wave lability , or T wave morphologic changes during therapyBradycardia which may be related to a fall in local extracellular [K], leading to enhanced drug-induced inhibition of IkrCongenital long QT syndrome or “silent” mutations in LQTS genes
15 Risk Factors for Drug-Induced TdP Metabolic FactorsElectrolyte disturbances, such as hypokalemia, hypomagnesemia, hypocalcemiaImpaired hepatic and/or renal functionOtherUnderlying heart disease, particularly heart failure and LV hypertrophyRecent conversion from AFFemale sex
16 Isolated cells/tissue ESC-Proposed Algorithm for Evaluating QT Effects of Drugs in DevelopmentCritical Evaluation of the Expected Clinical Value of New CompoundMOLECULE STRUCTUREAny similarities to compounds known to prolong ADP/QT?IN VITRO TESTSCloned ChannelsIsolated cells/tissueIsolated heartUse model with which you have greatest experienceUse reference compounds known to affect ADP/QtUse appropriate experimental conditions (long cycle length, ↓KInclude “major” metabolitesADP/QT↑No EffectReevaluateIN VIVO TESTSUse models applied in toxicology/safety pharmacologyPerform serial ECG measurementsAbandonProceedQT↑No EffectReevaluatePHASE I/II CLINICAL TRIALSAbandonProceedUse appropriate study design, adjust ECG recordings with plasma levels. timing should include “active metabolites, assess gender-related effects
17 Schematic of Representative Design of Thorough QT Study Schematic of representative design of thorough QT study. The parallel design (A) is used primarily for drugs with long half-lives, active metabolites, or tachyphylaxis at high doses, but the preferred method is the crossover (B). The doses used as well as the magnitude of dose escalation are determined by Phase I single ascending dose or multiple ascending dose studies. Often, thorough QT studies use only a single supratherapeutic dose arm. Statistical power increases with the number of sessions performed, but there is no fixed requirement.Link M G et al. Circ Heart Fail 2010;3:
19 Magnesium Sulfate First Line Therapy Effective for both treatment and prevention of LQT-related ventricular ectopic beats or TdPBenefit occurs without QT shorteningBenefit occurs in pts. with normal serum [Mg] at baselineStandard 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 infusionBolus dose in children mg/KgNo data on IV maintenance dosing in children
20 Temporary Transvenous Overdrive Pacing Generally reserved for pts. with LQT-related TdP unresponsive to IV MgPacing rates of ≈ 100 bpm ↓ dispersion of refractoriness and EADs development and may shorten surface QT, especially with bradycardiaMany class IA and III antiarrhythmic drugs that cause TdP have “reverse use dependency” mediated in part by changes in the extracellular [K] changes
21 IsoproterenolInitial dose mcg/Kg/min in children and 2mcg/min in adults, then titrated to achieve HR of 100 bpmCan be used to ↑ sinus rate and ↓ QTCan be used as temporizing measure before pacing
22 Other Acute Therapy Alkalinization of the Plasma: IV K Sodium bicarbonateUseful when TdP is due to quinidineQud +OH- <-> QudOHIV KMay 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 dispersionEffectiveness in preventing or reversing Tdp uncertain
23 Chronic Management of Acquired LQTS Treatment of underlying causeDiscontinuation of offending drugCorrection of metabolic abnormalitiesAvoidance of drugs that prolong QT intervalNutritional rehabilitation in pts. with eating disordersPPM in pts. with chronic bradycardia or pause-dependent TdPThorough history and ECG screening of immediate family members because of occasional association with congenital LQTS
24 Cumulative Probability of Death in Patients with LQTS with ACA or Recurrent Syncope Zareba W et al. J Cardiovasc Electrophysiol 2003; 14:
25 Diuretic Use and the Risk of Mortality in Patients with Left Ventricular Dysfunction Mortality Risk by Diuretic Use at BaselineDiuretic (n=2901)No Diuretic (n=3896)P valueDeath: all cause101312.80.001CV DeathN Incidence5865.3Sudden DeathN Incidence11.49032411.73.15101834.6Slide 63This study compared the arrhythmogenicity of dobutamine with nesiritide in patients with heart failure Two doses of nesiritide (0.015 and 0.030) were compared to dobutamine in 305 hospitalized patients with symptomatic decompensated HF, NYHA Functional Class III or IV. During study drug infusion patients had continuous clinical hemodynamic and electrocardiographic monitoring.The dobutamine and nesiritide patients had similar baseline characteristics and baseline use of antiarrhythmic agents. Serious arrhythmias and the incidence of cardiac arrest were more frequent in patient given dobutamine as compared to nesiritide.SOLVD databaseCooper HA et al. Circulation. 1999; 100(12): 1311
26 Side Effects of Aldactone Aldactone complications more frequent vs. trialsDosing tends to be higher in the communityRALES dose mg/dBozkurt et. al., JACC 2003;41:211
27 after RALES: RXJuurlink et al. NEJM 2004;351:543
28 after RALES:DeathJuurlink et al. NEJM 2004;351:543
30 Mortality Odd Ratios Pair-Wise Treatment Comparisons Analysis*NES (n=4663)VsMIL (n=1534)NES (n=4270)DOB (n=3301)NES (n=4402)NTG(n=5668)Unadjusted0.53 (0.44–0.64)†0.37 (0.32–0.44)†1.64 (1.38–1.94)†Adjusted for covariatesa0.59 (0.48–0.73)†0.47 (0.39–0.56)†0.95 (0.78–1.16)‡Adjusted for covariates & propensity scoreb0.94 (0.77–1.16)‡Hosmer-Lemeshow goodness-of-fit test not significant at 5% levels for the models adjusted for risk factors and/or propensity, except for covariate-adjusted NTG vs. DOB comparison, where p Area under the receiver operator curve or higher. Because of multiple pair-wise comparisons, only p values were considered significant using Bonferroni correction. *Patients taking both medications were excluded from each pair-wise analysis. †-p ‡-p §-p for covariate adjustment and for covariate and propensity score adjustment. aCovariates include age, gender, SBP, DBP, BUN, creatinine, sodium, heart rate, and dyspnea. 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
31 OPTIME-CHF: Etiology and Mortality Survival;Felker GM et al. J Am Coll Cardiol. 2003
32 Effect of Levosimendan on Mortality Days Following RandomizationREVIVE IIPlaceboLevosimendanREVIVE IPlaceboLevosimendanREVIVE I + IIPlaceboLevosimendanCirc.in press32
33 Use of Inotropes in HF Therapy Dobutamine is know to be associated with an increase in myocardial oxygen consumption, heart rate and risk of arrhythmias1,2Milrinone produces tachycardia and other arrhythmias, and is limited by hypotension in many patients2,3Stimulation of the B-adrenergic pathway has been linked to HF disease progression4MOA on heart for both Milrinone and DobutamineRationale for use of B-blockers in chronic HF therapyOther observations, including RCTs, have shown worse outcomes with positive inotropic agents in the treatment of ADHF2,5,61. Burger AJ, etal. Am Heart J 2002;144:1102– 82. 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;274:1462–75. Felker GM etal. J Am Coll Cardiol 2003;41:997–1003.6. Felker GM, Oconner CM. Am Heart J 2001;142:393– 401.
34 ConclusionsThe majority of iatrogenic sudden deaths are due to the effects of drugs on cardiac repolarizationDrugs-induced QT prolongation is more common in women than in menThe occurrence of iatrogenic sudden death is influenced by drug regimen, ECG abnormalities, cardiac and metabolic abnormalitiesThe risk of individual patients must be carefully assessedKnowledge of the acute and chronic treatment of iatrogenic sudden death is lifesaving