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Drugs and the QT Interval –What Do Pharmacists Need to Know?
Drugs and the QT Interval –What Do Pharmacists Need to Know?
• Conflicts of interest:o None
• Disclosures:o I am a voluntary (unpaid) member of the Advisory
Board for the QT drugs list at www.crediblemeds.org
Drugs and the QT Interval –What Do Pharmacists Need to Know?
• Learning Objectives:o Describe common drugs and drug classes that may prolong
the QT interval and provoke torsades de pointes (TdP)o Describe the most important QT interval-prolonging drug
interactions that pharmacists should pay attention to, as well as which potential drug-interactions are not important
o Describe methods of assessing risk of drug-induced QT interval prolongation and TdP – which patients are high vs low risk?
Patient Case
Clin Pharmacol Ther 2004;75:242-7.
• A 65 year old woman presents to the ED with weakness, diminished urine production, and diarrhea
• Admitted to the hospital with:o Acute kidney injuryo Urinary tract infection
PATIENT CASE
5
• Discharged from the hospital 8 days prior to this presentation after receiving treatment of osteomyelitis of the left hip
HPI
Clin Pharmacol Ther 2004;75:242-7.
PMHx• Hypertension• Chronic stable angina• Systemic lupus erythematosus• Penicillin allergy
PATIENT CASE
6
• Ciprofloxacin 500 mg orally twice daily• Vancomycin 1g IV every 8 hours• Ranitidine 150 mg orally twice daily• Lisinopril 40 mg orally once daily• Metoprolol XL 100 mg orally twice daily• HCTZ 25 mg orally once daily• Fexofenadine 60 mg orally twice daily
Medications Prior to Admission
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
7
• Na 143 mEq/L• K 2.9 mEq/L• Mag 1.4 mg/dL• SCr 7.9 mg/dL• BUN 34 mg/dL
Select lab values on admission
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
8
• Ciprofloxacin and vancomycin d/c• Other home meds initiated• KCL• Hydroxyzine 200 mg orally twice daily• Metoprolol 100 mg orally twice daily• Ranitidine 150 mg orally twice daily• Hydroxychloroquine 200 mg orally twice daily• Levofloxacin 250 mg orally once daily
Medications Initiated in the Hospital
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
9
• ECG in the morning found QTc interval = 605 ms
• 12:50 pm – found unresponsive• Placed on ECG monitor, which revealed
torsades de pointes (TdP)
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
QT Interval
• QT Interval : the ECG manifestation of ventricular depolarization and repolarization
• Varies inversely with heart rate
• Corrected QT interval “QTc”
• Bazett’s formulaQTc = QT interval / √ RR interval
• Normal QTc = 360-470 ms (males)QTc = 360-480 ms (females)
Circulation 2010;121:1047-1060.
PATIENT CASE
11
• ECG in the morning found QTc interval = 605 ms
• 12:50 pm – found unresponsive• Placed on ECG monitor, which revealed
torsades de pointes (TdP)
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
QT Interval
Curr Med Res Opin 2013;29:1729-1736.
Relationship Between ECG and Ventricular Action Potential
Torsades de Pointes
Heart 2003;89:1363-1372
Torsades de Pointes
Normal sinus rhythm
Monomorphic ventricular tachycardia
Torsades de pointes
Drug-Induced TdP• Several drugs have been withdrawn from the
market as a result of causing deaths due to TdP.o Cisaprideo Terfenadineo Astemizoleo Grepafloxacin
• However, > 150 drugs with the potential to cause TdP remain available and are commonly used in clinical practice.
• QT drugs lists on www.crediblemeds.org
Drugs That May Cause TdPCategory DefinitionKnown Risk of TdP These drugs prolong the QT interval AND are clearly associated with a
known risk of TdP, even when taken as recommended
Possible Risk of TdP These drugs can cause QT prolongation BUT currently lack evidence for a risk of TdP when taken as recommended
Conditional Risk of TdP
These drugs are associated with TdP BUT only under certain conditions of their use (eg excessive dose, in patients with conditions such as hypokalemia,or when taken with interacting drugs) OR by creating conditions that facilitate or induce TdP (eg by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that induces TdP)
Drugs to Avoid in Congenital Long QT
These drugs pose a high risk of TdP for patients with CLQTS and include all those in the above 3 categories PLUS additional drugs that do not prolong the QT but have a special risk because of their actions
www.crediblemeds.org
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Antiarrhythmic AmiodaroneDisopyramideDofetilideDronedaroneFlecainideIbutilideProcainamideQuinidineSotalol
www.crediblemeds.org
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Antibiotic AzithromycinClarithromycinErythromycinCiprofloxacinLevofloxacinMoxifloxacin
BedaquilineGemifloxacinOfloxacinTelavancinTelithromycin
MetronidazolePiperacillin-tazobactam
Antiviral AtazanavirEfavirenzLopinavir and ritonavirRilpivirineSaquinivir
AmantadineAtazanavirNelfinavirTelaprevir
www.crediblemeds.org
PATIENT CASE
21
• Ciprofloxacin and vancomycin d/c• Other home meds initiated• KCL• Hydroxyzine 200 mg orally twice daily• Metoprolol 100 mg orally twice daily• Ranitidine 150 mg orally twice daily• Hydroxychloroquine 200 mg orally twice daily• Levofloxacin 250 mg orally once daily
Medications Initiated in the Hospital
Clin Pharmacol Ther 2004;75:242-7.
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Antidepressant CitalopramEscitalopram
ClomipramineDesipramineImipramineLithiumMirtazapineNortriptylineTrimipramineVenlafaxine
AmitriptylineDoxepinFluoxetineParoxetineSertralineTrazodone
www.crediblemeds.org
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Anti-cancer Arsenic trioxideEribulinVandetanib
BortezomibBosutinibCeritinibCrizotinibDabrafenibDasatanibLapatanibNilotinibPazopanibSorafenibSunitinibVemurafenibTamoxifenPanobinostatVorinostat
www.crediblemeds.org
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Anti-emetic OndansetronDroperidol
DolasetronGranisetronPromethazine
Metoclopramide
Antifungal FluconazolePentamidine
ItraconazoleKetoconazolePosaconazoleVoricinazole
www.crediblemeds.org
Drugs That May Cause TdPDrug Class Drugs With
Known RiskDrugs with Possible Risk
Drugs with Conditional Risk
Antimalarial ChloroquineHalofantrine
Artenimol + piperaquine
HydroxychloroquineQuinine
Antipsychotic ChlorpromazineHaloperidolPimozideThioridazine
AripiprazoleClozapineIloperidoneOlanzapinePaliperidoneQuetiapineRisperidoneSertindoleZiprasidone
www.crediblemeds.org
Other Important Drugs With Known Risk of TdP
Drug Class Drugs With Known RiskCholinesterase inhibitor Donepezil
Opiate Methadone
Phosphodiesterase-3 inhibitor AnagrelideCilostazol
www.crediblemeds.org
Azithromycin and Risk of Cardiovascular Death
New Engl J Med 2012;366:1881-1890.
Outcome No antibiotic(n=1,391,180)
Amoxicillin(n=1,348,672)
Azithromycin(n=347,795)
Total CV death 1.0 0.95 (0.55-1.63) 2.88 (1.79-4.63)
Sudden cardiac death 1.0 0.85 (0.45-1.60) 2.71 (1.58-4.64)
Other CV death 1.0 1.30 (0.44-3.84) 3.54 (1.28-9.76)
Total mortality 1.0 0.86 (0.58-1.28) 1.85 (1.25-2.75)
• Study of Tennessee Medicaid patients• 5-days of oral azithromycin (Z-pack)• Data in table are hazard ratio with 95% confidence intervals• 95% confidence intervals that do not include 1.0 are statistically significant
Antipsychotics and Risk of Sudden Cardiac Death and Sudden Unexpected Death – Meta-Analysis
Clin Pharmacol Ther 2016;99:306-314.
• Two cohort studies (n=740,306 person-years) and• Four case-control studies (n=2,557 cases; n=17,670 controls)• 95% confidence intervals that do not include 1.0 are statistically significant
Antipsychotic Agent Odds Ratio (95% CI) for sudden cardiac death and/or sudden unexpected death
Chlorpromazine 1.66 (0.83-3.29)
Clozapine 3.67 (1.94-6.94)
Haloperidol 2.97 (1.59-5.54
Flupentixol 9.40 (0.21-420.75)
Thioridazine 4.58 (2.09-10.05)
Fluphenazine 0.06 (0.00-6.00)
Olanzapine 2.04 (1.52-2.74)
Quetiapine 1.72 (1.33-2.23)
Risperidone 3.04 (2.39-3.86)
Prevalence of Drug-Induced TdP• Swedish study: annualized incidence of TdP of 4
cases per 100,000 peopleo Would translate to ~12,000 cases per year in US
• Study in Berlin: annualized incidence of drug-induced LQTS/TPD of 2.5 per million in men and 4 per million in womeno Would translate to ~1000 cases per year in US
Eur Heart J 2001 (suppl K):K70-K80Europace 2014;16:101-108.
Prevalence of QTc Interval Prolongation in Hospitalized Cardiac Patients
Drug Saf 2012;35:459-470.
Total n=900
QTc interval prolongation on admission 27.9% (n=251)
QTc interval > 500 ms on admission 18.4% (n=166)
Prevalence of QTc Interval Prolongation in Hospitalized Cardiac Patients
Drug Saf 2012;35:459-470.
Patients with QTc interval prolongation on admission who were subsequently prescribed QT interval prolonging drugs
34.7% (87/251)
Proportion of these who experienced additional QTcprolongation
34.5% (30/87)
Prevalence of QTc Interval Prolongation in Hospitalized Cardiac Patients
Drug Saf 2012;35:459-470.
Patients with QTc interval > 500 ms on admission who were subsequently prescribed QT interval prolonging drugs
42.2% (70/166)
Proportion of these who experienced additional QTcprolongation
57.1% (40/70)
Prevention of Torsade de Pointes in Hospital Settings. A Scientific Statement From the American Heart Association and the American College of Cardiology
Foundation
Circulation 2010;121:1047-1060.
• Purpose – to raise awareness about the risk of TdP in hospitalized patients
• Suggests methods to minimize occurrence of TdP:• Identify patients with risk factors• Continuous QTc interval monitoring of patients at risk
Circulation 2010;121:1047-1060.
Risk Factors for Drug-Induced TdP• QTc > 500 ms• Female• Age > 65 years• Hypokalemia, hypomagnesemia, hypocalcemia• Heart failure with reduced ejection fraction• Bradycardia• Elevated plasma concentrations of QT-prolonging drugs
o Inadequate dose adjustment for kidney failure or liver diseaseo Drug interactionso Rapid IV infusion
Curr Med Res Opin 2013;29:1729-1736.
PATIENT CASE
35
• Na 143 mEq/L• K 2.9 mEq/L• Mag 1.4 mg/dL• SCr 7.9 mg/dL• BUN 34 mg/dL
Select lab values on admission
Clin Pharmacol Ther 2004;75:242-7.
Risk Factors for Drug-Induced TdP• Analysis of 144 published articles describing 249
patients with drug-induced TdP• Nearly 100% had ≥ 1 risk factor• 71% had ≥ 2 risk factors
Medicine 2003;82:282-290.
Risk Factors for QT Interval Prolongation
Number of Risk Factors Odds Ratio for QT Prolongation (95% CI)
p
1 3.2 (2.1-5.5) < 0.0012 7.3 (4.6-11.7) < 0.001
≥ 3 9.2 (4.9-17.4) < 0.001
J Electrocardiol 2010; 43(6):572-6
• Objective: • Develop and validate a risk score to identify hospitalized patients at
highest risk of QTc interval prolongation
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Development and Validation of a Risk Score to Predict QT Interval Prolongation
• Prospective, observational study in 1200 patient admissions to the 56-bed CCU from October 2008 –October 2009
• Risk score developed in first 900 patients• Risk score then validated in subsequent 300 patients
Methods
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Development and Validation of a Risk Score to Predict QT Interval Prolongation
• All patients had continuous cardiac monitoring and/or baseline ECGs within 4 hours of admission to the CCU
• QT intervals were measured by an investigator (HW ~90%) and a technician (~10%) in lead II of 12 lead ECG or from continuous telemetry monitoring strip
• QT was corrected using Bazett’s correction (QTc)
Methods
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Development and Validation of a Risk Score to Predict QT Interval Prolongation
Change in QTc interval ≥ 60 ms Change resulting in a QTc interval to ≥ 500 ms QTc interval of ≥ 500 ms at anytime during
hospitalization
Definition of QT Interval Prolongation
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Development of QT Interval Prolongation Risk Score
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Development of QT Interval Prolongation Risk Score
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
QT Interval Risk Score Categories
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Risk Score for QT Interval Prolongation
• A risk score using easily obtainable clinical risk factors predicts patients at highest risk for QTc prolongation during hospitalization and may be useful in guiding monitoring and treatment decisions.
Conclusion
Circ Cardiovasc Qual Outcomes 2013;6:479-487.
Risk Factors for QT Interval Prolongation and TdP
Drugs Known to Cause TdP That Require Dose Adjustment in AKI or CKD
CiprofloxacinDisopyramide
DofetilideEribulin
FlecainideFluconazoleLevofloxacin
ProcainamideSotalol
Vandetanib
Inadequate Dose Adjustment for Acute Kidney Injury (AKI) or Chronic Kidney Disease (CKD)
Tisdale JE, Miller DA, eds. Drug-Induced Diseases. Prevention, Detection and Management, 3rd ed. ASHP, 2018
Drug Metabolism Interactions
CYP 3A4/3A530%
CYP 2D6 20%CYP 2C9
13%
Contribution of Cytochrome P450 Enzymes to Drug Metabolism
CYP 3A4 CYP 2D6 CYP 2C9 CYP 1A2 CYP 2B6 CYP 2C19 CYP 2C8 CYP 2A6 CYP 2E1 CYP 2J2
9%
7%
7%
5%
Pharmacol Ther 2013;138:103-141
70-80% of all drugs metabolized via the CYP 450 system
Risk Factors for QT Interval Prolongation and TdP
Precipitant Drug Mechanism QT Interval-Prolonging Drug
Antifungals:Itraconazole, ketoconazole, posaconazole, voriconazole
Inhibition of CYP 3A4 • Amiodarone• Disopyramide• Dofetilide• Dronedarone• Pimozide
Macrolide antibiotics: Erythromycin, clarithromycin, telithromycin (notazithromycin)
Inhibition of CYP 3A4 • Amiodarone• Disopyramide• Dofetilide• Dronedarone• Pimozide
HIV drugs: Atazanavir, darunivir/ritonavir, fosamprenavir, nelfinavir, ritonavir,saquinavir, tipranavir, indinivair
Inhibition of CYP 3A4 • Amiodarone• Disopyramide• Dofetilide• Dronedarone• Pimozide
Which Drug Interactions are Most Important?
Risk Factors for QT Interval Prolongation and TdPWhich Drug Interactions are Most Important?
• Avoid combinations of QT interval-prolonging drugs wherever possible
Precipitant Drug Mechanism QT Interval-Prolonging Drug
Antidepressants: Bupropion, duloxetine, fluoxetine, paroxetine
Inhibition of CYP 2D6 • Flecainide• Quinidine• Thioridazine
Others: Ritonavir, terbinafine Inhibition of CYP 2D6 • Flecainide• Quinidine• Thioridazine
Management of Torsades de Pointes
Tisdale JE. Acute Management of Arrhythmias. In: Erstad B, ed. Critical CarePharmacotherapy. Lenexa KS; American College of Clinical Pharmacy, 2015
PATIENT CASE
51
• Received MgSO4 2g IV• Arrhythmia terminated, patient regained
consciousness
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
52
• 2:30 pm:o ECG revealed TdP againo Patient found pulselesso TdP stopped spontaneously, patients was
intubated and transferred to ICU
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
53
• 3:50 pm:o ECG again showed TdPo Patient found pulselesso Patient underwent defibrillation, sinus rhythm
restored
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
54
• 3:55 pm:o Patient went into ventricular fibrillationo Patient underwent defibrillation x 3, received IV
MgSO4 2go Sinus rhythm restored
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-7.
PATIENT CASE
55
• Levofloxacin discontinued• K+ and Mg++ replaced aggressively• 24 hours later: QTc = 399 ms• No additional episodes of TdP• Discharged to home on day 9
Outcome:
Clin Pharmacol Ther 2004;75:242-7.
Drugs and the QT Interval –What Do Pharmacists Need to Know?
Know where to find the drugs that are associated with QTcprolongation and TdP (www.crediblemeds.org)
Monitor risk factors for QTc prolongation and TdPo Pay attention to diuretics, which can cause hypokalemia and
hypomagnesemia
Where possible – avoid QT-prolonging drugs in patients with risk factors
Where possible – avoid combinations of QT interval prolonging drugs
Be attentive to drug-interactions/dose adjustment for kidney disease where appropriate
Drugs and the QT Interval –What Do Pharmacists Need to Know?