drugs and the qt interval – what do pharmacists need to know? · • several drugs have been...

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?