Drug-Induced Proarrhythmia: Discussion and Considerations for Clinical Practice Ralph J

Clinical and Case Study Article

Drug-induced proarrhythmia: Discussion and considerations for clinical practice Ralph J. Klotzbaugh, FNP-BC, PhD1, Alejandra Martin, PA-C2, & John Rick Turner, PhD, DSc3

ABSTRACT The clinical practice of pharmaceutical medicine includes contributions from physicians, pharmacists, nurse practitioners, and physician assistants. Drug safety considerations are of considerable importance. This article discusses drug-induced proarrhythmia, with a specific focus on Torsade de Pointes (Torsade), a polymorphic ventricular tachycardia that typically occurs in self-limiting bursts that can lead to dizziness, palpitations, syncope, and seizures, but on rare occasions can progress to ventricular fibrillation and sudden cardiac death. A dedicated clinical pharmacology study conducted during a drug’s clinical development program has assessed its propensity to induce Torsade using prolongation of the QT interval as seen on the surface electrocardiogram (ECG) as a biomarker. Identification of QT-interval prolongation does not necessarily prevent a drug from receiving marketing approval if its overall benefit-risk balance is favorable, but, if approved, a warning is placed in its Prescribing Information. This article explains why drugs can have a proarrhythmic propensity and concludes with a case presentation. Keywords: Delayed depolarization; hERG cardiac ionic current; QT-interval prolongation.

DOI# 10.1097/JXX.0000000000000348

Introduction rare polymorphic ventricular arrhythmia that typically This article discusses the important role of clinicians in the occurs in self-limiting bursts that can lead to symptoms of anticipation, identification, and treatment of one particular dizziness, palpitations, syncope, and seizures, but the one cardiac occurrence in the practice of pharmaceutical that can occasionally progress to ventricular fibrillation medicine, namely the polymorphic ventricular tachycardia and sudden cardiac death. As shown in Figure 1,theelec- Torsade de Pointes (Torsade). Although drugs from diverse trocardiogram (ECG) waveform of Torsade is very different pharmacological classes can lead to multiple types of from that seen during normal sinus rhythm. It is charac- arrhythmias, the focus is on Torsade as many drugs pro- terized by rapid, irregular QRS complexes that appear to long the cardiac repolarization period, a phenomenon twist around the isoelectric baseline. associated with Torsade. The mechanism of action of re- Torsade can result from inherited condition called long polarization prolongation is discussed in due course. QT syndrome (LQTS), and of importance in the practice of Sudden death caused by drug-induced arrhythmia has pharmaceutical medicine, it can also be drug induced by a been described as one of the most feared complications in wide range of drugs and drug classes. In both cases, Tor- fi medicine (Link, Yan, & Kowey, 2010). Torsade was rst de- sade is associated with prolongation of the QT interval, the scribed by Dessertenne (Dessertenne, 1966: see also time between the onset of the QRS complex and the offset Bubien, 1999, for discussion in the nursing literature). It is a of the T wave, as seen on the surface ECG. Figure 2 presents a stylistic representation of the QT interval and QT-interval prolongation. For each cardiac cycle, ventric- JAANP and JAAPA have arranged to publish this article simultaneously ular depolarization is reflected in the QRS waveform, in their February 2020 issues. Although the two articles may have whereas ventricular repolarization is reflected in the T minor style differences, they are essentially the same. wave. Delayed ventricular repolarization is manifest as 1 University of New Mexico College of Nursing, Albuquerque, New prolongation of the QT interval (Turner et al., 2018). Mexico, 2Goodwin Community Health Center, Somersworth, New Hampshire, 3Cardiovascular Center of Excellence, Durham, North In recent years, a dedicated clinical pharmacology Carolina study has been conducted for each new drug under de- Correspondence: Ralph J. Klotzbaugh, FNP-BC, PhD, College of velopment to assess its propensity to induce Torsade using Nursing, University of New Mexico, Albuquerque, NM 87131. Tel: 6077611800; E-mail: [email protected] QT-interval prolongation as a biomarker. When Received: 17 June 2019; revised: 12 September 2019; accepted submitting a New Drug Application to the US Food and Drug 17 September 2019 Administration and similar documents to regulatory

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practitioners and physician assistants. Table 1 provides a summary of key take-home messages.

Inherited long QT syndrome Although drug-induced (acquired) QT prolongation is the primary focus of this article, it is important to be familiar with inherited (congenital) LQTS. In clinical medicine, QT prolongation is of concern because it is the defining phe- Figure 1. An electrocardiogram showing an episode of notypic characteristic of a constellation of LQTSs that have torsade. been associated with Torsade and sudden death (Fernandez-Falgueras,´ Sarquella-Brugada, Brugada, Bru- agencies in other geographic jurisdictions, the results of gada, & Campuzano, 2017). Of specific interest in the pres- this study are included in the sponsor’s application dos- ent context is long QT syndrome 2 (LQT2), discussed shortly. sier. Identification of QT-interval prolongation does not As noted previously, QT-interval prolongation is a necessarily prevent a drug from receiving marketing ap- manifestation of delayed ventricular repolarization. Both proval if its overall benefit-risk balance is favorable, but, if depolarization and repolarization are governed by the approved, a warning is placed in the drug’s Prescribing flow of ionic currents through cardiac ion channels. Ion Information (Turner, Karnad, Cabell, & Kothari, 2017). channels, which occur in multiple biological systems, are When prescribing, dispensing, and administering such a structured transmembrane protein complexes that are drug to a patient, health care professionals need to con- embedded in cell plasma membranes. Multiple subunits sider this information in conjunction with the patient’s within these complexes organize to form a trans- likelihood of receiving required therapeutic benefitandhis membrane (central) pore through which ionic currents or her susceptibility for Torsade. This susceptibility is flow across cell membranes. Multiple cardiac ionic cur- influenced by biological risk factors including advanced age rents influence both depolarization and repolarization. and female sex, concurrent clinical characteristics including Ikr, a repolarizing current, is of direct relevance here. hypocalcemia, hypokalemia, and hypomagnesemia, and LQT2 is seen when an individual’s genetic inheritance concomitant medications that also prolong the QT interval. includes an abnormal variant of the human ether-a-go- Monitoring patients’ ECGs and calcium, sodium, and mag- go–related gene (hERG) that encodes a protein compris- nesium electrolyte levels in hospital settings is also im- ing the subunit forming the central pore of the cardiac portant (Turner et al., 2018). potassium ion channel (known as the hERG channel)

This article explains why drugs can have a proar- through which Ikr flows. Abnormal variants of hERG lead rhythmic propensity, discusses the origins and nature of to a cascade of consequences as follows: loss of function the regulatory landscape that governs current pre- of the expressed ion channels, reduced Ikr flowing marketing assessments, provides examples of resulting through them, reduced net repolarizing influence, Prescribing Information warnings, and presents a sce- delayed repolarization, QT-interval prolongation, and nario illustrating clinical practice implications for nurse sometimes proarrhythmia, that is, the potential genera- tion of a new arrhythmia or the worsening of an existing arrhythmia (Turner & Durham, 2009).

Drug-induced QT prolongation Ion channels have various deﬁning characteristics. One, just discussed, is that abnormal variants of genes encoding them can cause speciﬁc arrhythmias. Another is that their activities can be affected by drugs. (Murray & Granner, 2006). In the case of the hERG channel, drugs can lead to a reduction in function. This results in a cascade of consequences—

reduced Ikr, reduced net repolarizing influence, delayed repolarization, QT-interval prolongation, and sometimes proarrhythmia—that are in many ways similar to those resulting from abnormal variants of hERG and the resultant inherited LQT2. Given this similarity, hERG channel blockade hasbecomeasignificant scientific, clinical, and regulatory Figure 2. Stylistic representation of the QT interval and QT- concern during the past three decades (Turner et al., 2018). A interval prolongation. brief summary is provided in the following section.

Journal of the American Association of Nurse Practitioners February 2020 · Volume 32 · Number 2 129 © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. Clinical and Case Study Article Drug-induced proarrhythmia

Table 1. Key points for clinicians Clinicians play a key role in the practice of pharmaceutical medicine. As such, they need to be aware of the therapeutic beneﬁts of drugs, risks associated with them, and the concepts of favorable and unfavorable beneﬁt–risk balances.

This article highlights one rare but potentially catastrophic cardiac side effect, a ventricular arrhythmia called Torsade de Pointes (Torsade).

Torsade typically occurs in self-limiting bursts that can lead to symptoms of dizziness, palpitations, syncope, and seizures, but it can occasionally progress to ventricular ﬁbrillation and sudden cardiac death. Drug-induced sudden cardiac death from Torsade is one of the most feared complications in pharmaceutical medicine.

Torsade is associated with delayed cardiac repolarization, which is reﬂected in prolongation of the QT interval as seen on the ECG. Prolongation of the QT interval is therefore considered a biomarker of proarrhythmic liability.

A dedicated clinical pharmacology trial that is conducted before marketing approval of a new drug is granted identiﬁes drugs that prolong the QT interval and, in certain clinical circumstances, may induce proarrhythmia. This information is then placed in the new drug’s Prescribing Information.

Drug-induced Torsade typically requires multiple demographic and clinical risk factors to be present at the same time. These risk factors are summarized in Table 2.

Examples of drugs with an identiﬁed proarrhythmic liability are presented in Table 3. When a clinician is considering prescribing one of these drugs for a patient, the risk factors summarized in Table 2 must be considered judiciously to determine whether there is likely to be a favorable or unfavorable beneﬁt–risk balance.

When judicious consideration of these risk factors is undertaken, there are many occasions when the use of a drug with an identiﬁed proarrhythmic liability has a favorable beneﬁt–risk balance. In some of these cases, cardiac and electrolyte monitoring strategies are appropriate.

Note: ECG = electrocardiogram.

Origins of the proarrhythmic cardiac regulatory concurrent heart rate, yielding a measurement called landscape and the thorough QT/QTc study QTc. This is done because, regardless of the adminis- Multiple drugs were removed from the United States and tration of a drug, heart rate affects the QT interval: other markets in the late 1980s to the early 2000s be- higher heart rates are associated with shorter QT cause of proarrhythmic concerns, including astemizole, intervals and vice versa. cisapride, grepafloxacin,prenylamine,sparfloxacin, Study participants receive two doses of the test sertindole, terfenadine, and terodiline (Satin, Durham, & drug: the intended clinical dose should the drug be Turner, 2011; Talbot & Waller, 2004). Concerns regarding approved for marketing, and a supratherapeutic dose these marketing withdrawals sparked a chain of events that, if tolerable, is several multiples of the intended that culminated in the design of the dedicated clinical clinical dose. The purpose of administering the pharmacology study mentioned in the Introduction supratherapeutic dose is to evaluate drug-induced section of this article. This study, the thorough QT/QTc changes in ECG parameters under “worst case scenar- (TQT) study, was introduced in a guideline released by ios,” that is, the highest exposures that would likely be the International Council for Harmonisation (ICH). This attained in patients due to effect modifiers including guideline, ICH E14 (ICH, 2005), has been adopted by pharmacokinetic variability, drug–drug interactions, multiple regulatory agencies worldwide, which recom- alterations in metabolism or elimination, and/or un- mend that sponsors conduct a TQT study for a new drug derlying heart disease. under development to assess its propensity to prolong The ICH E14 guideline threshold of concern is a mean the QT interval. A TQT study is typically conducted at a of TQT study participants’ increases in QTc from a placebo clinical pharmacology unit in which study participants baseline of “around 5 ms.” The guideline also recom- reside for the length of the study to allow very tight mends categorical descriptive statistical summarization control of their daily activities. It is also a safe environ- of data from outliers, that is, individual participants who ment should any untoward drug reactions occur. Elec- have notably larger increases. The number of participants trocardiograms are collected digitally after dosing and showing increases in QTc of greater than 30 and 60 ms is then transmitted to specialized laboratories where any presented in the study report. In addition, description of drug-induced QT-interval prolongation is measured by absolute values is recommended. The number of partic- expert ECG readers. Before the data are analyzed, the ipants showing values greater than 450, 480, and 500 ms QT-interval measurements are “corrected” for is reported.

These QT values were chosen for specific reasons. familiar with all sections. It is also appropriate to direct First, drugs that produce mean changes of less than 5 ms patients prescribed a drug with a proarrhythmic liability at high supratherapeutic exposures in healthy partic- to the “information for everyone” section (Table 3). ipants have rarely been associated with significant cardiac risk in clinical use. This criterion can therefore Treatment strategies be reasonably used to exclude risk. Second, proar- Interventions should be made when episodes of Tor- rhythmic events have usually been associated with sade (rather than just QTc prolongation) occur. The first individuals having QTc values greater than 480 ms or intervention to consider is termination, or dose re- having changes from baseline in QTc greater than 60 ms duction, of the drug. If this is not possible or desirable, (Turner et al., 2018). for example, if there is no other drug that can provide the desired therapeutic benefit, other interventions are Risk factors for Torsade possible. It is important to emphasize that QTc interval pro- When Torsade occurs in recurrent self-terminating longation by itself does not necessarily lead to Torsade. bursts, the more common occurrence, treatment has Drug-induced Torsade typically requires multiple fac- two aims: stabilize the myocardium using magnesium tors to be present at the same time. Therefore, the most sulfate; and shorten repolarization (the QTc interval) by important risk-reducing intervention clinicians can increasing heart rate using either chronotropic drugs make is undertaking a careful review of other risk factors such as isoproterenol and atropine or cardiac pacing when prescribing medications (Beach et al., 2018). Var- (Thomas & Behr, 2016). Magnesium sulfate is recom- ious authors have discussed about risk factors (Heem- mended as an immediate first-line treatment and is skerk et al., 2018; Vandael, Vandenberk, Vandenberghe, simple and relatively safe to administer. That said, care Willems, & Foulon, 2017; Vlachos, Georgopoulos, Efre- should be taken not to induce hypermagnesemia. midis, Sideris, & Letsas, 2016), and Table 1 provides a Higher doses can lead to conditions such as nausea, summary of this information. These factors can act as vomiting, and drowsiness, whereas substantially higher effect amplifiers that can make an otherwise relatively doses can lead to a variety of more serious outcomes safe drug potentially unsafe with regard to the risk for including cardiac arrhythmias, coma, and cardiac arrest Torsade in the setting of QT-interval prolongation (Thomas & Behr, 2016). (Vlachos et al., 2016). Prolonged episodes of continuous TdP associated with severe hypotension or cardiac arrest should be The CredibleMeds web site terminated by electrical cardioversion (Drew et al., CredibleMeds (Woosley, Black, Heise, & Romero, 2018) 2010). maintains a list of drugs known to prolong QTc. To assess the risk of harm from medicines scientifically, this or- fi ganization has developed a risk-strati cation process, Table 2. Risk factors for Torsade the Adverse Drug Event Causality Analysis, that includes monitoring and analysis of multiple related sources to Category Risk Factors yield a list of several hundred drugs of interest (Woosley Demographic characteristics Older age et al., 2017). This list is divided into categories based on a Female sex ’ drug s likelihood to cause QTc prolongation or Torsade. Cardiac characteristics Bradycardia List 3 contains those with a conditional risk; list 2 con- Conduction disease tains those with a possible risk; and list 1 contains drugs Structural heart disease with a known risk of Torsade. Examples are provided in Increased drug bioavailability Hepatic conditions Table 2. Renal conditions There is also a fourth category comprising drugs that pose a high risk of Torsade de Pointes for patients with Channelopathies LQTS, including LQT2 inherited LQTS. Drugs in this category include all those in Concomitant medications Antiarrhythmics the conditional, possible, and known categories plus Diuretics (especially loop additional drugs that do not prolong the QT interval per diuretics) Other QT-prolonging se but which have a “Special Risk” because of other as- drugs sociated drug-induced effects that could lead to proarrhythmia not necessarily linked with QT prolongation. Electrolyte imbalances Hypocalcemia There are three sections to the web site as follows: Hypokalemia Hypomagnesemia information for everyone, information for health care providers, and information for research scientists. Note: LQTS = long QT syndrome; LQT2 = long QT syndrome 2. Readers of this article are encouraged to become

Journal of the American Association of Nurse Practitioners February 2020 · Volume 32 · Number 2 131 © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. Clinical and Case Study Article Drug-induced proarrhythmia

Table 3. CredibleMeds drug risk categories for QT-interval prolongation and occurrence of Torsade and examples of drugs and indications

Torsade Risk Categories Category Deﬁnitions and Examples

Conditional Drugs that are associated with Torsade but only under certain conditions of their use (e.g., excessive dose, in patients with conditions such as hypokalemia, or when taken with interacting drugs) or by creating conditions that facilitate or induce Torsade (e.g., by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that induces Torsade): Amantadine (inﬂuenza and Parkinson disease) Atazanavir (HIV/AIDS) Diphenhydramine (allergic rhinitis and insomnia) Esomeprazole (gastric hyperacidity and gastroesophageal reﬂux disease) Metoclopramide (nausea and vomiting) Metronidazole (trichomoniasis, amebiasis, and bacterial infection) Telaprevir (hepatitis C) Ziprasidone (schizophrenia)

Possible Drugs that can cause QT prolongation but currently lack evidence for a risk of Torsade when taken as recommended: Bedaquiline (multidrug-resistant tuberculosis) Crizotinib (metastatic non–small cell lung cancer) Felbamate (epilepsy) Lithium (bipolar disorder) Nicardipine (hypertension) Vemurafenib (melanoma) Venlafaxine (depression) Vorinostat (lymphoma)

Known Drugs that prolong the QT interval and are clearly associated with a known risk of Torsade, even when taken as recommended: Arsenic trioxide (leukemia) Chloroquine (malaria) Ciproﬂoxacin (bacterial infection) Donepezil (Alzheimer disease) Fluconazole (fungal infection) Methadone (narcotic dependence and pain) Propofol (anesthesia) Vandetanib (cancer and thyroid)

Case presentation Patient 1 is a 65-year-old woman. Her medical history The following scenario, developed by the authors, is is as follows: diabetes mellitus type 2, for which she had presented to discuss practical considerations when been prescribed metformin; hypertension, which has prescribing a medication with proarrhythmic potential in been well controlled on hydrochlorothiazide and lisi- the clinical setting. Specifically, the use of a fluo- nopril; and hypercholesterolemia, for which she is roquinolone antibiotic is discussed, as these drugs are taking atorvastatin, which is well tolerated. Her last frequently prescribed and have (to a greater or lesser annual check-up was 6 months before today’sacute extent, depending on the specific fluoroquinolone) visit. At that time, her body mass index was calculated at demonstrated proarrhythmic potential (Gorelik et al., 29.0, and her laboratory test results were unremarkable 2019; Mehrzad & Barza, 2015). Much of the current litera- with the exception of hemoglobin A1c at 7.6, a total ture has discussed and provided clinical considerations cholesterol of 238, and a creatinine clearance of 62 for the use of fluoroquinolones as they relate to risk of ml/min. Based on her annual laboratory test results, tendon rupture and central nervous system complica- adjustments in her medications were made to include tions, particularly among the older person. Although the addition of sitagliptin to her metformin and an in- these continue to be important considerations in the creased dose adjustment in her atorvastatin. In addi- judicious use of these medications, the purpose of this tion to changes made to her medications, L.E. had also scenario is to focus on the use of fluoroquinolones as agreed to follow-up with the in-house diabetes edu- they relate to risk of QT prolongation and possible cator in an effort to reduce her blood glucose levels. She dysrhythmia. was to have followed up in 3 months’ time, but due to

132 February 2020 · Volume 32 · Number 2 www.jaanp.com © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. R. J. Klotzbaugh et al. transportation issues missed the appointment date and However, the clinician avoids this option because L.E. is did not reschedule. also on an angiotensin-converting enzyme inhibitor L.E. presents to her primary care clinic for an acute (ACEI) which could potentially increase the risk of visit. Her chief complaint is consistent with a urinary tract hyperkalemia (Merel & Paauw, 2017). L.E. is educated re- infection (UTI), including a persistent urge to urinate with garding proper use of current medications and instructed burning sensation. Her symptoms have been going on for to call the clinic if symptoms have not resolved within 48 the past three days, and she reports that “I maybe felt a hours or if symptoms worsen. little warm” the night before today’s visit but denies any Urine culture and sensitivity results are received by other symptoms. L.E. is recently widowed and denies any the clinician 48 hours later and reveal the infective or- recent sexual activity. She states that she thinks “I have ganism as Escherichia coli. Sensitivity analysis reveals another urinary tract infection.” A previous infection was multiple drug resistance to include L.E.’s currently pre- treated successfully 6 months before this visit at an ur- scribed antibiotic. On further review of the results, the gent care clinic, but she cannot recall the medication she highest susceptibility demonstrated for appropriate was given. There is no record from this visit in her current outpatient antibiotic treatment at this time is medical record. levofloxacin. Physical assessment for L.E. reveals vital signs within In the meantime, L.E. has not contacted the clinic to normal limits. She is not currently febrile, has no palpable report any lack of improvement or worsening of symp- bladder distension, and has no costovertebral angle toms. Based on the culture and sensitivity results; how- tenderness. She does have mild suprapubic discomfort ever, the clinician contacts her to discuss the results of exhibited on palpation. Urine void is cloudy, without the laboratory test report and to inquire as to her current discernibly foul odor. Urine dipstick reveals a moderate state of health. Her symptoms have essentially worsened amount of leukocytes, positive for nitrates, and a small with continued subjective fevers as well as recent onset amount of blood with a trace amount of protein, no glu- of nausea and loose stools within the last 8–12 hours. cose, and no ketones. She denies having had anything to Based on her report and the culture and sensitivity eat before her appointment, and her finger stick glucose results, the clinician decides to have her come back that is 128 mg/dl. Based on her history of present illness, same day for an assessment. physical examination, and urinalysis, the clinician’s Repeat assessment reflects symptoms consistent working diagnosis is cystitis versus pyelonephritis. The with pyelonephritis, including mild fever, costovertebral clinician decides to treat for cystitis rather than pyelo- angle tenderness, nausea, and recent onset of loose nephritis because of lack of costovertebral angle pain or stools/diarrhea (Nitzan, Elias, Bibiana, & Saliba, 2015). tenderness and her vitals at this visit, all being within Moreover, the provider’s diagnosis is further informed normal limits. by a known infectious organism and antibiotic sensi- Although current research suggests that UTIs among tivities for said organism. Although fluoroquinolones are patients diagnosed with diabetes mellitus need not known to the clinician as carrying a risk of sudden death immediately be considered complicated, the clinician due to QT prolongation, the clinician must consider the decides to send her urine for a urine culture test (Vinken specific risk(s) related to this individual patient. In ad- et al., 2018). The clinician bases this decision on her dition, based on the high sensitivity of the infectious history of suboptimal hemoglobin A1c levels combined organism to fluoroquinolone and the serious compli- with an UTI 8 months prior. Although this past diagnosis cations associated with an improperly treated UTI, the does not reflect the accepted definition of a recurrent clinician must consider the benefitofthisparticular UTI (i.e., three or more UTI in 12 months), the clinician therapy weighed against this patient’sspecificrisk(s). considers this history as additional cautious reasoning This is of particular importance for this patient because for sending her urine for a urine culture test (Arnold, the clinician is aware that diabetic patients have worse Hehn, & Klein, 2016; Malik, Wu, Christie, Alhalabi, & UTI outcomes than nondiabetic patients. These com- Zimmern, 2017). paratively worse outcomes include the need for in- L.E. verifies she has not taken any antibiotics since her patient management with longer hospitalizations, prior diagnosis of an UTI 8 months ago. She also verifies bacteremia, and septic shock. In addition, the clinician is having no known drug allergies. To begin treatment, the also aware that related mortality rates from UTI are five clinician prescribes nitrofurantoin ER based on current times higher in diabetic patients aged 65 years and older evidence and treatment recommendations (Arnold et al., (Nitzan et al., 2015). 2016; Malik et al., 2017; Zhanel et al., 2006) for un- As discussed earlier and outlined in Table 1, risks for complicated UTIs, as well as pyridium to alleviate asso- this patient include female sex and age 65 years, which, ciated urinary symptoms. according to the World Health Organization, is generally Another first-line agent commonly prescribed in this considered the age at which one is considered older per- scenario might be trimethoprim–sulfamethoxazole. son (WHO, 2010). In addition, this patient’s medical history

Journal of the American Association of Nurse Practitioners February 2020 · Volume 32 · Number 2 133 © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. Clinical and Case Study Article Drug-induced proarrhythmia has demonstrated a potential risk of increased drug bio- fluoroquinolone treatment because of possible fluid loss availability based on her renal function. Her renal function related to fever and recent onset of diarrhea, as well as to could be due to age-related changes and/or previously reduce her risk related to concomitant medication use. In poorly controlled blood glucose levels. She was unable to addition, the clinician understands that medications with return for follow-up after appropriate medication adjust- proarrhythmic propensity may vary within a given class of ments were made at her last annual visit over 8 months medication. In this patient, for example, the fluo- ago. It is reasonable to predict an improvement in renal roquinolone levofloxacin differs from ciprofloxacin in function because of effective changes in her antidiabetic terms of proarrhythmic propensity from improbable to medication. At this time, her preprandial glucose level is in very improbable, respectively (Al-Khatib, Allen LaPointe, an appropriate range, and there were no glucose or Kramer, & Califf, 2003; Liu, 2010). ketones present in her urine. In addition, age-related In a further attempt to decrease risk of possible car- changes in kidney function might be a bit premature, al- diac complications in this patient due to fluoroquinolone though reasonable to consider. use, the clinician opts to treat her infection with cipro- In terms of concomitant medication use that might floxacin, given its very improbable status for causing QT place this patient at increased risk, she is taking a prolongation. Finally, the clinician takes the opportunity thiazide-type diuretic, which could potentially cause to educate her about the use of ciprofloxacin and decreased potassium levels. However, she is also taking instructs her to immediately report if she is unable to take an ACEI, which may minimize her risk of secondary hy- the medication because of worsening nausea or vomiting. pokalemia caused by diuretics (Palmer, 2008). It is im- The provider makes a note to follow-up with her the fol- portant to still consider electrolyte imbalances for this lowing day through telephone as the patient is reluctant patient, however, as she is currently febrile and has to return to the clinic for follow-up. In addition, she is reported subjective fevers since her first office visit. In educated about symptoms of QT prolongation including addition, she is now experiencing loose stool/diarrhea. any shortness of breath, tachycardia, or any episodes of For these reasons, the clinician orders a comprehensive syncope and to seek emergency care if any of these metabolic panel and a serum magnesium level to assess symptoms develop. for any electrolyte imbalance and to re-evaluate her The provider has realized that when drugs with renal function. Cardiac characteristics for the patient are proarrhythmic potential are used, the potential bene- negative at this time. Her vital signs have not evidenced fits are an essential consideration and that individual any bradycardia. She denies congenital heart disease patient risks are recognized and minimized. Although and has no current medical history to suggest any in-clinic follow-up to include a repeat ECG would be a structural heart disease. It is important that, however, reasonable consideration for this patient, the provider there is no baseline ECG for this patient to determine has carefully informed her of potential risks to assist any conduction abnormalities as an added potential the patient in making an informed decision. Following- risk. Although her past visits have not elicited any clin- up with the patient through telephone revealed the ical suspicion for possible conduction abnormalities, patient tolerating the medication with no symptoms of the clinician finds it important to establish a baseline QT prolongation and improvement of symptoms ECG before prescribing a fluoroquinolone for her UTI. In overall. this scenario, the patient’s ECG demonstrates no evidence of QT prolongation. Practical implications and conclusions Given the serious complications associated with When considering the use of medications that carry a medications that may induce QT prolongation, the clini- Prescribing Information warning of proarrhythmic po- cian has made themselves familiar with these medi- tential, providers must consider individual patient risk (or cations. In this scenario, the use of fluoroquinolone is risks) for developing QT prolongation and the potential determined necessary as evidenced by the sensitivity for Torsades. When prescribing such medications, health results and the patient being an appropriate candidate care providers must understand that these risks are for outpatient management. The clinician considered influenced by biological factors including advanced age current recommendations addressing monitoring and female sex, current clinical characteristics including parameters including obtaining an ECG before treatment hypocalcemia, hypokalemia, and hypomagnesemia, with any drug with proarrhythmic propensity in an effort structural heart disease, and/or conduction irregularities to detect baseline prolonged QT intervals. The clinician that affect normal cardiac electrophysiology, as well as considered obtaining this patient’s electrolytes to correct concomitant medications that might also potentially (if indicated) any abnormalities, particularly hypokalemia prolong the QT interval. It is important that physician or hypomagnesemia (Blancett, Flynn, Akers, & Smith, assistants, nurse practitioners, and indeed all health care 2006). The clinician also recommended that this patient providers are aware of all these considerations, as op- discontinues her hydrochlorothiazide during tional medication treatments may be few or impractical.

In addition, despite the potential for QT prolongation Mehrzad, R., & Barza, M. (2015). Weighing the adverse cardiac effects of fl among certain medications, judicious use is often ap- uoroquinolones: A risk perspective. The Journal of Clinical Pharmacology, 55, 1198–1206. propriate and necessary based on the potential thera- Merel, S. E., & Paauw, D. S. (2017). Common drug side effects and drug- peutic benefits of these drugs. drug interactions in elderly adults in primary care. Journal of the American Geriatrics Society, 65, 1578–1585. ’ Murray, R. K. & Granner, D. K. (2006). Membranes: Structure and Authors contributions: R. J. Klotzbaugh: contributions function. In R. MurrayK. K., D. K. Granner, & V. W. Rodwell (Eds.), include concept, case study development, organization, Harpers illustrated biochemistry (27th ed.). New York, NY: Lange and editing. A. Martin: contributions include case study Medical Books/McGraw Hill (pp. 422–441). Nitzan, O., Elias, M., Bibiana, C., & Saliba, W. (2015). Urinary tract development and editing. J. R. Turner: contributions in- infections in patients with type 2 diabetes mellitus: Review of clude concept development and editing. prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 8, 129–136. fl Palmer, B. F. (2008). Improving BP control with combined renin- Competing interests: The authors report no con icts of angiotensin system blockade and thiazide diuretics in hyperten- interest. sive patients with diabetes mellitus or kidney disease. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Inter- ventions,8,9–14. References Satin, L. Z., Durham, T. A., & Turner, J. R. (2011). Assessing a drug’s Al-Khatib, S. M., LaPointe, N. M., Kramer, J. M., & Califf, R. M. (2003). What proarrhythmic liability: An overview of computer simulation clinicians should know about the QT interval. Journal of the modeling, nonclinical assays, and the Thorough QT/QTc study. American Medical Association, 289, 2120–2127. Drug Information Journal, 45, 357–375. ’ Arnold, J. J., Hehn, L. E., & Klein, D. A. (2016). Common questions about Talbot J. & Waller P. (Eds.). Stephens detection of new adverse drug recurrent urinary tract infections in women. American Family reactions (5th ed.). Chichester, UK: John Wiley & Sons; 2004. Ap- Physician, 93, 560–569. pendix 1. Beach, S. R., Celano, C. M., Sugrue, A. M., Adams, C., Ackerman, M. J., Thomas, S. H., & Behr, E. R. (2016). Pharmacological treatment of ac- Noseworthy, P. A., & Huffman, J. C. (2018). QT prolongation, Torsades quired QT prolongation and torsades de pointes. British Journal of – de Pointes, and psychotropic medications: A 5-year update. Psy- Clinical Pharmacology, 81, 420 427. chosomatics, 59, 105–122. Turner, J. R. & Durham, T. A. (2009). Integrated cardiac safety: as- Blancett, J. R., Flynn, J. D., Akers, W. S., & Smith, K. M. (2006). Staying in sessment methodologies for noncardiac drugs in discovery, de- rhythm: Management of patients at risk for torsade de pointes. velopment, and postmarketing surveillance. Hoboken, NJ: John Orthopedics, 29, 31–33. Wiley & Sons. Turner, J. R., Karnad, D. R., Cabell, C. H., & Kothari, S. (2017). Recent Bubien, R. (1999). Torsade de pointes. The American Journal of developments in the science of proarrhythmic cardiac safety of Nursing, 99, 36–37. new drugs. European Heart Journal: Cardiovascular Pharmaco- Dessertenne, F. (1966). La tachycardie ventriculaire a deux foyers therapy, 3, 118–124. opposes variables. Archives des maladies du couer et des vais- Turner, J. R., Rodriquez, I., Mantovani, E., Gintant, G., Kowey, P. R., sieux, 59, 263–272. Klotzbaugh, R. J., … & Strnadova, C., (2018). on behalf of the Cardiac fi Drew, B. J., Ackerman, M. J., Funk, M., Gibler, W. B., Klig eld, P., Menon, V., Safety Research Consortium. Drug-induced proarrhythmia and … Zareba, W. (2010). American Heart Association Acute Cardiac Care Torsade de Pointes: A primer for students and practitioners of Committee of the Council on Clinical Cardiology; Council on Car- medicine and pharmacy. Journal of Clinical Pharmacology,58, diovascular Nursing; American College of Cardiology Foundation. 997–1012. Prevention of torsade de Pointes in hospital settings: A scientific Vandael, E., Vandenberk, B., Vandenberghe, J., Willems, R., & Foulon, V. statement from the American Heart Association and the American (2017). Risk factors for QTc-prolongation: Systematic review of the College of Cardiology Foundation. Journal of the American College evidence. International Journal of Clinical Pharmacy, 39, 16–25. of Cardiology, 55, 934–947. Vinken, J. E. M., Mol, H. E., Verheij, T. J. M., van Delft, S., Kolader, M., ´ Fernandez-Falgueras, A., Sarquella-Brugada, G., Brugada, J., Brugada, R., Ekkelenkamp, M. B., & Broekhuizen, B. D. L. (2018). Antimicrobial & Campuzano, O. (2017). Cardiac channelopathies and sudden resistance in women with urinary tract infection in primary care: death: recent clinical and genetic advances. Biology (Basel), 6, pii:E7. No relation with type 2 diabetes mellitus. Primary Care Diabetes, 12, Gorelik, E., Masarwa, R., Perlman, A., Rotshild, V., Abbasi, M., Muszkat, 80–86. M., & Matok, I. (2019). Fluoroquinolones and cardiovascular risk: A Vlachos, K., Georgopoulos, S., Efremidis, M., Sideris, A., & Letsas, K. P. systematic review, meta-analysis and network meta-analysis. (2016). An update on risk factors for drug-induced arrhythmias. – Drug Safety, 42, 529 538. Expert Review of Clinical Pharmacology, 9, 117–127. Heemskerk, C. P. M., Pereboom, M., van Stralen, K., Berger, F. A., van den WHO. (2010). Proposed working definition of an older person in Africa … Bemt, P. M. L. A., Kuijper, A. F. M., Becker, M. L. (2018). Risk factors for the MDS project. Geneva, Switzerland: World Health Organiza- for QTc interval prolongation. European Journal of Clinical Phar- tion. Retrieved from http://www.who.int/health- – macology, 74, 183 191. info/survey/ageingdefnolder/en/index.html. ICH. (2005). Harmonised Tripartite Guideline E14. The clinical evalu- Woosley, R. L., Black, K., Heise, C. W., & Romero, K. (2018). Credi- ation of QT/QTc interval prolongation and proarrhythmic poten- bleMeds.org: What does it offer? Trends in Cardiovascular Medi- tial for non- antiarrhythmic drugs. May 2005. Retrieved from cine,28,94–99. fi https://database.ich.org/sites/default/ les/E14_Guideline.pdf. Woosley, R. L., Romero, K., Heise, C. W., Gallo, T., Tate, J., Woosley, R. D., … Link, M. G., Yan, G.X., & Kowey, P. R. (2010). Evaluation of toxicity for Ward, S. (2017). Adverse drug event causality analysis (ADECA): A heart failure therapeutics: studying effects on the QT interval. process for evaluating evidence and assigning drugs to risk cat- Circulation. Heart Failure, 3, 547–555. egories for sudden death. Drug Safety, 40, 465–474. Liu, H. H. (2010). Safety profile of the fluoroquinolones: Focus on Zhanel, G., Hisanaga, T., Laing, N., Decorby, M., Nichol, K., Weshnoweski, levofloxacin. Drug Safety, 33, 353–369. B., … Karlowsky, J. (2006). Antibiotic resistance in Escherichia coli Malik, R. D., Wu, Y., Christie, A. L., Alhalabi, F., & Zimmern, P. E. (2017). outpatient urinary isolates: Final results from the North American Impact of allergy and resistance on antibiotic selection for re- Urinary Tract Infection Collaborative Alliance (NAUTICA). In- current urinary tract infections in older women. Urology, 113, 26–33. ternational Journal of Antimicrobial Agents, 27, 468–475.

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