Minimizing the risk of arrythmia with QT-prolonging drugs

Frågedatum: 09.07.2021

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Minimizing the risk of arrythmia with QT-prolonging drugs

Fråga: How should we manage the risk of drug-induced QT prolongation?

Svar: This is a translated version of <a href="https://svelic.se/utredning/?id=14-499" target="_blank">Hantera läkemedelsorsakad risk för QT-förlängning</a>. <h3>Aim and scope</h3> The following information is intended for prescribers who treat patients with drugs that may cause QT prolongation. The document concerns the treatment of both children and adults. The aim of the document is to support the prescriber in making risk assessments for each individual patient. Pharmacological treatment of acute QTc prolongation is out of scope for this document. For information regarding emergency treatment, please refer to the local Poisons Information Centre and/or consultant cardiologist. <h3>Background</h3> Many drugs inhibit potassium channels in myocardial cells, which can lead to a prolongation of the QT interval (1). This can in rare cases lead to syncope or death by the ventricular arrhythmia torsades de pointes (TdP). One in six patients ≥ 65 years of age in Sweden had 2015 been prescribed at least one drug with known or suspected risk of TdP (2). Around half of the prescribed drugs consisted of antidepressants, and together with antipsychotics, some antibiotics, and urological agents these drugs accounted for more than 90% of the total prescription. For examples of drugs that may lead to QT prolongation, see appendix. The probability of drug induced TdP is very low, and the condition is difficult to diagnose due to the brief duration of the arrhythmia: it either self-terminates or progresses into ventricular fibrillation. This makes it very difficult to estimate the incidence and the propensity of individual drugs to cause arrhythmia. New drugs are tested for their QT prolonging properties, but for older drugs this information is often missing. Arrhythmias may occur at any time after the initiation of one or more QT prolonging drugs, especially if risk factors change, such as electrolyte abnormalities due to fluid loss. Anti-arrhythmic drugs that are known to cause TdP to a greater extent, are usually prescribed in specialist cardiology care, with protocols for minimizing risk. For other drugs with a known risk of QT prolongation and TdP, the risks are often first noted when prescribing a second QT prolonging drug, which results in an interaction warning in the electronic health record. It is established that two or more QT-prolonging drugs increase the risk of QT prolongation, and the general recommendation is to avoid such situations (3). In practice, however, this is not always possible or advisable. Below is a recommendation on how these situations can be handled. <h3>Assessing the drug</h3> The following three sources should be consulted for assessment of the drug in question: <ul><li>The interaction warning in the local electronic health record in Uppsala is derived from the database Janusmed interaktioner from the Health and Medical Care Administration in Region Stockholm. The warnings generated from this database concern mainly pharmacokinetic interactions, but in many cases, they also warn about pharmacodynamic interactions when two or more drugs have a known risk of TdP. Additional information and recommendations on alternative treatments can often be found in the warning.</li> <li>The SmPC of the drug should always be consulted regarding contraindications, warnings, and interactions.</li> <li>QTdrugs on Crediblemeds.org is a freely available, continuously updated list of drugs that have a risk of QT prolongation and cardiac arrhythmias. It is recommended to create a user profile to access more detailed information. The medicines on the list are divided into four groups (4):</li> <ul><li>Known Risk of TdP: These drugs prolong the QT interval and are clearly associated with a known risk of TdP, even when taken as recommended. <li>Possible Risk of TdP: These drugs can cause QT prolongation but currently lack evidence for a risk of TdP when taken as recommended. <li>Conditional Risk of TdP: These drugs are associated with TdP 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 TdP (e.g., by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that induces TdP). <li>Drugs to Avoid in Congenital Long QT Syndrome</ul></ul> <h3>Risk factors</h3> The available scientific evidence indicates that patients with drug-induced TdP most often have several concurring risk factors (2). There is evidence that the following factors increase the risk of TdP (5,6). Unmodifiable risk factors: <ul><li>advanced age (≥ 65 years) <li>female sex <li>known prolonged QT interval or QTc ≥ 480 ms before initiation of a QT prolonging drug <li>family history of sudden cardiac arrest <li>heart disease <ul><li>acute/recent myocardial infarction <li>heart failure</ul></ul> Modifiable risk factors: <ul><li>electrolyte abnormalities <ul><li>hypokalemia <li>hypomagnesemia <li>hypocalcemia</ul> <li>treatment with diuretics, as this may increase the risk of electrolyte abnormalities <li>bradycardia <li>increased exposure of the drug, e.g., high doses, and intravenous administration, as the risk of QT prolongation increases with increasing plasma concentration <li>impaired kidney or liver function that may lead to increased exposure by reduced elimination of the drug in question; may require dose adjustment <li>genetic variants that may reduce the metabolism of the drug in question and thereby increase exposure; may require dose adjustment <li>interacting drugs that do not themselves increase the risk of QT prolongation, but increase the concentration of the QT prolonging drug <li>concomitant treatment with several QT prolonging drugs</ul> Quantification of the different risk factors is not possible as their significance may differ between various patient populations. There are several risk calculators available to estimate the risk of QT prolongation or TdP. These are usually only validated in a specific population and the underlying clinical data are often limited. Risk calculators must therefore never substitute the clinical risk assessment. In conclusion, a comprehensive risk assessment should be carried out on a case-by-case basis. The risk assessment consists of evaluating the QT prolonging drugs, the patient's risk factors and other concomitant medications. The risk of TdP can be reduced by oral administration at the lowest possible dose. Electrolyte levels should be assessed, and any abnormalities corrected. Consider dose reduction of or temporarily stopping treatment with diuretics and drugs that slow the heart rate (e.g., beta-blockers*, digoxin), other QT prolonging drugs and interacting drugs that may increase the concentration of the QT prolonging drug. Waiting 2-3 half-lives should in most cases be sufficient to reduce the risk of interaction. By then the concentration of the interacting drug has dropped to 25-12.5%. However, waiting for this may not always be clinically feasible. *This depends on the indication for treatment. Beta-blockers are used as arrhythmia prophylaxis in long QT syndrome (LQTS). In case of known LQTS, consult a cardiologist before adjusting the beta-blocker dose. <h3>Assessment of the QT interval</h3> The QT interval is considered prolonged when the corrected QT time (QTc) is ≥ 480 ms (3) nd the risk of TdP is considered increased when the QTc is > 500 ms or has increased by > 60 ms after initiation of a QT prolonging drug (5). In most cases, the automatically measured QT interval on the ECG can be used. However, in case of uncertainty, measurements may have to be repeated manually, preferably in lead V2, V3 or II. To find the end of the QT interval, a tangent line is extrapolated from the T wave at the point of maximum downslope to the isoelectric baseline. <a href="https://en.wikipedia.org/wiki/QT_interval#/media/File:QT_interval.jpg" target="_blank">See illustration.</a> The QT interval changes in response to the heart rate: as heart rate increase the QT interval shortens and as heart rate decrease the QT interval is prolonged. To account for this the QT interval must be corrected for heart rate. The corrected interval is referred to as QTc. This is done automatically by the ECG device, which uses Bazett's formula for correction. It should be noted that this formula tends to over-correct the QT interval at heart rates above 90 beats per minute and under-correct at heart rates below 60 beats per minute. In these cases, the Friderica’s or Framingham’s formulas should be used instead. <a href="http://icd.internetmedicin.se/korrigerad-QT-tid" target="_blank">This is most easily done with online calculators.</a> Automatically measured QTc is not considered reliable in children. Instead, the QTc should be measured using the tangent method (see above) in lead II (or V5) during sinus rhythm between 60 and 100 beats per minute in three subsequent sinus beats, using the Bazett’s formula. In conclusion, the risk of TdP is increased when, after initiation of a QT-prolonging drug, QTc is > 500 ms or has increased by > 60 ms. In these cases, a different drug should be considered. <h3>When should ECG be assessed?</h3> Whether ECG control should be done or not is based on a comprehensive risk assessment. It is reasonable to assess the ECG prior to initiation in cases where the use of a drug with risk of QT prolongation is deemed necessary despite several concomitant risk factors being present. In this case, a renewed ECG is recommended when steady state has been reached, and after any increase in dose or if additional risk factors appear. Steady state is achieved after 4-5 half-lives, which for most drugs occurs within 1-2 weeks. For drugs with a short half-life, such as ciprofloxacin, steady state is achieved within 1-2 days. Refer to the SmPC for the half-life (t1/2) of the drug in question. For drugs with a short half-life and short treatment duration, such as short antibiotic courses, ECG control may not always be clinically feasible. There may also be other situations where ECG control cannot be done. In these cases, the patient's modifiable risk factors should be optimized as much as possible. If the QTc interval after initiation of the drug is > 500 ms, has increased by >60 ms, or assistance is needed in interpreting the ECG, a cardiology consultation is recommended. Patients who are diagnosed with drug-induced QT prolongation often turn out to be carriers of mutations for congenital long QT syndrome, which is why genetic analysis should also be considered. This decision is usually made by a cardiologist. For in-depth information about a drug's risks or discussion about alternative treatments, please contact the local Drug Information Center. <h3>Attachment. Examples of drug classes and drugs that have a risk of QT prolongation</h3> Please note that the list is not comprehensive. For more information, see the SmPC and <a href="https://crediblemeds.org/drugsearch" target="_blank">crediblemeds.org</a>. <table><tbody><tr><td>Therapeutic class</td><td>Examples of substances</td></tr><tr><td valign="top">Antiarrhythmic drugs (Class IA and Class III)</td><td>amiodarone, disopyramide, sotalol</td></tr><tr><td valign="top">Antidepressants</td><td>SSRIs(citalopram, escitalopram, fluoxetine, sertraline) SNRI (venlafaxine) tricyclic antidepressants(amitriptyline, clomipramine, nortriptyline)</td></tr><tr><td valign="top">Antiemetics</td><td>droperidol, ondansetron</td></tr><tr><td valign="top">Antimicrobials</td><td>macrolides(azithromycin, erythromycin, clarithromycin, roxithromycin) fluoroquinolones(ciprofloxacin, levofloxacin, moxifloxacin) fluconazole, voriconazole</td></tr><tr><td valign="top">Antipsychotics</td><td>flupenthixol, haloperidol, chlorprothixene, clozapine, levomepromazine, melperone, olanzapine, perphenazine, quetiapine, risperidone, sertindole, ziprasidone, zuclopenthixol</td></tr><tr><td valign="top">Sedatives</td><td>hydroxyzine, promethazine</td></tr><tr><td valign="top">Drugs for pain or opioid dependence</td><td>methadone</td></tr><tr><td valign="top">Drugs for Alzheimer's disease</td><td>donepezil</td></tr><tr><td valign="top">Malaria drugs</td><td>hydroxychloroquine, quinine, chloroquine</td></tr></tbody></table>

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