The Unit: A Cardiology Blog: arrhythmias

Showing posts with label arrhythmias. Show all posts

Wednesday, March 20, 2013

From the headlines: azithromycin and the risk of fatal arrhythmias

Azithromycin (Zithromax®) made headlines again last week after the US Food & Drug Administration (FDA) issued a safety alert to warn patients and prescribers of an increased risk of fatal arrhythmias associated with its use. As outlined in a previous blog entry from May, this latest announcement is the result of an investigation by the FDA following an analysis originally published by the New England Journal of Medicine [1], which found an increased risk of sudden cardiac death associated with azithromycin use. At the time, the reason for this increased risk was unknown, but many suspected it was due to QT interval prolongation, a cardiac conduction abnormality already well-described with other macrolide antibiotics. In its latest alert, the FDA warns that azithromycin be avoided in patients with known risk factors for sudden cardiac death, such as a history of arrhythmias or existing QT interval prolongation, hypokalemia, hypomagnesemia, or concomitant antiarrhythmic drug therapy.

For providers looking for more information about azithromycin use in patients with cardiovascular disease, please see this previous entry, which outlines alternative management strategies in at-risk patients.

References

Ray WA, Murray KT, Stein CM, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90.

Sunday, February 17, 2013

Adjunct antiarrhythmic therapy in refractory ventricular tachycardia: lidocaine versus procainamide

Few management decisions are more controversial at my institution than which antiarrhythmic agent to select in patients with ventricular tachycardia (VT) that remains refractory to first-line therapies (e.g., amiodarone, maximally-tolerated doses of beta blockers) or in whom these therapies are contraindicated. In many patients with advanced structural heart disease, lidocaine and procainamide are the only two remaining options. While some renewed enthusiasm for procainamide has emerged as of late -- in part a result of its re-appearance in the advanced cardiac life support algorithm for VT [1] -- much of the evidence to support procainamide is derived from studies evaluating its use as monotherapy. When used alone, procainamide appears to be more effective than lidocaine in a heterogenous patient population [2,3]. However, for a growing number of patients with refractory VT, the challenge facing clinicians is rarely which agent to utilize first (as this is unquestionably amidoarone [4,5]) -- it is which agent to use as adjunct therapy, a scenario where minimal to no data exists to guide clinical decision-making.

Although many clinicians prefer procainamide for this purpose, I hope to make a case for at least attempting a trial of lidocaine, and why I often favor it as the initial adjunct antiarrhythmic to select in patients with advanced structural heart disease and refractory VT.

First, several disadvantages of using procainamide in this patient population are worth highlighting. From a pharmacokinetic standpoint, procainamide has a large volume of distribution, requiring that patients receive a considerable loading dose (i.e., 17 mg/kg) to produce a therapeutic effect. Moreover, procainamide and its active n-acetyl metabolite (NAPA) have a longer half-life than lidocaine -- about 3 and 5-8 hours, respectively, in patients with normal metabolic function. These times may be prolonged by as much as five-fold in patients with hepatic and/or renal impairment, conditions that are common in patients with end-stage heart failure. If toxicities (i.e., negative inotropy, hypotension) do emerge following the administration of procainamide, they may persist for extended periods of time, which is especially problematic in patients with compromised baseline hemodynamics. Although monitoring serum concentrations of procainamide and NAPA may ameliorate these risks, few medical centers still perform these tests and the turnaround time for referral assays may take up to a week to produce results. Finally, oral procainamide is no longer available in the US, so in patients for whom a more permanent solution (e.g., cardiac transplantation, ventricular assist device implantation, VT ablation) is not available, procainamide does not represent a long-term management strategy.

Anecdotally, in the patients with refractory VT that we have treated with procainamide, I have seen at least a third become hemodynamically unstable, many requiring the initiation of inotrope and/or vasopressor therapy and almost all requiring a reduction in their maintenance infusion (often not adequate enough to maintain suppression of the arrhythmia), if not discontinuation of the drug altogether.

Although lidocaine may be less effective as monotherapy, its use in conjunction with amiodarone has not been evaluated in clinical trials, and the combination may actually produce synergistic antiarrhythmic effects. Theoretically, the addition of lidocaine to amiodarone results in more pronounced blockade of sodium channels (given that lidocaine inhibits both open and inactivated channels) as well as prolongation of the effective refractory period. Furthermore, lidocaine demonstrates enhanced activity in depolarized myocardial cells, a characteristic that is common in ischemic tissue. Given the limited hemodynamic reserve in patients with advanced structural heart disease, the increased myocardial oxygen demand that results from prolonged periods of VT is likely to produce transient periods of ischemia where lidocaine may be especially useful.

From a pharmacokinetic standpoint, lidocaine has a smaller volume of distribution than procainamide, so smaller loading doses (i.e., 1-1.5 mg/kg) are required to produce a therapeutic response. Moreover, the much shorter half-life of lidocaine (1-2 hours in patients with normal hepatic function) means that if a therapeutic effect is not observed soon after initiation (or if toxicities emerge), the drug is essentially eliminated from the body within hours. While lidocaine may also produce adverse hemodynamic effects, these are more rare at the doses used clinically and are far less pronounced than those observed with procainamide. Finally, if patients do respond to lidocaine and are not candidates for the advanced therapies mentioned above, the drug may be converted to oral mexiletine for chronic maintenance therapy.

In summary, there is little evidence to guide the management of patients with advanced structural heart disease and refractory VT who are already receiving amiodarone or other antiarrhythmic therapy. Although procainamide appears to be more effective than lidocaine when used as monotherapy, no data exists to compare their adjunct use with amiodarone, a clinical scenario that is becoming more common in patients who are awaiting advanced therapies (or in whom these therapies are not viable). While the advantages of lidocaine in this scenario are largely theoretical (but reasonable based on existing data), it is the arguably the safer of the two drugs in this population, and the only one for which a long-term oral option exists. As a result, unless a more permanent solution for managing refractory VT is already known and imminent, I think it is reasonable to at least attempt a trial of lidocaine as the adjunct antiarrhythmic in most patients.

References

Saturday, May 19, 2012

Azithromycin in patients with cardiovascular disease

In a study published in the New England Journal of Medicine earlier this week, investigators observed an increased risk of sudden cardiac death associated with the macrolide antibiotic azithromycin (Zithromax^®) [1]. Azithromycin is considered a first-line option in the management of several types of upper respiratory tract infections and is one of the most widely-prescribed antibiotics in the US. The results of the trial by Ray, et al prompted the US Food & Drug Administration (FDA) to issue a safety alert addressing the use of azithromycin in patients with cardiovascular disease and further investigation is currently underway.

Using electronic medical records and prescription-use data from patients enrolled in the Tennessee Medicaid program, investigators found a small but statistically significant increase in the risk of cardiovascular death (hazard ratio 2.88, 95% CI 1.79 - 4.63, p < 0.001) when azithromycin (5-day course) was compared to no antibiotic therapy, a result that was significant both in terms of sudden cardiac death as well as other types of cardiovascular death. When compared to amoxicillin, the risk of cardiovascular death associated with azithromycin was similarly increased (hazard ratio 2.49; 95% CI 1.38 to 4.50; p = 0.002).

While there are some limitations with the use of any retrospective analysis, the findings do call into question the widely-held notion -- one that I believed until now -- that azithromycin is less cardiotoxic than other macrolides (clarithyomcin, erythromycin), where the risks of sudden cardiac death are fairly well-established. Given the known association of these agents with QT prolongation and the types of deaths observed (i.e., sudden cardiac death), the most likely etiology is a disturbance in cardiac conduction that results in a fatal ventricular arrhythmia. Similar risks have been attributed to the respiratory fluoroquinolones levofloxacin and moxifloxacin, which further limits the antibiotic choices available in this patient population.

So, in light of this new evidence, how does one manage the risk of cardiovascular death associated with azithromycin? It would be unreasonable to avoid azithromycin in all patients with cardiovascular disease; however, the results of the present study (not to mention the litigious nature of the current health care environment) should at least warrant a more careful consideration of the risks and benefits of azithromycin use.

Who is likely at risk?
The increased risk of sudden cardiac death observed in the present study likely does not apply to every patient with cardiovascular disease, especially those with milder forms (e.g., hypertension) or those who only have risk factors (e.g., dyslipidemia) for more advanced forms of cardiovascular disease. Those at greatest risk likely include:

Patients with a recent myocardial infarction, especially those with new-onset heart failure and those not receiving beta blockers (which reduce the risk of ventricular arrhythmias and sudden cardiac death in this population)
Patients with advanced heart failure, especially those who have not yet received an automatic implantable cardioverter-defibrillator (AICD)
Patients with severe electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), which are often associated with the use of chronic high-dose diuretic therapy
Patients taking anti-arrhythmic medications with known risk of QT prolongation and torsade de pointes (e.g., dofetilide, flecainide); for a list of drugs associated with QT prolongation (by risk category), please see this resource developed by the Arizona Center for Education on Research and Therapeutics

Alternative strategies in high-risk patients
If the risk of sudden cardiac death is thought to outweigh the benefit of azithromycin therapy in an individual patient, alternative antibiotics should be considered. By far, the most common indication for azithromycin is in the management of community-acquired pneumonia (CAP), where it is recommended as monotherapy in patients with no risk factors for drug-resistant Streptococcus pneumoniae, or in combination with a beta lactam in patients with comorbidities and/or risk factors for drug-resistant pathogens (e.g., chronic disease, immunosuppression, recent antibiotic use, etc) [2]. Some alternatives to consider include:

In the lowest risk population (i.e., minimal structural heart disease and no additional co-morbidities) for whom azithromycin monotherapy would have been considered, doxycycline alone is a reasonable alternative
For moderate risk patients, a combination beta lactam / beta lactamase inhibitor (e.g., amoxicillin/clavulanic acid) or second to third generation cephalosporin (cefuroxime, cefpodoxime) is likely adequate; for higher risk patients (i.e., in whom the addition of a macrolide would have been considered), addition of doxycycline is a reasonable alternative
Azithromycin is often added as adjunct therapy in patients who are at risk for atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella species), which include those with chronic pulmonary disease, long-term immunosuppression, residence in long-term care facilities, etc; in these patients, the addition of doxycycline is a reasonable alternative
Alternatives are more limited in patients with penicillin allergies; if the allergy to penicillin is reported as "rash", "upset stomach" or similar mild reactions (i.e., not true Type I hypersensitivity reactions), use of a second or third generation cephalosporin (+/- doxycycline) is reasonable, as the reported cross-reactivity with penicillins is around 5-10% or less. For true beta lactam allergies, options are further limited, as the respiratory fluoroquinolones (usually the first-line alternative in patients with penicillin allergies) have cardiotoxicities that are comparable to the macrolides; in these patients, monotherapy with doxycycline may be effective, but more thoughtful consideration as to risks and benefits of azithromycin or fluoroquinolone therapy is probably warranted, including whether additional monitoring (e.g., ambulatory ECG) should be performed
When used as part of the management of CAP, some advocate the use of loading/higher doses of doxycycline (e.g., 200 mg twice daily for at least the first day) in order to achieve adequate serum concentrations early in the treatment course [3]; given the low toxicity profile of short doxycycline courses, this strategy is probably reasonable

While the increased risk of sudden cardiac death observed with azithromycin significantly limits the choice of antibiotics used for the management of CAP in the ambulatory care setting, reasonable alternatives exist for the vast majority of cases. Also on the bright side, these findings should lead to a more careful evaluation of the risks and benefits of azithromycin therapy in this high-risk patient population, which many would argue is a step in the right direction anyway.

Acknowledgment: Thanks goes to Emily Heil, PharmD, BCPS, a clinical pharmacy specialist in infectious diseases at the University of Maryland Medical Center, who reviewed and made suggestions to the above recommendations.

References