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APRIL 27, 2020 -- The COVID-19 pandemic has elevated the electrocardiographic heart-rate-corrected QT interval (QTc) to A-list celebrity status in medicine, when before, it barely made the B list.
The widespread and off-label use of certain QTc-prolonging agents intended to treat or prevent COVID-19 has intensified the need for 12-lead ECG monitoring of patients presenting with the infection, say some experts, creating safety and staffing challenges, but also inspiring some creative alternatives.
Such agents, notably hydroxychloroquine and azithromycin (AZM), can put patients at heightened risk for malignant arrhythmias and perhaps sudden death, especially those already on QT-prolonging agents or with inherited conduction disorders. The risk in individuals is fairly small, but the risk climbs overall the longer that a patient is on the drugs.
"We're nowhere close to seeing a cessation in the use of chloroquine or hydroxychloroquine — mostly hydroxychloroquine in the United States, with or without azithromycin — so we're going to be in this phase where the drugs are going to be empirically used," Michael J. Ackerman, MD, PhD, Mayo Clinic, Rochester, Minnesota, told theheart.org | Medscape Cardiology.
Early studies of the drugs in COVID-19 aren't promising and plenty of skepticism is in order pending completion of more definitive trials. So far the studies are "incredibly undersized and underpowered to show a true efficacy signal, and they're not going to see a death signal," Ackerman said. "It's going to take thousands of cases to see exactly whether there is a proarrhythmic, drug-induced death signal."
Pending reliable efficacy and safety data, "We all hope these drugs work, but the well-intended prescribing just needs to be balanced with a healthy dose of respect," he said. "If you're not even aware of the QTc issue, or you've been dismissive of it, that's when the dark side of these drugs rear their ugly head."
Their QTc-Prolonging Potential
As stated by US government bodies such as the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH), "There are insufficient clinical data to recommend either for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19." But if the drugs are prescribed for patients with the infection, "clinicians should monitor the patient for adverse effects, especially prolonged QTc interval."
In practice, calls to keep tabs on the QTc in hospitalized patients on the drugs for COVID-19 to some may seem based on an abundance of caution.
Nassir F. Marrouche, MD, speaking with theheart.org | Medscape Cardiology, wondered "whether we are overdoing it" with calls to monitor the QTc for side effects of the off-label treatments.
"We've done intensive monitoring, but so far, I'm still waiting to see a patient who has had major side effects from these drugs," said Marrouche, of Tulane University School of Medicine, New Orleans, Louisiana.
"I haven't seen any problems so far, except in one patient with long-QT syndrome," he said. "Do those patients exist? Yes, but it can also happen with amiodarone or sotalol," which pose a similar risk of QTc prolongation.
More useful, Marrouche said, would be to track the QTc in outpatients taking the QTc-prolonging agents. For them, regular 12-lead ECG follow-ups can be planned in a way that doesn't cause staffing issues. "Take your time and get as much 12-lead ECG as you can," he said. Otherwise, they could be monitored with some sort of mobile or handheld ECG monitor.
Although sudden death is indeed rare in patients taking QTc-prolonging agents, patients in the hospital with COVID-19 are already at increased risk, Ackerman noted. Not only are they sick from the infection, 10% to 20% may already be on a drug that can promote QTc prolongation, such as many antidepressants or, by causing hypomagnesemia, proton-pump inhibitors.
Even patients initially with a QTc in a range considered low risk may show an inherently pronounced QTc response to drugs that have the potential side effect. Or a patient may have an inherited propensity for prolonged QTc, said Ackerman, who is senior author on a guidance for managing the potential for drug-induced QTc prolongation in COVID-19 patients, published April 7 in the Mayo Clinic Proceedings.
"Although the percentage of individuals at risk is small, given the pandemic nature of COVID-19, in absolute terms the number of individuals potentially at risk for lethal drug side effects is large," the guidance notes. "This would be especially true if these medications are adopted for post-exposure prophylaxis."
12-Lead ECG for All?
But the unprecedented volume of COVID-19 patients at hospitals makes it impossible to put them all on telemetry to monitor their QTc, Ackerman said, and scaling up the use of 12-lead ECG monitoring burdens already-stretched ECG technicians and other staff, worsens their chances of exposure to the virus, and uses up valuable personal protective equipment (PPE).
The 12-lead ECG "doesn't make sense" for patients hospitalized with COVID-19, he said. "You've got a big machine that can get contaminated, you have exposure risk to the ECG professional coming in and out, combined with him or her wearing PPE and using that up. So it's not a very practical way of obtaining the QTc measurement."
So, he said, "if the QTc is an important vital sign in COVID-19, or, frankly, in any patient with [QTc prolongation] risk factors, then how do we start to obtain this vital sign more easily?"
A portable or even smartphone-based ECG monitor with QTc-measuring capabilities, of which several are available, may be one answer, Ackerman observed. His group's guidance points out that the 6-lead ECG version of one of the best known of such devices, the KardiaMobile 6L (AliveCor), was recently cleared by the FDA for measuring QTc specifically in patients with COVID-19 receiving potentially QTc-prolonging agents.
"Similarly, many telemetry systems are equipped with real time QTc monitoring features which could be used for hospitalized patients," the guidance observes.
(As the document notes, both Ackerman and the Mayo Clinic have a royalty agreement with AliveCor. Also, the Mayo Clinic has equity interest in the company.)
Applying a "Single-Lead" Handheld Device
Even the single-lead version of KardiaMobile may be useful for tracking QTc in patients, whether hospitalized for COVID-19 or if the patient is in a high-risk group for severe QTc prolongation, suggests a recent study in which the device was used off-label to capture three ECG vectors that are among the more useful for observing QTc prolongation.
"Generally, in a perfect world, they should all have a 12-lead ECG. And we don't disagree, we think the 12-lead is probably the best way to go for evaluating the QT interval," Christopher C. Cheung, MD, University of British Columbia, Vancouver, Canada, told theheart.org | Medscape Cardiology.
The concern, he said, is that clinicians will resort to a single-lead handheld device like the first-generation KardiaMobile, which — used as directed — doesn't generate enough ECG information to effectively assess the QTc.
But Cheung and his colleagues, in their April 7 report in JACC: Clinical Electrophysiology, describe a method for using the single-lead device to capture leads I and II of the 12-lead ECG plus a precordial vector that stands as a surrogate for the 6 precordial leads.
"We found that, at least using the 3 'leads,' we can assess the QT interval in a way that is more accurate and better than doing a single lead, and likely to be more representative of the 12-lead ECG."
The group prospectively tested 22 patients under evaluation for a genetic arrhythmia syndrome, including some with symptoms and others who were first-degree family members. The maximal QTc as measured by 12-lead ECG was similar to the maximal QTc measured via the three lead positions collectively.
The QTc by 12-lead ECG was significantly longer than that assessed via lead I and the precordial lead. But it was comparable to the QTc using the handheld's lead II.
The study confirms that lead I alone, and therefore the single-lead KardiaMobile used as originally intended, is unreliable for measuring the QTc. "It suggests that you should do a multi-lead, and that lead II might be one of the more useful leads for measuring the QTc."
Still, the recent KardioMobile 6L approval for QTc assessment "is a very positive thing," Cheung said. "You could say that at least the AliveCor 6-lead device gets you that lead II, and that at least gets you very close to the 12-lead."
A next step might be to compare the 6-lead device to the 12-lead ECG, "But in terms of obtaining more complete data, it goes a long way and is much better than just a single-lead device."
Another Way to Free Up Resources
Logistically somewhere in between a handheld ECG monitor and a 12-lead ECG apparatus, an ambulatory telemetry monitor that is approved for documenting and reporting QTc changes would seem to be another resource-conserving alternative for patients with COVID-19.
In one week at a major center, 117 unselected patients with COVID-19 and on hydroxychloroquine, with or without AZM, were fitted with such a device, the Mobile Cardiac Outpatient Telemetry (MCOT, BioTelemetry), in lieu of regular 12-lead ECG sessions or assignment to a telemetry floor, notes a report published April 21 in the Journal of the American College of Cardiology.
Technicians operated the devices to transmit reports on QTc and other parameters to electrophysiologists twice daily. The monitors also issued "urgent alerts" whenever the patient's QTc extended beyond 500 ms, observe the authors, led by David Chang, MD, North Shore University Hospital, Manhasset, New York.
There were 28 such urgent alerts in 18 patients over a total of 295 patient-days, of which 16 alerts led to changes in management, report Chang and colleagues. "Hydroxychloroquine was discontinued in one patient after three days due to QTc prolongation from 460 ms to 565 ms," they write.
The study — which the authors acknowledge has major limitations, such as few patients seen at a single center and an observational design — at least suggests that "the MCOT may be utilized for arrhythmia and QTc monitoring while reducing both hydroxychloroquine exposures and PPE use."
Proper Trials Underway
As the NIH has unwaveringly stated, "At present, no drug has been proven to be safe and effective for treating COVID-19," and no drugs have been approved specifically to treat patients with the infection. That might or might not change in the future, depending on the results of proper clinical trials of hydroxychloroquine with or without AZM now underway.
Ackerman said he can only speculate, but he "suspects the efficacy signal in severe COVID-19 is going to be tiny, at best." If so, and that helps cut back on the drugs' off-label use in patients with the infection, there may be a more limited in-hospital role for QTc monitoring.
But if it turns out there's an ongoing risk of recurrent COVID-19 in previously exposed patients, some sort of ongoing maintenance therapy may become common. Trials are also underway to explore that possibility as well as pre-exposure prophylaxis.
For previously exposed persons, "I bet you that on a population basis there will probably be an efficacy signal. If so, we're going to be living in this coexistence with the coronavirus for a long time. Then we'll be talking about post-exposure prophylactic hydroxychloroquine," Ackerman speculated, adding that in such a world, QTc monitoring will likely become more important.
Ackerman has consulted for Abbott, Audentes Therapeutics, Biotronik, Boston Scientific, Daiichi Sankyo, Gilead Sciences, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate; Ackerman and the Mayo Clinic have a royalty agreement with AliveCor, and the Mayo Clinic has equity interest in the company.
Marrouche has previously disclosed receiving honoraria from or consulting or holding stock options for Biosense Webster, sanofi-aventis, MRI Interventions, Bristol-Myers Squibb, Boehringer Ingelheim, Biotronik, Ecardio, St. Jude Medical, Medtronic, Arapeen, MARREK, Daiichi Sankyo, Cardiac Designs, and VytronUs and receiving research grants from MRI Interventions, Sanofi, Biosense Webster, Boehringer Ingelheim, Biotronik, MARREK, Medtronic, Boston Scientific, Catheter Robotics, and VytronUs.