Exploring the effects of hydroxychloroquine with or without azithromycin on QT interval in COVID-19 patients through comprehensive research analysis
Every heartbeat tells a story—a sophisticated sequence of electrical impulses that maintain the perfect rhythm of life. Central to this story is the QT interval, a measurement on an electrocardiogram (ECG) that represents the time it takes for the heart's ventricles to contract and then fully recover. Think of it as the heart's "recharging phase." When this recharging phase becomes abnormally prolonged, it creates a vulnerable window that can trigger dangerous, potentially fatal heart rhythms.
The QT interval measures the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, representing ventricular depolarization and repolarization.
Prolonged QT interval increases risk of torsades de pointes, a life-threatening arrhythmia that can lead to sudden cardiac death if not treated promptly.
Under normal circumstances, the QT interval is carefully regulated by the heart's electrical system. However, certain medications can disrupt this delicate balance, interfering with the heart's ability to recharge properly. This phenomenon became a critical concern during the COVID-19 pandemic when physicians worldwide began repurposing existing medications—particularly hydroxychloroquine and azithromycin—in their desperate fight against a novel virus. What unfolded was a complex medical detective story that would reveal important lessons about cardiac safety, risk assessment, and the unintended consequences of repurposed treatments 4 9 .
As COVID-19 swept across the globe in early 2020, the medical community faced an unprecedented challenge: how to treat a deadly new disease with no proven therapies. In this urgent climate, existing drugs became the most viable candidates for rapid repurposing. Hydroxychloroquine, a medication used for decades to treat malaria and autoimmune conditions like lupus and rheumatoid arthritis, showed promise in early laboratory studies against the SARS-CoV-2 virus. Similarly, azithromycin, a common antibiotic, was considered for its potential anti-inflammatory properties and possible antiviral effects 4 .
Early in the pandemic, hydroxychloroquine was thought to potentially inhibit SARS-CoV-2 entry into cells by altering ACE2 receptor glycosylation, while azithromycin was hypothesized to reduce secondary bacterial infections and modulate immune response.
There was just one problem—both medications were known to affect the heart's electrical system. Hydroxychloroquine could block particular potassium channels in heart cells, while azithromycin had similar QT-prolonging potential. Using them together created theoretical concerns about a synergistic effect that might dramatically increase the risk of QT prolongation and torsades de pointes—a French term meaning "twisting of the points" that describes a specific type of life-threatening ventricular arrhythmia that can degenerate into sudden cardiac death 1 9 .
Blocks potassium channels, delaying ventricular repolarization
Inhibits potassium currents, prolonging action potential duration
Potential synergistic effect increasing QT prolongation risk
This created a perfect storm: physicians were treating severely ill patients with medications that might save them from COVID-19 but could potentially trigger fatal heart rhythms. The medical community needed answers quickly—was this theoretical risk an actual concern in clinical practice?
Among the many studies that sought to answer this question, one particularly comprehensive investigation was conducted at Babol University of Medical Sciences hospitals in 2020. This retrospective cohort study examined 172 hospitalized COVID-19 patients between March and April 2020—the exact period when the pandemic was raging worldwide and treatment protocols were evolving daily 1 .
The research team designed their study to mirror real-world clinical decision-making. They divided patients into two groups: those receiving hydroxychloroquine alone (16.9% of patients) and those receiving hydroxychloroquine plus azithromycin (83.1% of patients). This distribution itself reflected what was happening in hospitals worldwide—most clinicians were opting for the combination therapy despite the theoretical risks 1 .
The study employed several sophisticated safety measures:
The results revealed a complex picture that neither completely confirmed nor alleviated initial fears. The mean QTc interval after treatment was slightly longer in the combination therapy group (464.3 ± 59.1 milliseconds) compared to the hydroxychloroquine-only group (462.5 ± 43.1 milliseconds), but this difference was not statistically significant (p = 0.488). This finding surprised many clinicians who expected a more dramatic difference between the two groups 1 .
However, the broader data told a more nuanced story. Across both groups, 22.1% of all patients developed prolonged QTc intervals after treatment. Perhaps more importantly, the study identified specific risk factors that made certain patients more vulnerable:
| Risk Factor | Effect on QTc Prolongation Risk |
|---|---|
| Male Gender | Increased likelihood |
| Baseline QTc ≥ 450 ms | Significantly increased risk |
| High-Risk Tisdale Score | Markedly increased susceptibility |
| Advanced Age | Correlation with greater prolongation |
| Electrolyte Imbalances | Potentiated drug-induced QT prolongation 1 |
The clinical implications were substantial—fourteen patients (8.1%) had to discontinue therapy after four days specifically due to concerning QTc prolongation. This highlighted that while the average difference between groups was small, individual patients faced significant risks that required careful management 1 .
| Parameter | Hydroxychloroquine Only | Hydroxychloroquine + Azithromycin | Overall |
|---|---|---|---|
| Number of Patients | 29 (16.9%) | 143 (83.1%) | 172 |
| Mean Post-Treatment QTc | 462.5 ± 43.1 ms | 464.3 ± 59.1 ms | 463.9 ± 56.3 ms |
| Patients with QTc Prolongation | Not specified | Not specified | 22.1% |
| Therapy Discontinuation Due to QTc | Not specified | Not specified | 8.1% |
The Babol University study and subsequent research identified several patient characteristics that significantly increased the risk of developing clinically significant QT prolongation when treated with hydroxychloroquine with or without azithromycin.
Identification of these risk factors allowed clinicians to implement targeted monitoring strategies. High-risk patients received more frequent ECG monitoring, electrolyte correction before initiating therapy, and consideration of alternative treatments when available.
The findings from the Babol University study were not isolated. Research conducted worldwide revealed remarkably consistent patterns, strengthening our understanding of this phenomenon.
A prospective study from Morocco that included 87 patients receiving combination therapy found that 36.7% of patients experienced QTc prolongation, with 15% having severe prolongation (QTc >500 ms or increase >60 ms). Interestingly, this study noted that chloroquine appeared to cause more significant QTc and QRS interval prolongation than hydroxychloroquine, suggesting important differences between these closely related medications .
Another investigation published in the Spanish Journal of Cardiology tracked 161 COVID-19 patients and found that the average QTc interval significantly increased from 435 ms to 443 ms after 48 hours of treatment. Although 23% of patients were classified in the "at-risk QT group," no arrhythmia-related deaths occurred, suggesting that careful monitoring might mitigate the most severe consequences 7 .
Perhaps most intriguingly, a 2024 study examining temporal patterns found that COVID-19 infection itself was associated with QTc prolongation, with the interval remaining elevated during short-term follow-up (≤6 months) before gradually returning to baseline in the long term (>6 months). This raised the possibility that the virus itself, not just the medications, might affect cardiac electrophysiology 2 .
Babol University Study
Patients with QTc prolongation
Morocco Study
Patients with QTc prolongation
Spanish Study
"At-risk QT group"
Therapy Discontinuation
Due to QTc concerns
The collective research on hydroxychloroquine, azithromycin, and QT prolongation generated several important lessons that will influence how we approach drug repurposing in future public health emergencies:
Simple tools like the Tisdale score can identify high-risk patients who need alternative treatments or intensified monitoring.
Regular ECG monitoring and electrolyte replacement allowed most patients to continue therapy safely, with only a small percentage requiring discontinuation.
The cardiac risks of these medications had been well-established for years, but had rarely been problematic in their traditional uses. The COVID-19 experience revealed that higher dosing regimens and the unique physiology of acutely ill patients could uncover previously minor safety concerns 4 .
As evidence emerged that hydroxychloroquine provided limited benefit for COVID-19, the risk-benefit calculation shifted dramatically, leading organizations like the Infectious Diseases Society of America to recommend against its use 6 .
The story of QT prolongation and COVID-19 treatments represents a powerful case study in medical detective work under pressure. It illustrates how theoretical safety concerns can be rapidly investigated, quantified, and translated into clinical guidance during a global health crisis. While the specific medications involved have largely been replaced by more effective COVID-19 treatments, the electrophysiological lessons continue to inform how we evaluate cardiac safety for new medications—both during pandemics and in ordinary times.
The collaborative spirit of this research effort—with cardiologists, infectious disease specialists, and intensivists working together—exemplifies how modern medicine can rapidly respond to unexpected safety signals and protect patients while exploring new treatment approaches. As we continue to face new public health challenges, this integrated approach will undoubtedly serve as a model for future investigations at the intersection of drug safety and infectious disease.