Pharmacist-driven Evaluation of QTc Interval Prolongation in Cardiac Patients: Integrating Rautaharju’s Heart Rate Correction Formula and the Tisdale Risk Score

INTRODUCTION

Prolongation of the heart rate-corrected QT interval (QTc) indicates delayed ventricular repolarization and is considered a key marker of the risk of torsade de pointes (TdP). This condition is often triggered by drug use and underlying clinical risk factors, necessitating thorough evaluation by both clinicians and pharmacists to manage potential risks effectively.^[1]The importance of this issue is underscored by numerous population studies that consistently associate a prolonged QTc with increased cardiac mortality. This connection underscores the importance of precise measurement and practical risk assessment, particularly among hospitalized patients at increased risk.^[2]

Critically ill patients are experiencing a combination of risk factors that significantly intensify their chances of QTc prolongation. These factors include complex medication regimens, electrolyte imbalances, and severe multi-organ dysfunction, making them far more susceptible to complications.^[3] The challenge arises from the condition’s complex nature, including renal or hepatic dysfunction that can interfere with drug metabolism and metabolic imbalances that can directly disrupt cardiac repolarization.^[4]

CredibleMeds^® (www.crediblemeds.org), managed by the University of Arizona’s Center for Education and Research on Therapeutics (AzCERT), provides a comprehensive database of over 250 medications connected with TdP risk. The system classifies these drugs into distinct categories: those with a known risk (KR) of TdP, those with a possible risk (PR), those with a conditional risk (CR), and medications avoided in patients with congenital long QT syndrome.^[5]

To accurately assess the risk, precise measurement of the QTc is essential. Bazett’s formula is commonly used in clinical settings, but it tends to overestimate the QTc.^[2,6] For this study, we chose Rautaharju’s correction formula due to its superior accuracy in providing consistent QTc measurements across a broad range of heart rates. This approach helps minimize the rate-dependent bias commonly seen with Bazett’s formula.^[7,8]

To convert this accurate measurement into practical clinical guidance, we incorporated the Tisdale risk score (TRS), a validated tool for predicting risk of TdP.^[9] The TRS is widely used in clinical settings where prolonged QTc predictors are commonly prescribed, including cardiology, gastroenterology, and intensive care units (ICUs).^[10]

In view of these gaps, we conducted a prospective study in Pakistan to determine the prevalence of QTc prolongation and to assess the integration of Rautaharju’s QTc formula with the TRS. The goal was to enhance risk stratification and guide interventions to protect these highly vulnerable patients.

MATERIAL AND METHODS

RESULTS

DISCUSSION

Our study confirms a clinically significant burden of QTc prolongation among hospitalized cardiac patients, with over a quarter of our cohort affected and 4.1% reaching the critical threshold of QTc ≥500 ms. This prevalence is consistent with reports from other settings.^[11,12] The current findings revealed that among 485 hospitalized cardiac patients, a substantial proportion (28.6%) exhibited prolonged QTc, with a smaller subset (4.1%) showing severe prolongation (QTc ≥500 ms). In another study by Birda et al., 95 (34.1%) of 279 patients exhibited QTc prolongation, with 15% having a QTc ≥500 ms.^[13] Another study of 422 hospitalized elderly adults found that 32% of participants had QTc prolongation.^[14]

The gender distribution showed male predominance across all QTc groups; however, the proportion of females increased notably in the QTc ≥500 ms subgroup (40%), suggesting a possible trend toward a higher risk of severe QTc prolongation in females, although this was not statistically significant. A similar study reported no significant difference between genders.^[3] When the age distribution was examined, it was observed that the prolonged QTc group had a considerably higher proportion of patients (≥60 years) (36.7%) than the normal QTc group (30.3%). Rossi et al. revealed that the prevalence of QTc ≥500 ms was more than 10% in geriatric inpatients, and they were frequently using QT-prolonging medications upon admission.^[15] Al-Azayzih et al. reported that the likelihood of prescribing TdP-associated drugs decreased with age (OR = 0.989, p < 0.001), although the odds were higher for patients taking more than five medications (OR = 4.281, p < 0.001).^[16] It has been reported that QTc prolongation occurs more frequently in the presence of one or more key risk factors, including sex, age above 65 years, electrolyte disturbances, underlying cardiac conditions such as heart failure or bradycardia, renal or hepatic impairment, and multiple QTc-prolonging medications.^[17,18] The risk is especially intensified when two or more of these factors coexist, underscoring the need for careful assessment and monitoring when initiating QT-prolonging therapies.^[19]

In the current study, more than 50% of patients in both the normal QTc and prolonged QTc groups had multiple comorbidities. Similarly, a study conducted in Taiwan reported findings almost identical to those reported.^[20] Another study reported the association between QTc prolongation and chronic kidney disease.^[21] Longer hospital admissions and higher mortality from cardiovascular events have been linked to this ECG change.^[22] Likewise, in the current study, hospital stays were consistently longer in patients with QTc prolongation, underscoring its clinical impact, as extended hospitalization is often necessary for continuous monitoring and interventions to manage underlying causes, such as electrolyte imbalances or medication adjustments.^[23] In the current study, each patient took an average of three drugs associated with QTc prolongation. Another study reported that 74/218 (34.0%) were taking as a minimum one prescription with a KR of TdP, whereas a large percentage (218/243 [89.7%]) were prescribed at minimum one QTc-prolonging medicine.^[15] Numerous studies have demonstrated that hospitalized individuals have a much increased chance of getting TdP as a result of receiving medications that raise the risk correlated with QTc prolongation.^[13,24]

More than 250 cardiac and non-cardiac medicines have the potential to prolong the QTc.^[25] A known TdP risk is assigned to drugs with a well-documented proarrhythmic potential under standard prescribing conditions.^[26] Despite a comparable overall burden of medications and QTc-prolonging drugs between the two cohorts, a substantial majority of patients (over 75%) were prescribed medications classified as high-risk by the AzCERT criteria.^[25] This finding may indicate a lack of cautious prescribing practices or suggest that high-risk QTc-prolonging medications are not always adequately recognized during clinical decision-making. Conversely, we observed that QTc-prolonging drugs were prescribed less frequently to patients with severe QTc prolongation (QTc ≥500 ms). This observation likely represents a “risk-treatment paradox,” where clinicians intentionally withheld potential offending agents in patients who presented with severe baseline instability or pre-existing prolongation.^[17] Macrolides, including azithromycin, have long been associated with QTc prolongation, TdP, and even sudden cardiac death.^[27] Several case reports published between 2001 and 2007 documented arrhythmias associated with azithromycin, leading the U.S. Food and Drug Administration to issue a cardiac safety warning about the drug in 2013.^[28] The American Heart Association consensus statement recommends that, in hospitalized patients at risk of TdP, the use of QTc-prolonging drugs should be on an individual basis. This guidance emphasizes the importance of carefully selecting treatments to limit the usage of drugs known to cause TdP, particularly in high-risk patients.^[29]

Certain risk factors suggest an increased likelihood of QTc prolongation, as it is well established that patients with cardiovascular conditions are more prone to QTc prolongation.^[22] Our findings highlight that a combination of clinical risk factors influences cardiac patients’ susceptibility to QTc prolongation. We confirmed that hypokalemia is a significant and modifiable risk factor (OR = 1.55, p = 0.035), supporting its well-recognized role in increasing arrhythmia risk.^[30] The prevalence of this electrolyte disturbance in our cohort is consistent with studies reporting rates of up to 40% in cardiac ICUs,^[31,32] highlighting it as a critical target for intervention. Furthermore, the strong association between reduced (EF<40%) and severe QTc prolongation (>500 ms) underscores the intrinsic link between a weakened myocardium and electrical instability.^[30] In these patients, structural heart disease provides a conducive environment for repolarization abnormalities, requiring heightened vigilance in monitoring.^[33]

The most compelling evidence of our intervention’s effectiveness lies in the significant risk reduction observed. After pharmacist-led interventions, there was a noticeable shift in the TRS categories. For example, the percentage of high-risk patients with prolonged QTc decreased from 57.6% to 30.2%, and even among the most vulnerable group (QTc ≥500 ms), the high-risk cohort was reduced from 80% to 50%. Although the p-value for this change (0.095) did not reach the traditional threshold for statistical significance – likely due to sample size – the consistent and substantial decrease across all groups reflects a meaningful improvement in patient safety. This highlights that the Tisdale score is not only a predictive tool but also a practical framework for guiding and evaluating the impact of clinical pharmacy services.

QTc prolongation is influenced by multiple factors and cannot be reliably measured or predicted using a single parameter in clinical practice.^[9] The TRS is advantageous because it is straightforward to calculate, and the necessary factors are readily available in clinical practice. In contrast, other QTc risk stratification scores, such as the RISQ-PATH (RIsk Score for QT-prolonging drugs - a Patient Adverse Tailored Healthcare tool) score are more challenging to calculate manually due to their complexity and the large number of parameters required.^[34] In addition, many of these scores have either not demonstrated strong performance outside the patient populations for which they were initially designed or have not been extensively validated in other patient groups.

In general, risk scores show great potential for recognizing patients at risk for QTc prolongation. Using the TRS can help identify individuals at higher risk, enabling timely, targeted interventions, such as adjusting or reducing QTc-prolonging medications, which could ultimately lower overall risk.^[26] This approach also generated more relevant alerts for physicians and pharmacists regarding QTc prolongation, while reducing the excessive notifications often seen in traditional clinical decision support systems. As a result, future studies should assess the effectiveness of the TRS and its value as a risk-stratification tool to guide pharmacist-led interventions across diverse patient populations.^[35-38]

A primary limitation of this research is its conduct within a single tertiary care institution. However, the protocols and patient population at our institution closely reflect those of major cardiac centers across Pakistan. More importantly, this study offers important foundational evidence for an area that has been largely overlooked in our region: pharmacist-led management of QTc prolongation. The lack of local data in this field further emphasizes the significance of our findings and underscores the need for future validation through larger, multicenter studies. Such research will be crucial for confirming the broader relevance of this pharmacist-led model and ensuring its integration into standard cardiac care practices.

CONCLUSION

This study provides strong evidence in support of a structured, pharmacist-led approach to managing the risk of QTc prolongation. We have demonstrated that incorporating the Tisdale score into routine clinical care facilitates the early identification of high-risk cardiac patients and enables targeted, effective interventions. Our findings advocate for the formal inclusion of pharmacist-led QTc risk assessments in cardiac care pathways, offering a cost-effective strategy to improve medication safety. By proactively addressing modifiable risks, such as hypokalemia, and optimizing pharmacotherapy, this approach can reduce arrhythmia risk and enhance outcomes.