Anticholinergic Medications and Out-of-Hospital Sudden Cardiac Arrest: a New Piece to the Puzzle?

Graphical Abstract

Out-of-hospital sudden cardiac arrest (OHCA) remains the major cause of cardiovascular mortality. Most of the OHCA cases occur in the general population, and in approximately half of the victims, OHCA is the first manifestation of a cardiovascular disease. Only 10.2% of adult OHCA cases survive to hospital discharge.¹

OHCA is a “perfect storm,” requiring both a susceptible substrate and a trigger. In recent decades, studies have focused on understanding the substrate of OHCA and risk stratification of susceptible individuals.^2,3 In this issue of the Journal, Tsai et al.⁴ shed light on one of the OHCA triggers by presenting new evidence of an association of anticholinergic medications with OHCA.

The study by Tsai et al. is methodologically robust and deserves discussion. It addressed the inferential question “why now?” or “why did patient A die suddenly on Friday, January 17th, and not on Monday, July 15th?” rather than the question “why did patient A, but not patient B, die suddenly?” The authors employed a case-crossover design, which is well-suited for examining intermittent exposure (anticholinergic medication burden) that could plausibly have caused the OHCA within a relatively short time frame. The induction period was 30 days in the main analysis, with 14, 45, and 60 days in the sensitivity analyses. The anticholinergic burden during the 30 days preceding OHCA was compared with the anticholinergic burden for the same patient in several control time windows that were taken from before the OHCA. To reduce bias from a gradual trend in anticholinergic burden over time, Tsai et al.⁴ selected control windows close in time to the case windows. The length of the time window (30 days) helps to avoid circadian effects and minimize other time patterns, such as seasonal variations.

The strength of the case-crossover design⁵ is that each case and its control information are matched on all characteristics, measured or unmeasured, that are stable within a patient (e.g., age, sex, medical history). Case-crossover design controls for all fixed confounders, whether or not they are measured. Nonetheless, bias can be introduced by time-varying confounders, and the authors employed several additional modifications of the case-crossover design. Case-case-time-control study is another variation of a self-control, or case-crossover design, when the earlier time period is selected as a separate “Control” observation.⁶ Furthermore, investigators also conducted a case-time-control study, matching OHCA cases using disease risk score matching.⁷

Confounding by indication

Despite a thorough study design, several potential biases may still be present.⁸ Confounding from transient co-exposure is one possible explanation. The list of anticholinergic medications is extensive and includes common over-the-counter drugs (analgesics, antihistamines, medications for gastrointestinal and urinary symptoms). It is plausible that, for example, an acute coronary syndrome can present with atypical symptoms (nausea, mild pain in the left arm) that may be misdiagnosed by a patient who opts for self-management and does not seek medical attention. In another scenario, a patient may develop another condition (e.g., COPD exacerbation, psychosis, pneumonia, or urinary infection) that results in the appropriate prescription of approved anticholinergic medications. In a predisposed patient who is at risk of sudden cardiac death,^2,3,9,10 exceeding a certain threshold of anticholinergic burden can lead to fatal consequences. Notably, such “confounding by indication” does not dismiss the importance of the study findings. It is well-known that many comorbidities listed in the study population can serve as acute triggers of OHCA. It is likely that, in most cases, true co-exposure of a comorbidity (e.g., worsening of depression)¹¹ and its treatment (increased anticholinergic burden) has a detrimental synergistic effect. Another example of “confounding by indication” and the synergistic effect of the disease substrate and a trigger is heart failure. Heart failure is a well-known risk factor of OHCA, with a well-studied electrophysiological substrate of sudden cardiac death.¹² At the same time, heart failure exacerbation is frequently treated by increased doses of diuretics, and sometimes digoxin and other cardiovascular medications with anticholinergic effects, thus increasing anticholinergic burden. Future prospective randomized controlled trials are needed to determine which management strategy can reduce OHCA incidence in such patients.

Selection bias in the selection of the control time window

Selection bias in a case-crossover study is nearly unavoidable and must be acknowledged. In these studies, it is crucial that control time windows are chosen independently of exposure. However, in any OHCA study, the selection of the control time window is also influenced by the timing of the OHCA. The case-case-time-control design helps to mitigate this bias by selecting control time windows of self-controls that are farther from the index OHCA event. Despite this, we cannot be completely certain that there is no selection bias.

Time trends in exposure to anticholinergic burden

Changes in the probability of exposure to anticholinergic medications between the control period(s) and the hazard period can introduce selection bias, as the selected control times may not be representative of the exposure distribution in the underlying study base. The person-time selected for the control period may have a different probability of exposure and a different probability of the risk of outcome, compared with the selected hazard period. Such selection bias can be reduced by conditioning on time. Tsai et al.⁴ used the case-time-control design, using the information on exposure trends obtained from a sample of matched, different individuals. Furthermore, they also used a Case-Case-Time-Control design to address time trends. Remarkably, all types of analyses provided consistent results, supporting the findings and the study conclusion.

Strengths in the National Database, Definitions of Exposure and Outcome

The study analyzed a unique, remarkable dataset, comprising nearly 174,000 OHCA cases, from the Taiwan National Health Insurance Research Database. The definition of OHCA was reasonably strong and well validated, which is an important strength of the study. However, it is important to acknowledge the difference in the OHCA definition in this study,¹³ which included only successfully resuscitated in the field cases that were hospitalized. We can speculate that the most severe OHCA cases that died on the field included catastrophic non-survivable injury, such as myocardial rupture, massive stroke, or ventricular fibrillation in a patient with end-stage heart failure.

The definition of the exposure, anticholinergic burden, was also strong, quantified by multiple scales. The authors conducted several sensitivity analyses, using variations in the definitions of exposure and study designs. The study convincingly showed that a transient increase in anticholinergic burden is associated with OHCA in a dose-dependent manner: the higher the anticholinergic burden, the higher the odds of OHCA.

Clinical Importance and Future Directions

The novel findings by Tsai et al. are biologically plausible and carry important clinical implications. The impact of sympathetic nervous system activation and parasympathetic withdrawal on life-threatening ventricular arrhythmias is well known.¹⁴ Additionally, many classes of anticholinergic drugs included in the study also have QT-prolonging properties, indicating multifactorial pro-arrhythmic mechanisms. To conclusively demonstrate that a transient increase in anticholinergic burden can cause OHCA, randomized controlled trials with interventions designed to eliminate or reduce such transient increases are necessary. Various interventions can be developed at the levels of pharmacists, primary care providers, cardiologists, and other subspecialty physicians. Patient education alone could potentially be life-saving. Changing the status of medications from over-the-counter to behind-the-counter, or complete removal from the market, is suggested for some medications.¹⁵ Importantly, future progress in personalized medicine and improvements in risk stratification of sudden cardiac death will be necessary to provide personalized advice. It is likely that an increase in anticholinergic burden would have a greater triggering effect in susceptible individuals with abnormal electrophysiological substrate.^3,10 The study by Tsai et al⁴. suggests that progress in the primary prevention of OHCA in the general population is feasible.