Sodium-Containing Acetaminophen Use Increases Risk of CVD, Mortality

Quick Takes

  • Increased risk of cardiovascular disease and mortality was associated with the use of sodium-containing acetaminophen (e.g., soluble or effervescent formulations) in individuals with and without a history of hypertension.
  • Nondietary sources of sodium, including excipients found in common over-the-the counter medications, may pose significant health risks and may warrant additional labeling.

Study Questions:

Does use of sodium-containing acetaminophen increase the risk of cardiovascular disease (CVD) and all-cause mortality compared to non–sodium-containing acetaminophen in patients with and without a history of hypertension?

Methods:

This was a population-based study of two cohorts of individuals between the ages of 60–90 years old registered for ≥1 year of continuous enrollment with a general practitioner in the United Kingdom between January 2000–December 2017, using data from The Health Improvement Network (THIN) database. The THIN database allowed identification of individuals receiving sodium-containing acetaminophen (effervescent or soluble formulations) or non–sodium-containing acetaminophen (tablet, oral suspension, or capsule formulations). The two cohorts consisted of individuals with or without a diagnosis of hypertension at baseline. Individuals were excluded if they had a history of cancer or CVD before the index date, prescribed an acetaminophen product 1 year prior to entering the study, or prescribed a compound acetaminophen product. The primary outcome was incident CVD (myocardial infarction, stroke, or heart failure) and all-cause mortality during a 1-year follow-up period. Other outcomes included dose response, risk of incident hypertension, and impact of sodium-containing ibuprofen and ranitidine on the primary outcomes, in addition to multiple sensitivity analyses.

Results:

A total of 151,398 individuals with hypertension (sodium-containing acetaminophen: n = 4,532; non–sodium-containing acetaminophen: n = 146,866) and 147,299 individuals without hypertension (sodium-containing acetaminophen: n = 5,351; non–sodium-containing acetaminophen: n = 141,948) were analyzed. Incident CVD risk at 1 year was higher among sodium-containing acetaminophen initiators compared to non–sodium-containing acetaminophen initiators in individuals with (5.6% vs. 4.6%; hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.32-1.92) or without (4.4% vs. 3.7%; HR, 1.45; 95% CI, 1.18-1.79) a history of hypertension. Similarly, mortality at 1 year was higher in sodium-containing acetaminophen initiators compared to non–sodium-containing acetaminophen initiators with (7.6% vs. 6.1%; HR, 2.05; 95% CI, 1.92-2.19) or without (HR, 1.87; 95% CI, 1.74-2) a history of hypertension.

A dose-response relationship was observed between the number of sodium-containing acetaminophen prescriptions (1, 2-4, and ≥5 prescriptions) and the risk of CVD (odds ratio [OR], 1.26, 1.33, and 1.45, respectively; p = 0.034) and mortality (OR, 2.77, 3.02, and 3.64, respectively; p < 0.001) in individuals with hypertension with similar findings in those without hypertension. The risk of incident hypertension at 1 year was higher in the sodium-containing acetaminophen initiators compared to non–sodium-containing acetaminophen initiators (4.4% vs. 3.6%; HR, 1.37; 95% CI, 1.22-1.64). Risk of incident CVD and mortality was also higher among sodium-containing ibuprofen or ranitidine users compared to non–sodium-containing formulations regardless of history of hypertension.

Conclusions:

Sodium-containing acetaminophen initiation was associated with a statistically significant higher risk of incident CVD and mortality than non–sodium-containing initiation among individuals with and without hypertension.

Perspective:

The American Heart Association recommends intake of no more than 2300 mg of sodium, with an ideal limit of 1500 mg, for most adults. A common misconception is that excess sodium intake primarily comes solely from dietary sources; however insidious nondietary sources of sodium, such as excipient ingredients used in effervescent and soluble medication formulations, can contribute substantially. For example, a 500 mg dose of effervescent acetaminophen contains 440 mg of sodium, whereas a 500 mg dose of soluble acetaminophen contains 390 mg of sodium. This large population-based cohort study showed associations between use of sodium-containing acetaminophen products and increased risk of CVD and mortality in individuals with or without hypertension. Rigorous statistical methods were utilized to limit the influence of potential confounders, though notably this study did not have access to individuals’ dietary sodium intake or over-the-counter acetaminophen use. The FDA requires that over-the-counter medications containing >5 mg of sodium have this information included on the label. Raising awareness of the increased risk of CVD and mortality associated with excess sodium intake from medications is paramount.

Keywords: Acetaminophen, Cardiovascular Diseases, Excipients, Heart Failure, Hypertension, Ibuprofen, Myocardial Infarction, Patient Care Team, Primary Prevention, Ranitidine, Risk, Sodium, Sodium, Dietary, Stroke, Vascular Diseases


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