Study Links Use of Sodium-Containing Oral Acetaminophen (TYLENOL) Formulations to Increased Risk of Cardiovascular Disease

Because of its perceived good safety profile, the over-the-counter and prescription drug acetaminophen (TYLENOL) — also known as paracetamol — is the most widely used fever- and pain-relief medication in the world.

the world. There are two types of oral acetaminophen formulations. The first is the regular, standard type, which does not contain sodium and is available in capsules, solutions and tablets. The second is fast-acting — because it contains sodium, which enhances the drug’s solubility or disintegration — and is available in dissolving packs, effervescent (fizzy) and other soluble formulations.[1]

A recent well-designed observational study showed that initiation of sodium-containing acetaminophen was associated with an increased risk of new-onset cardiovascular disease and hypertension (high blood pressure) as well as overall mortality compared with non–sodium-containing acetaminophen.[2] This increased risk occurred in individuals with and without hypertension. The study was published in the May 7, 2022, issue of the European Heart Journal.

About sodium

Sodium is an essential mineral that the body needs in relatively small amounts to maintain fluid balance.[3] High sodium intake draws water into the bloodstream, which can increase blood volume, leading to increased blood pressure. Uncontrolled high blood pressure can raise the risk of heart attack, heart failure and stroke, as well as kidney disease.

The Dietary Guidelines for Americans recommend consuming less than 2,300 milligrams (mg) of sodium (about one teaspoon of table salt) per day, and even less than that for children younger than 14 years.[4] However, most Americans consume too much sodium (on average about 3,400 mg of sodium per day) from their diet alone.[5]

In addition to dietary sodium, certain formulations of medications (including fast-acting acetaminophen as well as some antacids) and supplements can be significant sources of sodium, as this mineral is used to enhance solubility or disintegration of these products.[6]

The new study[7]

Using anonymized data from a network of electronic medical records pertaining to approximately 17 million primary care patients in the U.K., the study researchers identified new users of either oral non–sodium-containing acetaminophen or sodium-containing acetaminophen from 2000 to 2017. From those, the researchers selected individuals who were 60 years or older because the U.K. government covered the cost of both prescription and over-the-counter medications (including acetaminophen) for this age group during the study period.[8],[9] To identify new users of the drug, the researchers selected individuals who did not use acetaminophen in the previous year. They further limited their analysis to individuals with no history of cancer or cardiovascular disease (heart attack, heart failure or stroke). Finally, the researchers divided their sample into two cohorts: a cohort that had a diagnosis of hypertension before their initiation of acetaminophen use and a cohort without this diagnosis.

Of an overall 151,398 individuals in the hypertension cohort, only 3% initiated use of sodium-containing acetaminophen, and the remaining 97% initiated use of non–sodium-containing formulations of the drug. Of an overall 147,299 individuals in the cohort without hypertension, only 4% initiated sodium-containing acetaminophen, and the remaining 96% initiated non–sodium-containing formulations of the drug.

The amount of sodium present in the acetaminophen formulations that contained this mineral and were used by individuals in the study ranged from 390 to 440 mg per 500 mg of acetaminophen.[10] Therefore, individuals who took the maximum daily dose of acetaminophen (which is about 3,000 mg of acetaminophen in the U.K)[11] exceeded the daily recommended amount of sodium intake.

The researchers found that the risks of new-onset cardiovascular disease and overall mortality were higher among initiators of sodium-containing acetaminophen than initiators of non–sodium-containing acetaminophen, regardless of their baseline hypertension status. Specifically, the one-year risk of cardiovascular disease in the hypertension cohort was 5.6% among initiators of sodium-containing acetaminophen and 4.6% among initiators of non–sodium-containing acetaminophen. Likewise, the one-year risk of cardiovascular disease in the cohort without hypertension was 4.4% among initiators of sodium-containing acetaminophen and 3.7% among initiators of non–sodium-containing acetaminophen.

A similar pattern was observed with overall mortality. The one-year risk of this outcome in the hypertension cohort was higher for initiators of sodium-containing acetaminophen (7.6%) than that for initiators of non–sodium-containing acetaminophen (6.1%). Among the cohort without hypertension, the one-year risk of overall mortality for initiators of sodium-containing acetaminophen (7.3%) was higher than that for initiators of non–sodium-containing acetaminophen (5.9%).

Importantly, a greater number of prescriptions of sodium-containing acetaminophen were associated with an increasingly greater risk of cardiovascular disease among individuals in both study cohorts, suggesting a dose-response relationship between sodium consumption via the drug and these risks.

Additionally, the one-year risk of new-onset hypertension was higher among initiators of sodium-containing acetaminophen (4.4%) than initiators of non–sodium-containing formulations of the drug (3.6%).

The researchers also analyzed data pertaining to small numbers of initiators of sodium-containing formulations of the pain-relief drug ibuprofen (ADVIL, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN) and the now-discontinued stomach-acid suppressant ranitidine (ZANTAC) in the study sample. They found that the risks of new-onset cardiovascular disease and overall mortality were higher among initiators of these formulations than among those for initiators of non–sodium-containing formulations regardless of baseline hypertension status.

The findings of this study are in line with those from a previous small crossover randomized clinical trial in Spain that showed that use of effervescent acetaminophen increased 24-hour systolic ambulatory blood pressure by 4 to 5 millimeters of mercury compared with use of regular acetaminophen after three weeks of treatment.[12] Due to ethical considerations, no long-term clinical trials have assessed the effect of sodium-containing medications on the risks of cardiovascular disease and overall mortality.[13] Therefore, the current study is perhaps the best available recent evidence on this issue.

What You Can Do

Although it is generally safe to use sodium-containing acetaminophen on an occasional basis, it is best to avoid unnecessary excessive use of these products, whether you have hypertension or not. To avoid liver injury, do not exceed the maximum recommended dose and frequency of acetaminophen that are listed on the drug label.[14]

If you have hypertension and use acetaminophen products on a regular basis, monitor your blood pressure closely.[15]

Consult your doctor or pharmacist to ensure that your medications and supplements contain no or limited sodium, as appropriate.

To avoid overall excessive sodium intake, prepare your own meals and avoid processed foods. Eat more fruits and vegetables to increase your potassium intake; this mineral can lower your blood pressure.[16]

Report all adverse events related to acetaminophen or other medications to the Food and Drug Administration’s MedWatch adverse event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Thompson A. A spoonful of sugar helps the medicine go down. Postscript. 2022;34(July):34-35.

[2] Zeng C, Rosenberg L, Li X, et al. Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension. Eur Hear J. 2022;43(18):1743-1755

[3] Food and Drug Administration. Food facts: Sodium in your diet. June 2021. https://www.fda.gov/media/84261/download. Accessed September 8, 2022.

[4] U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th Edition. December 2020. https://www.dietaryguidelines.gov/sites/default/files/2020-12/Dietary_Guidelines_for_Americans_2020-2025.pdf. Accessed September 8, 2022.

[5] Food and Drug Administration. Food facts: Sodium in your diet. June 2021. https://www.fda.gov/media/84261/download. Accessed September 8, 2022.

[6] Thompson A. A spoonful of sugar helps the medicine go down. Postscript. 2022;34(July):34-35.

[7] Zeng C, Rosenberg L, Li X, et al. Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension. Eur Hear J. 2022;43(18):1743-1755.

[8] Ibid.

[9] The National Health Service. Why can't I get a prescription for an over the counter medicine. October 25, 2021. https://www.nhs.uk/common-health-questions/medicines/why-cant-i-get-prescription-over-counter-medicine/. Accessed September 8, 2022.

[10] Schutte AE, Neal B. The sodium hidden in medication: a tough pill to swallow. Eur Hear J. 2022;43(18):1756-1758.

[11] Aurobindo Pharma - Milpharm Ltd. Summary of product characteristics: Paracetamol 500mg tablets prescription only medicine. July 2022. https://www.medicines.org.uk/emc/product/10817/smpc#gref. Accessed September 8, 2022.

[12] Benitez-Camps M, Padrós RM, Pera-Pujadas H, et al. Effect of effervescent paracetamol on blood pressure: a crossover randomized clinical trial. J Hypertens. 2018;36(8):1656-1662

[13] Schutte AE, Neal B. The sodium hidden in medication: a tough pill to swallow. Eur Hear J. 2022;43(18):1756-1758.

[14] Food and Drug Administration. FDA drug safety communication: Prescription acetaminophen products to be limited to 325 mg per dosage Unit; boxed warning will highlight potential for severe liver failure. Last updated February 7, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit. Accessed September 8, 2022.

[15] MacIntyre IM, Turtle EJ, Farrah TE, et al. Regular acetaminophen use and blood pressure in people with hypertension: The PATH-BP trial. Circulation. 2022;145(6):416-423.

[16] Potassium: An essential but often overlooked nutrient. Worst Pills, Best Pills News. November 2021. https://www.worstpills.org/newsletters/view/1430. Accessed September 8, 2022.