Regular Use of Acetaminophen May Significantly Increase Hypertension and CV Risk

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Adults with hypertension who regularly take 4g of acetaminophen a day risk an increase in systolic blood pressure (BP) of approximately 5 mm Hg—an increase with meaningful long-term implications for cardiovascular disease, according to authors of the PATH-BP trial.

Their findings, published in the journal Circulation, call in to question the routine recommendation of acetaminophen as a safe alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) for common chronic painful conditions and particularly in persons with hypertension. The implications are significant given that acetaminophen is the most widely used over-the-counter and prescription analgesic worldwide, the authors write.

“The significant risks of acetaminophen in overdose are well-known,” wrote first author Iain M. MacIntyre, PhD, a specialist with National Health Service Lothian in the United Kingdom, and colleagues. “However, considerable uncertainty remains regarding the safety of chronic acetaminophen use at therapeutic doses because of reliance on observational data and cohort studies that often have conflicting results.”

To study the impact more closely, MacIntyre et al conducted a double-blind, placebo-controlled crossover study for which they randomized participants with physician diagnosed hypertension to receive either 1g acetaminophen 4 times/day or a matched placebo for 2 weeks. After a 2-week washout period for all participants, the groups crossed over to the alternate treatment for another 2 weeks. Assessment of BP was made by clinic measures and by 24-hour ambulatory measures taken at the beginning and end of each treatment period.

To meet inclusion criteria, individuals had to be aged ≥18 years of age and either be treated for hypertension with an average daytime ambulatory BP of <150/95 mm Hg on stable doses of ≥1 antihypertensive medication or untreated with an average daytime ambulatory BP ≥135/85 mm Hg but <150/95 mm Hg. Of 204 individuals screened at the University of Edinburgh’s Clinical Research Center, 110 were randomized into the study between Sept 2014 and June 2019. All participants were White, and the group was balanced on all baseline characteristics, according to the study.

The research team defined the primary outcome as a comparison of the change in mean daytime systolic BP from baseline to the end of treatment between the acetaminophen and placebo study arms. Secondary endpoints included change observed in ambulatory and clinic BPs between the 2 groups.

SBP increases seen across the board

Of the original 110 participants, 103 completed the study. Compared with those who received placebo, MacIntyre and colleagues report that participants who received acetaminophen experienced a significant increase in mean daytime systolic BP of 4.7 mm Hg (95% confidence interval [CI], 2.9–6.6; P<.001).

Looking at the secondary endpoint for ambulatory BP, when compared to placebo treatment, acetaminophen treatment was associated with a 4.2-mm Hg increase in mean 24-hour systolic BP (95% CI, 2.4–6.0; P<.001); a 1.6-mm Hg increase in mean daytime diastolic BP (95% CI, 0.5–2.7; P=0.005); and a 1.4-mm Hg increase in mean 24-hour diastolic BP (95% CI, 0.3–2.5; P=0.017). The investigators write that findings of a post hoc analysis showed no differences in change based on participants’ treatment status.

Similar increases in BP were seen for measures taken in the clinic. A change in systolic BP of 4.6 mm Hg (95% CI, 2.4–6.7; P<.001) was seen in the acetaminophen-treated group vs the placebo group with a corresponding change in diastolic BP of 1.6 mm Hg (95% CI, 0.1–3.0; P=0.031).

"Clear evidence"

The authors state the randomized placebo-controlled trial offers “clear evidence” that acetaminophen raised blood pressure and in a period of only 2 weeks. They also write that as a result of the established continuous relationship between BP and cardiovascular and cerebrovascular disease the 4.7 mm Hg difference in BP observed in the study “might be expected to translate to ~20% more cardiovascular events during any period of chronic treatment.”

Particularly for individuals with hypertension or who are at risk of ischemic heart disease, the authors write, the findings underscore extreme caution when recommending regular use of acetaminophen. Additionally, conclude MacIntyre et al, “acetaminophen should no longer be thought of as a ‘safe’ alternative analgesic to NSAIDs…Indeed, the rise in BP seen in this study matches that seen with NSAIDs. While the precise mechanism of action of acetaminophen remains unclear, it is believed to involve COX2 (cyclooxygenase-2) inhibition which may, at least in part, explain these similarities.”

Reference: MacIntyre IM, Turtle EJ, Farrah TTE, et al. Regular acetaminophen use and blood pressure in people with hypertension: the PATH-BP Trial. Circulation. 2022;145:416-423.