A Whole New Headache— Acetaminophen and Coronary Artery Disease

Abstract & Commentary

By Russell H. Greenfield, MD, Editor

Synopsis: It has long been assumed that acetaminophen, the common analgesic agent, is relatively safe for people with known coronary artery disease, in contrast to NSAIDs and COX-2 inhibitors. But assumptions can be dangerous, and this small study suggests that acetaminophen use may have similar risks associated with it, specifically increases in blood pressure.

Source: Sudano I, et al. Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation 2010;122:1789-1796.

Concerns about adverse cardiovascular effects with the use of either non-selective nonsteroidal anti- inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors in people with known coronary artery disease (CAD) often lead to recommendations to take acetaminophen (Tylenol) for the management of chronic pain. Acetaminophen is a weak analgesic, but has been considered a safer alternative to NSAIDs and COX-2 inhibitors in this setting. At least, that was the assumption.

The authors of this Swiss prospective, randomized, double-blind, placebo-controlled, crossover study sought to investigate the safety of acetaminophen in patients with stable CAD, focusing primarily on ambulatory blood pressure (ABP) readings, and endothelium-dependent and -independent vasodilation. People with known CAD on stable cardiovascular medications for at least the prior month were recruited from a cardiology specialty clinic in Zurich (exclusion criteria included left ventricular ejection fraction < 50%, chronic pain, and use of other analgesics).

Subjects were randomized to receive either 1 g acetaminophen (containing essentially no measurable sodium) three times daily or matching placebo for 2 weeks. There followed a washout period of 2 weeks, and then subjects were crossed over into the other treatment grouping. At baseline, 2, 4, and 6 weeks, endothelial function was measured, blood and urine were collected, and clinical status assessed, all before the subjects took their usual morning drug therapy. Regular medications and study drug were then taken and 24-hour ABP monitoring commenced (measurements were taken every 15 minutes during the day, every 30 minutes at night). Secondary measures of interest included platelet function, endothelial progenitor cells, and markers of inflammation and oxidative stress, among others.

Following analysis of data from 22 subjects, it was determined that a larger sample size was necessary for adequate statistical power. A total of 37 subjects were enrolled with final data available on 33 (4 subjects withdrew, reportedly for personal reasons, after their first visit).

Ingestion of acetaminophen 1 g TID for 2 weeks' time resulted in a significant increase in systolic blood pressure from 122.4 to 125.3 mm Hg (P = 0.021) and diastolic blood pressure from 73.2 to 75.4 mm Hg (P = 0.024) compared with placebo. Heart rate also increased while subjects were on acetaminophen, from 68.2 to 70.8 bpm, but not while on placebo, although the difference did meet statistical significance. No other differences between the treatment and placebo phase of the crossover trial were identified, including for flow mediated dilation. One subject experienced a significant increase in gamma-glutamyltransferase during the acetaminophen phase that normalized after cessation of treatment (subject denied alcohol use).

The researchers concluded that acetaminophen administration in the setting of known CAD results in a significant increase in both systolic and diastolic blood pressures, thus representing a potential public health concern.

Commentary

It is well established that selective and non-selective NSAIDs are associated with an increased risk of cardiovascular events, thus the current guidelines recommending avoidance of NSAIDs and COX-2 inhibitors in people with established CAD or who are at high cardiovascular risk for disease and a preference for acetaminophen. This is the first study to question the assumption of the cardiovascular safety of acetaminophen, and the findings are troubling. The observed increase in blood pressure noted with short-term use of acetaminophen was within the range of hypertensive effects seen with some traditional NSAIDs, and it is accepted that an incremental risk of cardiovascular and cerebrovascular disease exists with increasing blood pressure levels.

The authors note that acetaminophen (Tylenol) is one of the most commonly used drugs worldwide, often as a major ingredient in cold and flu medication, and that sporadic studies have linked acetaminophen with raised blood pressure or an increased risk of cardiovascular disease. Inhibition of prostaglandin synthesis is induced with NSAID use, but acetaminophen is considered to have weak activity in this regard. The authors speculate on there being a central mechanism at work due to the presence of increases in both blood pressure and pulse with acetaminophen.

A small sample size was employed because patients in the study did not present with pain, and a crossover design was used to limit the number of patients exposed to a drug from which they would likely not benefit. Future studies will certainly need to be designed carefully, as the ethical considerations of randomizing subjects in pain to active vs. placebo agents are substantial.

A significant proportion of people with CVD also experience chronic pain, which in light of this study begs the question, what types of analgesia should practitioners be recommending to patients with CVD? The answer is not yet clear. Acupuncture is an effective means of relieving some forms of chronic pain and there are suggestions in the medical literature that it may help lower blood pressure, but not everyone has access to or can afford acupuncture. Natural anti-inflammatory agents, such as turmeric, boswellia and ginger, may be beneficial but the same concerns about blood pressure need to be investigated.

Acetaminophen still may end up being considered a reasonable option for some cardiac patients with chronic pain—the trial lasted only 2 weeks and the adverse effects may have plateaued and dropped with more time. However, they also may have worsened with a longer duration of administration. In addition, concerns about liver toxicity with inappropriate acetaminophen use have been growing. We await further studies to help direct our clinical recommendations. Assumptions, it is clear, can be problematic whether they originate in conventional or in CAM therapeutics, and nothing can, or should, be taken for granted when it comes to optimizing health.