Acetaminophen and Hypertension

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Acetaminophen is able to induce a significant increase in BP in ambulatory subjects with CAD.

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

The United States Food and Drug Administration has mandated that a "black-box warning" be circulated for cyclooxygenase-2 (COX-2) selective inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) because of the demonstrated potential of these agents to increase adverse cardiovascular outcomes. Literally hundreds of millions of patients worldwide continue to require pain-relieving therapy to maintain an acceptable quality of life; therefore, the uncertainty about safely using NSAIDs and COX-2 inhibitors has created difficult management decisions for both physicians and patients. In fact, because of these uncertainties, current guidelines recommend using acetaminophen as the first-line analgesic of choice for the management of chronic pain, especially in patients at high cardiovascular risk or with established cardiovascular disease, even though its analgesic potency is weaker.1

Despite the fact that sporadic studies have actually linked acetaminophen to hypertension2,3 or to an increased risk for cardiovascular events,4 only a few interventional studies assessing the effects of acetaminophen on hypertension are available and the results have been inconsistent.5-7 Therefore, Sudano and her associates decided to prospectively evaluate the potential impact of acetaminophen on ambulatory blood pressure (ABP) and ventricular function in patients with established coronary artery disease (CAD) in whom traditional NSAIDs and COX-2 inhibitors are contraindicated and for whom acetaminophen currently represents the treatment of choice.

Sudano and her colleagues recruited and placed 33 patients with CAD into a randomized, double-blind, placebo-controlled, crossover study using acetaminophen (1 g three times daily) on top of standard cardiovascular therapy for 2 weeks. They measured the ABP, heart rate, and a variety of serum biomarkers as well as measures of platelet and vascular function. They observed a small but significant increase in mean 24-hour systolic and diastolic BPs similar to those effects which have been observed with many of the NSAIDs. Acetaminophen was found to have no significant effect on platelet adhesion, endothelial cells, or the numerous metabolic parameters which were measured. They concluded that the study, for the first time, demonstrated that acetaminophen induced a small but significant increase in ABP but had no significant effect on vascular function in patients with CAD and recommended that the drug should be used with the same caution as is applied to traditional anti-inflammatory drugs, particularly in patients at increased cardiovascular risk.

Commentary

The Sudano study was performed with only a very small number of patients; therefore, before drawing firm conclusions, a much larger randomized, double-blinded, and placebo-controlled study would have to be performed. The clinical status of acetaminophen will not be effectively changed in the short term because of the results of this very small new study; however, the results do suggest that acetaminophen should be used with caution in patients with cardiovascular disease. In addition, it should be recognized that acetaminophen, although relatively effective for some forms of minor pain, is quite ineffective for treatment of symptoms due to significant inflammatory diseases such as moderate to advanced osteoarthritis or rheumatoid arthritis8 and that most clinical trials have not demonstrated it to be superior to placebo. In addition, the hepatic safety of acetaminophen, particularly in large doses has proven to be of major concern recently and, in fact, the drug has been implicated in a number of cases of hepatic failure requiring liver transplantation.9

In summary, because of the new findings demonstrated by the Sudano study, it is quite clear that a lot more may be unknown about acetaminophen from a cardiovascular safety point of view than about the conventional NSAIDs and selective COX-2 inhibitors. Before recommending widespread use of this drug, especially in patients at increased cardiovascular risk, randomized controlled clinical trials of significant power specifically addressing the safety of this agent would have to be conducted.

References

1. Antman EM, et al. Use of nonsteroidal anti-inflammatory drugs: An update for clinicians: A scientific statement from the American Heart Association. Circulation 2007:115:1634-1642.

2. Chalmers JP, et al. Effects of indomethacin, sulindac, naproxen, aspirin and paracetamol in treated hypertensive patients. Clin Exp Hypertens A 1984;6:1077-1093.

3. Chan AT, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578-1587.

4. Forman JP, et al. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007;167:394-399.

5. Montgomery B. Does paracetamol cause hypertension? BMJ 2008;336:1190-1191.

6. Radack KL, et al. Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Intern Med 1987;107:628-635.

7. Pavlicevic I, et al. Interaction between antihypertensives and NSAIDS in primary care: A controlled trial. Can J Clin Pharmacol 2008;15:e372-e382.

8. Towheed TE, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257.

9. Reisch JS, et al; Acute Liver Failure Study Group. Acetaminophen-induced liver failure: Results of a United States multicenter, prospective study. Hepatology 2005;42:1364-1372.