New murine studies have expanded on the important role of prostacyclin (PGI₂) inhibition and thromboxane A₂ (TxA₂) in the development of hypertension, cardiac hypertrophy, and cardiac fibrosis associated with cyclooxygenase (COX-2) inhibitors, and suggest that blocking unrestrained TxA₂ actions with low doses of aspirin might protect against end-organ damage without affecting blood pressure, according to the new research published in the September 14 issue of Cell Metabolism.¹

"Our results suggest that blocking thromboxane (TP) receptors, or perhaps reducing TxA₂ generation by low-dose aspirin, might protect against cardiac end-organ damage associated with the predominant reduction of prostacyclin (PGI₂) associated with COX-2 inhibition," the researchers conclude. "However, the practical utility of such an approach would require demonstration that GI protection is retained."

The study found that mice lacking both the PGI₂ and the TP receptors continued to suffer from hypertension, but do not develop cardiac hypertrophy and cardiac fibrosis.

While the abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension was not known until now. The new study found that a strain of mice lacking the receptor for PGI₂ developed salt-sensitive hypertension, enlarged hearts, and exaggerated cardiac fibrosis. Moreover, the unrestrained action of TxA₂ in the mice accentuated the intensity of cardiac damage caused by the high blood pressure.

"Deletion of the TP protects against the myocardial damage, but, interestingly, not against the rise in blood pressure caused by IP deletion," study author Garret FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia, tells CIAOMed. "While thromboxane is the major product of COX-1 in platelets, we still need to know if it is the only COX-1 product that might be suppressed by low-dose aspirin," he says. "We still don't know if COX-1 inhibition (as opposed to TP antagonism) will mitigate the rise in blood pressure consequent to COX-2 inhibition."

Dr. FitzGerald added that "this paper shows that suppression of COX-2–derived prostacyclin can contribute to the rise in blood pressure on nonsteroidal anti-inflammatory drugs (NSAIDs), including those specific to COX-2 inhibition."

"Some [have] suggested that hypertension was [particular] to Vioxx and unrelated to a mechanism-based effect on thrombosis," Dr. FitzGerald says. "It is likely hypertension interacts with an effect on atherogenesis and the vascular remodelling response to disturbed flow," he indicates, adding that research has previously shown that both can derive from suppressing PGI₂ to result in gradual risk transformation, as was observed during other trials including the Adenomatous Polyp Prevention on Vioxx trial (APPROVe).

The new findings build on a theory known as "the Fitzgerald hypothesis," which contends that cyclooxygenase-2 (COX-2) inhibitors suppress systemic PGI₂ without concomitant inhibition of platelet-derived TxA₂. This action can result in an augmented response to thrombotic and hypertensive stimuli and the acceleration of atherogenesis.

The researchers will next explore the effects of COX-2 inhibitors themselves in the salt-sensitive mice. Further study of the animals might also reveal the genetic factors that predispose particular individuals to develop hypertension and cardiac complications during therapy with cox-2 inhibitors. 

GI complications still a factor

A. Mark Fendrick, MD, professor of internal medicine and health management and policy at the University of Michigan Health System in Ann Arbor, reminds CIAOMed that "if you take aspirin with rofecoxib, the presumed gastrointestinal (GI) safety advantage is markedly diminished or completely eliminated, so the idea that you might want to take aspirin [with rofecoxib] to offset concerns about cardiovascular (CV) risks needs to be combined with the fact that rofecoxib and aspirin in combination is a serious risk for GI complications."

He adds that the only evidence in humans stems from the Adenoma Prevention with Celecoxib (APC) trial,² which found that people taking aspirin for cardiac protection had no different risk of serious cardiovascular events than those who did not take aspirin.

"You can't get Vioxx anymore," Dr. Fendrick says. Merck & Co pulled Vioxx from the market on September 30, 2004, after APPROve showed there was an increased risk of confirmed CV events including MI and stroke in the rofecoxib-treated arm after 18 months of continuous treatment.

Stressing his earlier point, Dr. Fendrick says, "These drugs were designed to be safer to the stomach—not better. We still do not recommend the use of these drugs with or without aspirin in people with known risk factors for coronary heart disease, and won't until large controlled studies in humans show confirmed CV safety."

References

1. Francois H, Athirakul K, Howell D, et al. Prostacyclin protects against elevated blood pressure and cardiac fibrosis. Cell Metabolism. 2005;2:201-207.

2. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. New Engl J Med. 2005;352:1071-1080.