Further support for a theory commonly known as the "FitzGerald Hypothesis" has been provided by new research suggesting that cyclooxygenase-2 (COX-2)-derived prostacyclin (PGI₂) mediates changes in vascular endothelium in response to pressure-related changes in blood flow, thus mechanistically linking COX-2 inhibitors to an increased risk of heart attack or stroke.

The new findings, which appear in Circulation Research, suggest that during prolonged dosing with selective COX-2 inhibitors, there is an increase in blood pressure, early development of atherosclerosis, and architectural and functional responses to these stresses, even in healthy individuals.¹

The study "adds a third strand to how transformation of risk can occur in healthy people treated for prolonged periods," says Garret FitzGerald, MD, lead author of the study and director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia. "First, a rise in blood pressure; second, a direct effect on initiation and early development of atherosclerosis (which itself can be accelerated by hypertension); and now an effect on the vascular architectural response to hemodynamic stress," he tells CIAOMed.

All three effects "are mediated through the same mechanism - the suppression of COX-2-dependent PGI₂ - and then all three can join to result in hardening of the arteries," he says. Dr. FitzGerald's group has previously shown that this mechanism can destabilize formed plaques and prime the thrombotic response that results in heart attack or stroke.

While the group has previously shown that shutting down prostacyclin hastens the development of atherosclerosis, the new study sought to answer questions about how this molecule might modulate vascular structure and integrity when hemodynamic stress is sustained in the presence of intact endothelium, such as might occur in hypertension.

 

The FitzGerald hypothesis

COX-2 inhibitors depress systemic PGI₂ without concomittant inhibition of platelet-dervied thromboxane A₂ (TxA₂). This can result in an augmented response to thrombotic and hypertensive stimuli and the acceleration of atherogenesis. This mechanistic explanation is supported by data from the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial2 and the Adenoma Prevention with Celecoxib (APC) trial.³

APC showed at least a 2.5-fold increased risk of fatal and nonfatal cardiovascular (CV) events compared with placebo. Patients in this trial received 400 mg to 800 mg of celecoxib daily, a 2- to 4-fold higher dose than that recommended for the management of arthritis. In APPROVe, rofecoxib doubled the risk of myocardial infarction (MI) and stroke in patients who had used it for at least 18 months. Moreover, similar results were seen in trials of valdecoxib. Merck & Co, Inc, voluntarily pulled rofecoxib from the market in September and the FDA asked Pfizer, Inc to pull valdecoxib in April 2005, citing increased risk and no added advantage to this agent over other available drugs.

FitzGerald et al employed genetic and pharmacological approaches in two animal models. They found that deletion of the PGI2 receptor or suppression of PGI₂ with nimesulide, a selective COX-2 inhibitor used in Europe and Asia, both augmented intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide and prostacyclin receptor deletion augment the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Thus, prostacyclin may act to remodel blood vessels to preserve adequate blood flow.

 

Aspirin may mitigate risks

In further results also reported in the paper, FitzGerald et al show that the adverse effects of shutting down COX-2-derived prostacyclin could be limited, in part, by removing a TxA2 receptor in platelets. This mirrors a similar balancing effect between COX-1 and COX-2, which has been noted in the case of blood clotting, blood pressure, and atherosclerosis. This suggests that suppression of thromboxane with low-dose aspirin could reduce the risk of heart disease in a patient taking COX-2 inhibitors.

"We need to determine whether these mechanisms are operative in people and, if so, we should be able to develop tests which reflect this process," says Dr. FitzGerald. "This may allow us to detect the small number of individuals at risk of rapidly developing heart disease and stop the drugs before they run into trouble."

He adds that "we could also determine how quickly risk might dissipate when stopping the drugs. Certainly, the development of a rational approach to risk management will be key to giving Celebrex or other COX-2 inhibitors safely, even to healthy patients, for extended periods."

 

Sea-change in risk discussion

"It looks like the FitzGerald hypothesis is becoming more reasonable," comments Lee S. Simon, MD, rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts. "It is not the simplistic imbalance of COX-1 versus COX-2 inhibition that leads to prothrombosis," he tells CIAOMed. "It is that COX-2 inhibition leads to multiple events whether or not COX-1 is inhibited. In the right patient, these events (including left ventricular strain or load) may increase risk for a CV event, whether it is thrombosis or congestive heart failure." He adds that this model suggests that CV risk is associated with all of these drugs, both nonselective as well as selective NSAIDs.

"This is clearly a sea change in the discussion of risk of some drugs versus other drugs,"

References:

1. Rudic RD, Brinster D, Cheng Y, et al. COX-2 Derived prostacyclin modulates vascular remodeling. Circ Res. May 19, 2005; [Epub ahead of print].
2. Bresalier RS, Sandler RS, Quan H, et al, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102.
3. Solomon SD, McMurray JJ, Pfeffer MA, et al, Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-1080.