SNOWMASS, COLO. — The time is right to consider organizing large randomized clinical trials looking at whether tight pharmacologic control of systemic inflammation will lower the high cardiovascular morbidity and mortality associated with rheumatoid arthritis, Dr. Sherine E. Gabriel declared at a symposium sponsored by the American College of Rheumatology.
“The only way we're going to be able to figure out how to approach cardiovascular risk reduction in RA patients is the way the diabetologists did when they conducted very large trials of tight metabolic control and looked at its effect on long-term cardiovascular outcomes. We're getting pretty close to the limit of what our observational data can tell us,” said Dr. Gabriel, the William J. and Charles H. Mayo Professor of Medicine and Epidemiology at the Mayo Clinic, Rochester, Minn.
The large observational studies that have tried to examine the impact of RA drugs on cardiovascular end points are fraught with potential confounders. This may explain the conflicting results. For example, last November's annual meeting of the ACR saw presentation of two large observational studies on the impact of tumor necrosis factor inhibitors on cardiovascular outcomes—with very different conclusions.
In a nested case-control study involving roughly 20,000 RA patients in the MediCal database, investigators at Stanford (Calif.) University concluded that those treated with a TNF inhibitor plus methotrexate had an adjusted 80% reduction in acute MI risk compared with those on methotrexate alone.
But in a cohort study involving nearly 6,000 Medicare patients with RA in two states, physicians at Brigham and Women's Hospital, Boston, determined that those with no baseline history of heart failure had an adjusted 3.1-fold greater risk of a first hospitalization for heart failure after being placed on a TNF inhibitor compared with those who got methotrexate. And among the 1,033 patients with a baseline history of heart failure, the adjusted risk of an exacerbation requiring hospitalization was 50% greater in those on a TNF inhibitor than with methotrexate.
“It's very tough to tease out what's going on with these drugs,” Dr. Gabriel commented. “I'm still not clear on their role.”
She and her coinvestigators in the Rochester Epidemiology Project have shown that the mortality gap between RA patients and the general population has been growing for decades, largely because of excess cardiovascular deaths in the RA population. Yet people with RA don't have a greater prevalence or severity of the traditional cardiovascular risk factors—and that has important implications for efforts to reduce the mortality gap in RA.
“Effective, even optimal control of the traditional cardiovascular risk factors in people with RA is important, but it's not going to be enough by itself,” said Dr. Gabriel.
That point was brought home in a recent report by Dr. Gabriel and her Mayo colleagues. They analyzed the relative impact of traditional cardiovascular risk factors in 603 patients followed for a mean of 15 years after diagnosis of RA and in 603 non-RA controls. While many of the risk factors imparted similar risk in the two groups, three of them—smoking, male gender, and personal cardiac history—imparted significantly less risk in the RA patients (Ann. Rheum. Dis. 2008;67:64–9).
The weaker impact of these traditional cardiovascular risk factors in the RA group suggests the existence of additional competing cardiovascular disease-promoting mechanisms present only in the RA group.
There is strong evidence to suggest that the systemic inflammation of RA may be the key factor, which is why it's time for randomized trials of the impact on cardiovascular events of TNF inhibitors, methotrexate, and other systemic inflammation-reducing drugs, Dr. Gabriel said.