Giving a generic anti-inflammatory drug widely used to treat rheumatoid arthritis to people who previously had a heart attack or stroke worked no better than placebo in preventing another cardiovascular event, researchers reported Saturday at a scientific meeting.
The trial, called the Cardiovascular Inflammation Reduction Trial (CIRT) and sponsored by the National Heart, Lung, and Blood Institute, tested methotrexate in people who had previous heart attacks or strokes in addition to having diabetes or metabolic syndrome, which can lead to inflammation. Methotrexate was an attractive option because people who took the relatively inexpensive, oral drug to treat their rheumatoid arthritis also appeared in observational studies to have lower rates of heart disease. The study was published in the New England Journal of Medicine and presented at the meeting of the American Heart Association in Chicago.
While methotrexate may have come up short in beating back heart disease, preventive cardiologists are calling its failure a vote of confidence in a more specific interpretation of what’s known as the inflammatory hypothesis. First proposed 25 years ago by Dr. Paul Ridker of Brigham and Women’s Hospital, the theory holds that inflammation causes atherosclerosis — hardening and narrowing of arteries that carry oxygen-rich blood to the heart — independent of “bad” cholesterol also clogging those coronary arteries.
Ridker recently led both CIRT and another randomized clinical trial in parallel to test whether drugs known to interfere with inflammation in other diseases would also lower the risk of future heart attacks or stroke in people who were at high risk of recurrence. In September, the first study, called Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) and sponsored by Novartis (NVS), showed that Novartis’ drug canakinumab, an injectable monoclonal antibody targeting a particular immune molecule, cut by 15 percent the rate of subsequent heart attacks, strokes, or death in people who had high levels of inflammation as measured by C-reactive protein in their blood.
The CIRT trial was stopped in the spring, earlier than planned, because its Data Safety and Monitoring Board concluded there was no benefit from the drug and little likelihood of any better results to come.
Dr. Robert Harrington, a cardiologist and chair of medicine at Stanford who sat on the safety board for the CIRT trial, said Wednesday the methotrexate results were disappointing but not surprising because those patients — unlike the patients in the CANTOS trial — did not have high levels of inflammation, possibly because their diabetes or metabolic syndrome were well-controlled by other drugs they were taking.
“I’m not sure you can say CIRT tested the inflammatory process the same way that CANTOS did,” he said. “That’s why CANTOS is so important, not so much for the drug itself but more for the step forward that says, if we inhibit the specific inflammatory pathways, we can actually improve outcomes for patients.”
The drug used in the CANTOS trial, canakinumab, has not been approved by the Food and Drug Administration for heart patients. It’s taken by people with juvenile idiopathic arthritis and other auto-inflammatory diseases; monthly injections cost $200,000 a year. In the CANTOS trial, there were some serious side effects, including fatal infections. In the CIRT trial of methotrexate, some patients had liver problems and there was a higher rate of non-basal cell skin cancer.
To Ridker, canakinumab is only a proof of principle, pointing toward a specific inflammatory pathway in which the innate immune molecule interleukin-1 beta is a prime target. C-reactive protein is also found in this pathway, and detecting its levels in a blood test indicates inflammation.
“I don’t think we yet have the perfect drug for this,” Ridker said. “I look at the CIRT trial as a very informative negative control. One study showed that lowering interleukin-1 beta and CRP clearly led to a substantial reduction in heart attack and stroke. The other study now says, if you give an anti-inflammatory that does not alter that pathway, you’re not going to see benefit.”
Dr. Erin Donnelly Michos, associate director of preventive cardiology of the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins University, also thinks the pathway matters.
“We need to be targeting inflammation in the direct causal pathway, which appears to be through IL-1B, rather than targeting some other marker of the inflammatory milieu that may not be a direct causal driver,” Michos, who was not involved in either study, said Thursday.
Michos holds out some hope for another generic, anti-inflammatory drug now being tested in heart patients: the gout treatment colchicine. The inexpensive drug targets adhesion molecules in an inflammatory pathway similar to the interleukin-1 beta pathway. That trial’s results are due next year.
Whether colchicine or a new drug eventually will control inflammation, right now preventive cardiologists tell patients already taking medications to lower LDL cholesterol and reduce blood pressure that they can reduce high levels of inflammation by quitting smoking, exercising, controlling their glucose levels, and eating a plant-based diet.
Ridker thinks a new drug may take 10 to 15 years to reach patients, but he’s more optimistic after CIRT and CANTOS.
“When you think about drug development and ultimately getting things to my patients, when you have a very good sense of what the correct pathway is likely to be, you can really start to focus effort,” he said.