Paul M. Ridker, MD
Each year in the United States there's almost a half million heart attacks and another 300,000 strokes. Most of us as cardiologists think of these as episodes related to high blood pressure, smoking, and, most importantly, cholesterol. All of these are major risk factors for heart disease. We clearly want to stop smoking, we want to lower our blood pressure, and we want to aggressively lower the cholesterol levels.
But there's more to the story than just cholesterol, a story that's very much a Brigham and Women's Hospital story over the last 20 years, has taught us that in addition to high blood cholesterol, inflammation, how your body fights off infection, how your body deals with issues that have to do with cancer, is also intimately related to atherosclerosis, the process of the inflammation in the heart itself. What I would like to talk about is whether or not targeting inflammation as a way to lower heart attack risk might be a new treatment for this disease.
Many years ago, basic scientists in this institution, Mike Gimbrone, Peter Libby and others, made observations about how inflammation, the immune system, affects this disease. In 1997, my group asked the question, could we measure inflammation to predict who would have a future heart attack and who would have a future stroke? We did this by measuring a certain molecule called C-reactive protein, or CRP. This molecule is a marker of the inflammatory process.
And what we discovered, in a study done here at the Brigham and Women's Hospital, was that middle-aged men with higher levels of CRP were at much higher risk of going on to have a future heart attack or a future stroke. That's a measure of inflammation telling us about future risk. And we made the observation in a randomized trial of aspirin, an anti-inflammatory drug, that the benefit of being on aspirin was greater in the presence of high inflammation than in its absence.
In 2001, we released the CRP test for commercial use. This made a lot of news coverage, both at Time and US News & World Report, talking about new ways of defining heart attack risk. And this has been added to our national guidelines now as a new way of thinking about who's at risk. In other words, even if your cholesterol level is low, if your CRP is high you have higher than anticipated risks of a future heart attack and a future stroke.
Across the United States now, millions of individuals have had this done as part of their physician's attempt to understand why are certain people at such high risk and what can we do about it.
At the end of the day, simply telling you that you're at high risk is part of the solution. Based on that information we hope that you diet, exercise, stop smoking, go to the gym. But we also want to ask the question, if we identify you at being at particularly high risk because you have this marker of inflammation, that is your CRP is high, is there some treatment or therapy I might give you that I otherwise would not have provided?
We made a discovery that when you gave statin drugs, the cholesterol-lowering drugs, you also lowered CRP levels. So we then designed a large clinical trial called JUPITER, which was done around the world with nearly 18,000 patients, who would never receive a statin drug under any current guideline. They entered the trial having never had a prior heart attack, with a low level of cholesterol but a high level of CRP. Published in 2008, the results of that trial were quite striking: a 44 percent reduction in ever having a first heart attack, stroke or cardiovascular death, a 55 percent reduction in myocardial infarction, a 50 percent reduction in stroke, and a 20 percent reduction in all cause mortality, simply by providing a statin to individuals whose cholesterol levels were actually low but whose CRP was high. That was the first step in saying, is there's something we can offer these individuals that would be life-changing for them?
With funding from the National Heart Lung and Blood Institute, we've launched a large-scale clinical trial structured here at the Brigham and Women's Hospital, but being run now across all the United States and Canada, called CIRT, the Cardiovascular Inflammation Reduction Trial. We're actually taking a technology, also discovered here, which has to do with a drug called low-dose methotrexate. We're now taking that same drug, but applying it to cardiovascular patients. Can we give a low dose of an anti-inflammatory drug and lower cardiac event rates?
At the same time my group has also launched a second large-scale clinical trial being done all over the globe called CANTOS, or the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Now CANTOS is asking a similar question using a very sophisticated drug called a monoclonal antibody that also targets the inflammatory response. So between these two studies, CIRT and CANTOS, we should know within two to three years whether or not individuals who have this pro-inflammatory response are likely to have fewer heart attacks and strokes if we give them these specific targeted anti-inflammatory drugs.
If I've had my CRP measured, and my physician has recommended diet and exercise and perhaps put me on a statin because my CRP level is high, is this something else I can do today? The answer is yes.
Exercise is a great way to lower your cardiac risk. It's a great way to feel fit and lose weight and it lowers C-reactive protein levels. That's part of why we think exercise is so effective.
There are foods that actually are clearly better for this inflammatory process. They're the same kinds of foods that can make us generally live longer, that is, whole grains, fish, and things like extra virgin olive oil and nuts.
So it's a great Brigham and Women's Hospital story. Starting with basic science about how the immune system affects atherosclerosis. Going through the ideas whether a biomarker like C-reactive protein can be used to predict disease, CRP is now part of national guidelines. The initial trials telling us that statin therapy should be given to people who have low cholesterol but a high CRP and our ongoing work suggesting can we actually target the inflammation.
Reducing Inflammation Without Lowering Cholesterol Cuts Risk of Cardiovascular Events.
Investigators from Brigham and Women’s Hospital today announced results of a clinical trial culminating from 25 years of cardiovascular research work. At the European Society of Cardiology meeting and in a paper published simultaneously in the New England Journal of Medicine, Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at BWH, and colleagues presented findings from CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), a trial designed to test whether reducing inflammation among people who have had a prior heart attack can reduce risk of another cardiovascular event in the future. Read more.
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