A research team in the US has found that anti-inflammatory drugs could reduce the risk of heart attacks, independent of cholesterol. Elly Earls finds out why this is being hailed as the biggest breakthrough since the discovery of statins.
Almost every cardiologist has dealt with the scenario. Middle-aged man goes out for a run and never comes back. Bereaved loved ones call, in shock, asking why. Doctor racks his brain to try and figure out, ‘Did I miss anything?’
For the first time, scientific evidence in the form of results from a ground-breaking trial in the US points to the fact that perhaps he did. CANTOS, which was led by investigators at the Brigham and Women’s Hospital (BWH ) in Boston and has been hailed as the biggest breakthrough since the discovery of statins, has found that reducing inflammation without lowering cholesterol in heart attack survivors cuts the risk of a future cardiovascular event.
It’s a particularly exciting moment for Dr Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at BWH , and leader of the research team, who has spent his entire academic career attempting to answer one fundamental question: can reducing inflammation in the absence of any change in cholesterol lower cardiovascular event rates?
“We wanted to explain the missing 30%-40% of heart disease – why were so many people having heart attacks or strokes who did not have high cholesterol? What was the missing piece of the biology?” he says. “CANTOS is a real game changer. Up until now, we’ve had tremendously powerful data telling us that if you focus on cholesterol reduction, you can lower event rates. This is the first piece of evidence we have that shows we get the exact same magnitude of benefit focusing strictly on lowering inflammation.”
Over and above expectations
Sponsored by Novartis , the CANTOS trial was designed to test whether patients who had already had a heart attack and who had persistent, elevated levels of high sensitivity C-reactive protein (hsCRP), a marker of inflammation, would be at reduced risk of having another heart attack if they received a targeted anti-inflammatory drug – canakinumab – that had no effect on cholesterol.
All of the more than 10,000 patients enrolled on the trial, who were followed for up to four years, received high doses of statins as well as either canakinumab or a placebo, both administered by injection every three months.
The results went over and above what the team anticipated. Not only did they report a 15% reduction in risk of a cardiovascular event, including fatal or non-fatal heart attacks and strokes, and a more than 30% drop in the need for expensive interventional procedures like bypass surgery and angioplasty, cancer deaths were cut in half, and the odds of succumbing to lung cancer slashed by more than 75%.
“We also saw reductions in arthritis, osteoarthritis and gout,” adds Ridker, noting that he wasn’t surprised by the multiplicity of benefits the team observed after patients were put on a long-term regime of canakinumab, which is currently licensed to treat juvenile arthritis.
“I treat people; I don’t treat heart, lungs or kidneys. Inflammation is an integrated process, in some ways, of aging. It’s really interesting to think about systems biology and the way we treat people – that’s another major lesson from CANTOS.”
BHF advises caution
The use of canakinumab to lower the risk of cardiovascular disease (CVD) is not without its downsides, however. For example, the researchers noted an increase in fatal infection among approximately one in every 1,000 patients treated.
For Jeremy Pearson, associate medical director at the British Heart Foundation (BHF), this didn’t come as a surprise, as the biochemical pathways being targeted to reduce CVD risk are very similar to those that increase infection risk. Nor does he believe it’s something to be taken lightly. “The downside [of the results] was the increased incidence of death due to severe infection – though very low it was nearly doubled, which is a clear warning flag to take into account when considering the potential long-term use of any anti-inflammatory drug to reduce CVD risk,” Pearson says.
Ridker, though, while acknowledging the seriousness of this finding, doesn’t believe it’s a difficult issue to address. “The increase is actually less than what clinicians routinely deal with when they give immuno-suppressive drugs such as IL-6 inhibitors and TNF inhibitors,” he explains. “These are routinely used to treat non-life threatening diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, so physicians are quite used to dealing with this small increased risk of infection.”
Pearson also advises caution over the trial’s results for several other reasons. “The trial was large and of long duration (almost twice as long as originally planned) because the size of the benefit was small and so could only be detected robustly with extended treatment,” he notes, adding that there is no evidence – or expectation – that the same results would be found in patients with normal or modestly raised CRP levels.
Additionally, canakinumab is expensive. “Even if it became cheaper, organisations such as NICE would be very unlikely to consider it as a licensed treatment for CVD, so a substantially cheaper drug would be needed,” he anticipates, concluding that the consensus view of those he has spoken to in the industry is that the results of the trial indicate that further preclinical research should be a priority, to understand whether selective inhibition of other pro-inflammatory pathways may have great efficacy and safety, before launching another Phase III trial.
Doing the right thing
It’s a hope echoed by Ridker who believes the results of the CANTOS trial will serve to “open the floodgates for research into other anti-inflammatory mechanisms to reduce CV event rates the same way the original statin trial opened the floodgates for alternative methods of lowering cholesterol.”
He’s also incredibly excited that, for the first time, the healthcare industry will be able to assess how patients should be treated based on whether they have residual cholesterol risk or residual inflammatory risk, although he’s realistic in realising that it’s going to be a long road before this becomes the norm.
“The clinical world will need substantial education about residual inflammatory risk being a very separate and distinct group of patients from those with residual cholesterol risk,” he says. “In fact, that might be the biggest hurdle right now. We now have evidence showing that these patients benefit from a different kind of therapy but physicians really need education and need to start thinking about how to do this. It’s a hurdle, but it’s also an enormous opportunity.”
For Ridker, it all comes back to the middle-aged man who went out for a run and never came back. “I think physicians want to do the right thing and, when it comes to that middle-aged man, we now have evidence that the doctor may have missed the residual inflammatory risk that was driving the disease in this particular patient. This change will be driven by the good physician trying to do the right thing for his or her patient,” he concludes.