Can Anti-Inflammatory Drugs Prevent Heart Attacks?

doctor and patient
Eva Catalina Kondoras

In the summer of 2017, investigators reported on results from the CANTOS trial, in which treatment with the anti-inflammatory drug canakinumab (Illaris, Novartis) significantly reduced the risk of major cardiovascular events in people who were at high risk.

Most experts believe that CANTOS will be remembered as a landmark trial, since it constitutes the first really solid clinical evidence that drug therapy specifically aimed at reducing inflammation can improve cardiac outcomes.

Identifying inflammation as a new target for preventive treatment is certainly a reason for optimism, and we can expect a great amount of research now to be focused in that direction. However, we should also be skeptical that the specific drug used in the CANTOS trial—canakinumab—will ever become an important treatment option for people at elevated cardiovascular risk.

Inflammation and Atherosclerosis

It has been known for decades that inflammation plays a role in atherosclerosis, and specifically, that inflammatory cells are a prominent feature of atherosclerotic plaques. Within those plaques, macrophages (a type of white blood cell) that have taken up oxidized LDL cholesterol release a host of inflammatory substances, triggering inflammation. It has been believed for years that this inflammation helps lead to plaque growth and even plaque rupture. The rupture of a plaque can be fatal. Plaque rupture is usually the event that finally triggers acute coronary syndrome, leading to unstable angina or a heart attack.

There is also evidence from clinical trials that strongly suggests that inflammation is important in determining a person’s outcome with atherosclerosis. In particular, elevated blood levels of two markers of inflammation—C-reactive protein (CRP) and interleukin-6—are associated with an increased risk of heart attacks, and other cardiovascular events.

Furthermore, studies have shown that statin drugs—which are famous for reducing cholesterol levels, but which also reduce inflammation—are effective in improving clinical outcomes of high-risk individuals who have high CRP levels, even when their cholesterol levels are not particularly elevated. (Many experts believe that it is because statins do much more than “merely” reducing cholesterol that makes them uniquely effective in lowering cardiovascular risk. Read about what makes statins “different.”)

However, until the CANTOS trial, no clinical study had ever demonstrated that reducing vascular inflammation, without also reducing cholesterol levels, would improve clinical outcomes.

The CANTOS Trial

The CANTOS trial took advantage of a unique drug that targets a specific component of the inflammatory response. Canakinumab is a monoclonal antibody that inhibits interleukin-1b, a cytokine that is critically important in the inflammatory pathway related to interleukin-6. Canakinumab has been approved for several years for the treatment of certain severe rheumatologic disorders, but had never been used to treat cardiovascular disease.

In the CANTOS trial, over 10,000 people who had survived heart attacks, and who had elevated CRP blood levels, were randomized to receive injections of either canakinumab or placebo.

After an average of 3.7 years of follow-up, people who were randomized to receive 150 mg injections of canakinumab (but not those who got either 50 mg or 300 mg) had a statistically reduced risk of cardiovascular events (as measured by a composite endpoint consisting of non-fatal heart attack, non-fatal stroke, or cardiovascular death). Overall mortality was not affected by canakinumab.

The benefit achieved with 150 mg injections, while statistically significant, was of relatively small magnitude, and of marginal clinical importance. In the placebo group, there were 4.11 clinical events per 100 person-years, vs 3.86 events per 100 person-years in people receiving 150 mg canakinumab.

In other words, the absolute reduction in risk in the study population was less than 1 percent after almost four years of treatment. While this level of benefit is not very impressive, it was still statistically significant. Thus, the results of the CANTOS trial clearly indicate, for the first time, that anti-inflammatory therapy can improve overall cardiovascular outcomes in high-risk individuals.

It is worth stressing again that canakinumab is not a run-of-the-mill anti-inflammatory drug. Instead, it is targeted at a particular and unique aspect of the inflammatory cascade. It is not at all clear that drugs that affect other aspects of inflammation would also be beneficial. In fact, it is well known that the non-steroidal anti-inflammatory drugs (NSAIDS) appear to worsen cardiovascular risk. So, the apparent cardiovascular benefit seen with canakinumab does not apply to other anti-inflammatory drugs.

As a side note, people in the CANTOS trial who received canakinumab were observed to have a reduced risk of death from lung cancer—another condition in which inflammation is thought to play a prominent role. So the CANTOS trial has also opened up a new avenue for research on inflammation and cancer.

The major adverse event seen with canakinumab in the CANTOS trial was a small but statistically significant increase in death due to infections. Since a robust inflammatory response is often necessary in fighting off infections, this finding was not a big surprise.

What All This Means

It is doubtful that the CANTOS trial will lead to the widespread use of canakinumab for reducing cardiovascular events in people who are at high risk. Not only does the actual clinical benefit from canakinumab look pretty marginal, but also this drug is extraordinarily expensive. Current treatment with canakinumab, in people with severe rheumatologic conditions, costs around $200,000 per year. The modest degree of cardiovascular benefit seen in the CANTOS trial will almost certainly not justify the use of such an expensive drug.

So, most likely, the significance of the CANTOS study is not that it has identified a specific new preventive therapy for heart disease, but rather, that it has identified a new target for research.

Until now, reducing cardiovascular risk with medication has been limited pretty much to cholesterol lowering (mainly with statins), and perhaps inhibiting thrombosis (with aspirin). It now appears, much more clearly than ever before, that suppressing specific aspects of the inflammatory response within blood vessels can also reduce the incidence of cardiovascular catastrophes.

We can expect pharmaceutical companies to rapidly take advantage of this new approach for therapy, and greatly step up their development of other agents that can mitigate vascular inflammation. If this effort pans out anything like what many experts now predict, the CANTOS trial indeed will eventually be regarded as a major breakthrough in the treatment of cardiovascular disease—whether or not the use of canakinumab itself ever becomes commonplace.

A Word From Verywell

It now appears virtually certain that inflammation plays a major role in the development of atherosclerosis, and in the outcome of people who have atherosclerotic vascular disease. The CANTOS trial has demonstrated that targeted therapy aimed at specific aspects of the inflammatory response can significantly improve the outcome of people who are at high risk.

While canakinumab—the drug employed in the CANTOS trial—may never come into widespread use for cardiovascular disease, researchers now have established a new avenue for treating this disease. In the coming years we can expect to hear a lot more about inflammation as a cause of atherosclerosis, and about new therapies aimed at suppressing this inflammation.

Sources:

Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on Atherothrombosis. Inflammation in Atherosclerosis: From Pathophysiology to Practice. J Am Coll Cardiol 2009; 54:2129.

Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory Therapy With Canakinumab for Atherosclerotic Disease. N Engl J Med 2017; DOI:10.1056/NEJMoa1707914.

Weber C, Noels H. Atherosclerosis: Current Pathogenesis and Therapeutic Options. Nat Med 2011; 17:1410.

Continue Reading