CANTOS Trial

Two or three decades ago, many experts predicted that the modification of risk factors, in particular, the treatment of high blood pressure and lipid disorders, would eliminate CAD in 10 – 20 years. Unfortunately, that prediction turned out to be wrong.

Although the death rate from coronary artery disease has dropped in most countries, the disease remains an important cause of death and disability worldwide. Even more worrying is the rising prevalence of obesity and type 2 diabetes which ultimately reverse the declining trend in mortality from cardiovascular disease.

Current drug therapies designed to slow the atherosclerotic process focus almost exclusively on reducing plasma levels of LDL cholesterol. However, experimental and clinical research supports that additionally targeting inflammation may be beneficial (2).

What Is Inflammation?

The body’s defenses are controlled by the immune system which is composed of biological structures and mechanisms that continuously protects us against diseases such as infections and cancer.

Inflammation is a protective response to injury or destruction of cells or tissues. It is one of the body’s most important defense mechanism. Without it, we would not be able to fight bacterial infections, injuries, and destruction of tissues.

Inflammation can be both acute and chronic. Acute inflammation is the initial response of the body to harmful stimuli.  Prolonged inflammation or chronic inflammation is characterized by simultaneous destruction and repair.

Inflammation is protective when it is appropriate. However, when inflammation is inappropriate or gets out of hand, it may cause disease.

Autoimmune disorders such as rheumatoid arthritis, Hashimoto’s thyroiditis, systemic lupus erythematosus, and type 1 diabetes are all associated with a dysfunction of the immune system. These disorders are characterized by an inappropriate immune response against cells and tissues in our body causing inflammation of tissues and organs.

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Inflammation and Atherosclerosis

Inflammation plays a significant role in atherosclerotic cardiovascular disease (3). Modern theories on the initiation of atherosclerosis suggest that modified lipoproteins, such as oxidized LDL (OxLD), may play a central role in promoting the inflammatory reactions that characterize and drive atherosclerosis (4).

Leukocytes, the type of white blood cells typically involved in most inflammatory reactions in the body, appear to play an important role in atherosclerosis. Leukocyte recruitment to the arterial wall is an important initial step in the formation of atherosclerotic plaques.

Cytokines are small proteins that are important in cell signaling (5). The cytokines interleukin-6 (IL-6), IL-1, and TNFα are elevated in most, if not all, inflammatory states and have been recognized as targets of therapeutic intervention (6).

Interleukin-1β is a cytokine that is central to the inflammatory response and drives the so-called interleukin-6 signaling pathway.

Inflammatory biomarkers are used to determine whether systemic inflammation is present or not. Many observational and clinical studies have used high-sensitivity C-reactive protein (hs-CRP)  to test the relationship between inflammation and cardiovascular disease (7).

CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study)

The CANTOS trial examined whether reducing inflammation with canakinumab in patients with a history of a prior heart attack can decrease the risk of another cardiovascular event happening in the future.

Canakinumab is a human monoclonal antibody that neutralizes interleukin-1β (8). It is approved in the United States and Europe as a treatment for several rare inflammatory diseases and has proven to be well-tolerated in people with diabetes or arthritis.

A total of 10.061 patients with a history of myocardial infarction (heart attack) and an hs-CRP equal to or above 2 mg/L were included in the CANTOS trial. Patients with a history of chronic or recurrent infections and cancer were excluded from the trial. The median follow-up was 3.7 years.

Patients with a history of chronic or recurrent infections and cancer were excluded from the trial.

The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every three months) with placebo. Enrollment began in April 2011 and was completed in March 2014. The median follow-up was 3.7 years.

The CANTOS Trial Population

The mean age of the participants who underwent randomization was 61 years, 25.7% of the patients were women.

The median body mass of the participants was 29.9, 40.0% had diabetes, 79.9% had hypertension, and 93.4% were on lipid-lowering therapy.

Median LDL cholesterol was 82.0 mg/dl (2.1 mmol/L), median HDL cholesterol was 43.7 mg/dL (1.1 mmol/L), and median triglyceride level was 139 mg/dL (1.56 mmol/L).

The CANTOS Trial Results

Canakinumab reduced the hs-CRP level, compared to placebo, by 26% to 41% depending on the dose administered. Similar effects were observed for the interleukin-6 level.

Canakinumab did not reduce lipid levels from baseline although a slight reduction in triglycerides was found.

Here’s how the main results are reported in the paper (you’ll find an easier version below if you read further):

At a median follow-up of 3.7 years, the incidence rate for the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group.

No significant effect, as compared with placebo, was observed with regard to the primary end point in the 50-mg group (hazard ratio, 0.93; P=0.30). By contrast, a significant effect for the primary end point was observed in the 150-mg group (hazard ratio vs. placebo, 0.85; P=0.02075, with a threshold P value of 0.02115). In the 300-mg group, the hazard ratio was similar to that in the 150-mg group, but the P value did not meet the prespecified threshold for significance (hazard ratio vs. placebo, 0.86; P=0.0314, with a threshold P value of 0.01058).

For the key secondary cardiovascular end point (the components of the primary end point plus hospitalization for unstable angina that led to urgent revascularization), the incidence rate was 5.13 events per 100 person-years in the placebo group, 4.56 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 4.29 events per 100 person-years in the 150-mg group, and 4.25 events per 100 person-years in the 300-mg group. In the group that received the 150-mg dose of canakinumab (for which the P value met the significance threshold for the primary end point), the hazard ratio versus placebo for the secondary cardiovascular end point was 0.83 (P=0.00525, with a threshold P value of 0.00529).

No significant differences in the number of cardiovascular deaths or total mortality were observed between canakinumab and placebo.

Significantly more deaths were attributed to infection or sepsis in the pooled canakinumab groups than in the placebo group. Cancer mortality was significantly lower with canakinumab than with placebo.

Interestingly, the CANTOS group has in a separate paper published in the Lancet, published data suggesting that canakinumab could significantly reduce incident lung cancer and lung cancer mortality (9).

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