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The recently published results of the long awaited CANTOS trial may forever change our approach to the prevention and treatment of coronary artery disease (1). Inescapably, there is now proof that targeting inflammation, in this case by a drug, significantly improves outcome for certain very high-risk patients.
But, as so often in clinical research, things are not open-and-shut, and the picture is not as lucid as it seems.
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.
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.
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).
The Final Verdict
There are three important issues I want to highlight, not only because they tend to be overlooked, but because they provide the key to understanding the implications of the CANTOS trial.
The first issue deals with the study population, the second has to do with the statistical methods used, and the third will take us back to the real world to understand if and how the results will affect current clinical practice.
Who Are the CANTOS Patients?
The CANTOS trial was not a simple study of a pharmacological intervention in patients with coronary artery disease. It was a study of patients with a history of myocardial infarction on top of a chronic low-grade systemic inflammation. That is a huge difference.
But why do some patients with coronary artery disease have chronic low-grade inflammation whereas others don’t? Interestingly, the answer may be found by looking closer at the CANTOS study population.
Most patients included in the CANTOS trial were overweight, almost half of them may be defined as obese based on body mass index criteria, a high proportion had diabetes, HDL cholesterol levels were low, and triglycerides were high. So, to a large extent, these were patients with metabolic syndrome and insulin resistance.
Patients with metabolic syndrome have visceral obesity reflected by increased waist circumference, they have low HDL cholesterol and high triglycerides, they have prediabetes or diabetes, and they often have hypertension. Furthermore, the prevalence of obstructive sleep apnea and atrial fibrillation is high.
Adipose tissue (fat tissue) produces a number of bioactive substances, known as adipokines, which during fat tissue expansion may trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess fat mass and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases (10).
Unraveling the Statistics
Interestingly, the authors of the CANTOS trial decided to present the incidence rates in the study as events per 100 person years. In many studies, the length of exposure to the treatment is different for different subjects, and the person-year statistic is one way of dealing with this issue (11). However, it may make it hard to figure out the absolute risk reduction as well as the number needed to treat (NNT) which are numbers we usually want to see as well.
Person years is the summing of the results of events divided by time. The calculation of events per patient-year is the number of incident cases divided by the amount of person-time at risk. For example, if 1000 patients are followed for five years, there are 5.000 years of follow-up. If there are 100 events in the group, the rate would be 100 events per 5.000 patient years or 2 events per 100 patient years.
But, let’s figure out the absolute risk reduction for the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in the CANTOS trial.
A total of 955 events were reported for the primary endpoint in the canakinumab group (all doses) and 535 in the placebo group. The total number of patients on canakinumab was 6.717 and 3.344 on placebo.
Hence, it can be calculated that the event rate for the primary endpoint was 14.2% on canakinumab and 16.0% on placebo. This corresponds to an absolute risk reduction of 1.8% and a relative risk reduction of 11.3%. However, the authors report a 15% relative risk reduction by looking solely at patients in the 150-mg group.
I have calculated that the corresponding number needed to treat (NNT) based on all dose groups vs. placebo is 56. Hence, 56 patients need to be treated with canakinumab for a median of 3.7 years to prevent one primary end-point event.
Does anybody doubt that the juice ain’t worth the squeeze?
The Clinical Implications
The CANTOS Trial is a landmark study because it tested for the first time the hypothesis that blocking an important component of the inflammatory cascade involved in atherosclerotic heart disease will be translated into an improved outcome.
The positive results of the study certainly open new doors to the prevention and treatment of cardiovascular disease.
The data suggesting that canakinumab may reduce incident lung cancer and lung cancer mortality are of great interest but need to be confirmed by further studies.
However, the modest absolute clinical benefit and the high price of canakinumab can hardly justify its routine use in patients with coronary artery disease. Furthermore, more data is needed to understand the safety trade-offs involved in the long-term use of the drug.
Interestingly, the CANTOS trial has defined a high-risk subgroup of patients with coronary artery disease and metabolic abnormalities characterized by visceral obesity, insulin resistance, inflammation and adipocyte dysfunction.
The results of the study inevitably raise the question whether reducing inflammation by improving diet and lifestyle will provide similar results as treatment with an expensive drug with potential side effects.