A talking point for the CANTOS trial


 

A year after the results of the CANTOS trial were first presented, they were still an important talking point at ESC Congress 2018 in Munich. They have established inflammation as another risk factor in atherosclerosis along with cholesterol.

The anti-inflammatory monoclonal antibody canakinumab, which targets the interleukin (IL)-1β innate immunity pathway, resulted in a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid lowering. Patients in the trial had elevated levels of high-sensitivity C-reactive protein (CRP), a marker of inflammation, and the median LDL cholesterol level was 82.4 mg/dL. The median reduction from baseline hsCRP at 48 months was between 26%-41% greater in patients receiving different doses of canakinumab.
It has led to cholesterol and inflammation being described as “partners in crime” because of the biological interrelation in their impact on hsCRP.
The study came with other revelations. Inhibition of IL-1β with canakinumab, is associated with reduced incidences of lung cancer confirming that inflammation is a critical component in tumour progression. It also has beneficial effects on gout.

In the cardiovascular field, CANTOS is seen as a potential turning point in the treatment of atherosclerosis. At ESC Congress 2018, Paul M Ridker and Eugene Braunwald Professor of Medicine, Harvard Medical School, described the initial findings as having opened the floodgate to a wide range of investigations. “Since ESC Congress 2017, the cardiovascular benefit of canakinumab has been shown to be directly related to the magnitude of inflammation reduction measured by on-treatment which sensitivity C-reactive protein levels,” he said.

CANTOS showed a 31% reduction in cardiovascular mortality and all-cause mortality among participants with robust inhibition of the inflammatory response, Ridker noted. Analyses on the relationship between the magnitude of canakinumab benefit and on-treatment levels of IL-6 were presented at a clinical trail update at the ESC Congress 2018.

However, a new treatment option is still some way off. A consensus statement from the ESC Working Group on Atherosclerosis and Vascular Biology in May, concluded that more evidence is needed before anti-inflammatory drugs can join statins as standard treatment to prevent cardiovascular events in patients with atherosclerosis.

Nonetheless, Dr José Tuñón, first author of the statement and cardiologist at the University of Madrid, predicted that we are on the cusp of a new era in cardiovascular disease. “With further evidence, anti-inflammatory drugs could become one more tool in the treatment of atherosclerosis,” he said.

It still has to be established if anti-inflammatory therapies are effective regardless of CPR levels. “There is a large and strong body of evidence showing that lipid-lowering drugs reduce the risk of cardiovascular disease. Anti-inflammatory drugs will not replace lipid-lowering drugs, but look set to become a complementary therapy in patients with atherosclerosis,” Tuñón said.

At ESC Congress 2018, Milton Packer, cardiologist at Baylor University Medical Centre in Dallas, Texas, identified the major benefit of canakinumab as a 20% reduction in the risk of myocardial infraction. He said CANTOS demonstrates the importance of inflammation in the genesis of chromatic coronary events.

However, he described canakinumab as “outrageously expensive” signalling that the costs could be prohibitive for its use in the treatment of atherosclerosis. Packer suggested the drug could be provided free the first time but treatment continued only with those who show a favourable response. He provided a detailed analysis of how patients could be assessed, including study of on-treatment levels of interleukin-6 and subsequent risk of MACE.

Packer suggested that hsCRP is measured in all at-risk patients, all CANTOS-candidate patients should be treated with canakinumab long-term, regardless of post-treatment changes in hsCRP, and the price of canakinumab needs to be reduced by 90%.

Ridker looked at the oncology implication of CANTOS. The trial showed that 300 mg of canakinumab caused a 67% reduction in incident lung cancer and a 77% reduction in fatal lung cancer. He said the effects of the drug on gout are independent of serum uric acid levels saying there are implications for NLPR3 inhibition. 

A sub-study will examine potential effects of treatment on VTE. This might provide an exciting link between inflammation, cancer and VTE.  We await the results!

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