Physicians' Academy for Cardiovascular Education

Response to anti-inflammatory treatment explains CV benefit in CANTOS trial

CANTOS - Relationship of CRP Reduction to Cardiovascular Event Reduction Following Treatment with Canakinumab

Presented at AHA 2017 Scientific Sessions in Anaheim, CA, USA by Paul Ridker (Brigham and Woman’s Hospital, Boston, MA, VS).

News - Nov. 13, 2017

Main results

Conclusion

At the start of his presentation, Paul Ridker had mentioned that the results he was about to present show ‘how elegant biology is able to affect clinical care’. In addition to the earlier conclusions that CANTOS provides critical proof-of-concept that inflammation inhibition, in the absence of lipid-lowering, can improve atherothrombotic outcomes, the current analysis now suggests that the magnitude of hsCRP reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest CV and cancer benefits from continued treatment. The differential outcomes observed in CANTOS on the basis of achieved hsCRP concentration were robust to the choice of on-treatment measures, were minimally affected by adjustment for baseline clinical characteristics, were observed at all individual canakinumab doses, and were consistent in causal inference analyses. The main hazard of canakinumab – a small but statistically significant increase in fatal infection – was not related to on-treatment hsCRP levels. As such, the use of biologic response to canakinumab may also provide a simple selection tool to maximize benefit without increasing clinical hazard.

Discussion

Discussant Ira Tabas (Columbia University, New York, NY, USA) discussed some issues arising from the original analysis, some of which were addressed by the current subgroup analysis. The current results strengthen the biologic premise and he thinks that the data are hypothesis-generating for future prospective studies using a targeted approach. These studies may optimize efficacy and minimize adverse effects via targeted approach and infectious disease monitoring. Also, the route of delivery and lower cost may be optimized, for instance with oral inflammasome inhibitors. The use in primary prevention in select subjects should be explored. Moreover, it will be interesting to integrate inflammation lowering and intense LDL lowering, and possibly with drugs for diabetes that have been shown to yield a CV benefit.

He observes that advanced human atheroma have impaired inflammation resolution and are deficient in resolution mediators. Resolution mediator therapy blocks plaque progression in animal models of advanced atherosclerosis. Thus, insights obtained in CANTOS open the door to future testing of inflammation-targeted strategies.

During the Q&A in the press conference, Ridker compared the observed effects to those seen with LDL-c: that lower is better, with the difference that with hsCRP a mortality benefit is seen. This suggests that the biology of changes in inflammation are different than of lipid-lowering. It should be remembered that inflammation can also be reduced by lifestyle changes, and specifically, patients should first be told to quit smoking. The million dollar question remains what the differences are between the responders and non-responders to canakinumab. Ridker replied that it cannot be explained by simple characteristics. He thinks this is classic pharmacology: patients respond differently. Even at low doses, those who achieved a low level showed benefit. At higher doses, more people achieved the threshold and thus benefitted.

Disclosures

- Our reporting is based on the information provided at the AHA 2017 congress -

The results were published simultaneously at The Lancet Watch webcast with Paul Ridker on this analysis

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