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).
The CANTOS Trial has been set up to study the question whether inflammation reduction, in the absence of lipid lowering, can reduce CV event rates. To lower inflammation, IL-1beta has been chosen as a target, upstream of CRP and IL-6. The primary CANTOS results have been presented at ESC2017 earlier this year, which showed that MACE was reduced by 15% in patients treated with the IL-1beta inhibitor canakinumab, once every 3 months, as compared with placebo. 35%-40% reductions in hsCRP and IL-6 were observed upon treatment with this monoclonal antibody, in the absence of changes in LDL-c.
This has led to the paradigm that residual risk may be due to residual cholesterol risk, when LDL-c levels are high, but hsCRP is low, or due to residual inflammatory risk, when LDL-c levels are below treatment targets, and hsCRP is high. The former patients should receive additional lipid-lowering therapy, while the latter group may be treated with anti-inflammatory approaches. Data from PROVE-IT and IMPROVE-IT suggest that about 29-33% of patients in these trials had residual inflammatory risk, and about 14% had both residual inflammatory and cholesterol risk.
Based on CANTOS, a few critical unanswered clinical questions remained, starting with whether we can predict who benefits the most from effective but expensive treatments. It is interesting to know both whether there are clinical subgroups for whom benefits are large that clearly outweigh hazards, as well as whether there are subgroups for whom benefits are small that may not outweigh hazards. Therefore, this analysis of CANTOS data aimed to evaluate whether there are baseline characteristics that can be used to define patient groups more or less likely to benefit from treatment with canakinumab. Alternatively, it would be evaluated whether evidence of biologic drug response could be used to define such patient groups (based on magnitude of reduction or level achieved).
- A consistent treatment effect is seen across all patient groups defined by baseline clinical characteristics.
- Dose-dependent percent changes in hsCRP and LDL-c were seen with treatment with canakinumab and as compared with placebo, while LDL-c was stable in all four treatment groups.
- In multivariate adjusted analyses, patients with on-treatment hsCRP ≥2 mg/L showed a non-significant 5% lower risk of MACE (HR: 0.95, 95%CI: 0.84-1.09, P=0.48).
- In multivariate adjusted analyses, patients who achieved on-treatment hsCRP <2 mg/L, showed a 25% reduction of risk of MACE (HR: 0.75, 95%CI: 0.66-0.85, P<0.0001), in the context of absence of LDL-c lowering.
- Choice of alternative thresholds for on-treatment hsCRP, namely 1.8 mg/L or 50% reduction of median% reduction, had little impact on the observed risk reduction.
- Increasing risk reduction was seen in incremental on-treatment hsCRP tertiles, with significant reductions in tertiles 2 (hsCRP >1.2- <2.6 mg/L, HR: 0.83, 95%CI: 0.72-0.96, P=0.014) and 3 (hsCRP <1.2 mg/L, HR: 0.71, 95%CI: 0.61-0.82, P<0.0001) as compared with placebo.
- In patients achieving on-treatment hsCRP <2 mg/L, significant reductions of CV death (HR: 0.69, 95%CI: 0.56-0.85, P=0.0004) and all-cause mortality (HR: 0.69, 95%CI: 0.58-0.81, P<0.0001) were seen.
- Consistent treatment effects were seen with all doses of canakinumab in patients who achieved hsCRP <2 mg/L.
- Greater risk reduction for incident lung cancer was also seen with greater hsCRP reduction (on-treatment hsCRP above median hsCRP: 71% reduction, no benefit in those achieving hsCRP above median).
- Incidence rates of fatal infection were not related to on-treatment levels of hsCRP (0.35 per 100 person-years in those with hsCRP ≥2 mg/L, and 0.27 in those with <2 mg/L).
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.
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.
- Our reporting is based on the information provided at the AHA 2017 congress -