More from CANTOS: Predicting patients likely to benefit most

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Macrovascular Residual Risk Studies

13 February 2018

In this pre-specified secondary analysis from CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) individuals with greater reduction in high-sensitivity C-reactive protein (hs-CRP) after first dose of canakinumab derived greater clinical benefit in terms of reductions in major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality with continued canakinumab therapy.

Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2017; doi: 10.1016/S0140-6736(17)32814-3. [Epub ahead of print]

STUDY SUMMARY

Objective:

To investigate whether the magnitude of benefit from interleukin-1β inhibition with canakinumab on cardiovascular events in CANTOS is influenced by baseline patient characteristics or the extent of hs-CRP reduction after first dose.

Study design:

CANTOS was a randomized, double-blind placebo-controlled trial that evaluated three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months versus matching subcutaneous placebo for the prevention of atherosclerotic events. The median follow-up was 3.7 years.

Study population:

CANTOS enrolled 10,061 patients with a previous history of myocardial infarction (MI) and hs-CRP ≥2 mg/L.

Efficacy variable:

The primary efficacy endpoint of CANTOS was a composite of recurrent MI, stroke, or cardiovascular death. The key prespecified cardiovascular secondary endpoint included these events as well as hospitalization for unstable angina requiring urgent coronary revascularization. Additional major endpoints in this analysis were recurrent MI, stroke and all-cause death, cardiovascular mortality, and all-cause mortality.

Methods:

This analysis addressed two issues. First, the effect of baseline clinical characteristics including age, sex, diabetes, smoking status, body-mass index (BMI), and hs-CRP or lipid concentrations on cardiovascular event rates was investigated. Second, the effect of the magnitude of the response to first dose of canakinumab, as assessed by the concentration of hs-CRP at 3 months (i.e. ≤2 mg/L or >2 mg/L) on relative hazards for major adverse cardiovascular events, cardiovascular mortality, all-cause mortality and infection versus placebo. This was a per-protocol analysis using Cox proportional-hazards models stratified by time since index MI. Multivariable modelling was used to adjust for baseline characteristics known to modestly affect hs-CRP (i.e. age, sex, smoking status, hypertension, diabetes, and BMI), as well as baseline hs-CRP and low-density lipoprotein cholesterol (LDL-C).

Results:

There was no effect of any of the specified baseline characteristics, as well as LDL-C values less than or greater than 2.06 mmol/L (80 mg/dl), on clinical benefit from canakinumab.

Univariable analyses showed that the magnitude of decrease in hs-CRP with canakinumab at 3 months was directly related to the magnitude of clinical benefit associated with canakinumab treatment. Patients who attained hs-CRP levels <2 mg/L at 3 months had a 25% reduction in major adverse cardiovascular events and 31% reduction in cardiovascular and all-cause mortality with continued treatment; however, those with hs-CRP levels ≥2 mg/L at 3 months derived no significant reduction in these endpoints (Table).

Table. Adjusted Hazard ratio (95% confidence interval) for prespecified cardiovascular endpoints, according to on-treatment hsCRP level (≥2 mg/L, <2 mg/L) at 3 months.

Endpoint	Placebo (n=3182)	Canakinumab, hs-CRP ≥2 mg/L at 3 months (n=2868)	Canakinumab, hs-CRP <2 mg/L at 3 months (n=3484)	p-value for trend across categories
Primary	1 (ref)	0.90 (0.79–1.02); NS	0.75 (0.66–0.85); p<0·0001	p<0.0001
MI, stroke or all-cause death	1 (ref)	0.93 (0.83–1.05), NS	0.73 (0.65–0.82) p<0.0001	p<0.0001
Cardiovascular death	1 (ref)	0.99 (0.82–1.21), NS	0.69 (0.56–0.85), p=0.0004	p=0.0004
All-cause death	1 (ref)	1.05 (0.90–1.22), NS	0.69 (0.58–0.81), p<0.0001	p<0.0001

NS not statistically significant

Authors’ conclusion:

The magnitude of hs-CRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab.

COMMENT

The CANTOS study can be regarded as a landmark proof–of-concept study, which showed that targeting inflammation with canakinumab, a human monoclonal antibody to interleukin-1β, significantly reduced major adverse cardiovascular event rates in the absence of effects on LDL-C.

The focus of this pre-specified analysis was to define those patients who derived greatest benefit from this intervention, specifically focusing on patient characteristics, as well as response to canakinumab, as assessed by reduction in hs-CRP.

The results of this analysis clearly show that the magnitude of reduction in hs-CRP after first dosing with canakinumab is a key determinant of subsequent clinical benefit. Notably, patients who attained hs-CRP levels <2 mg/L at 3 months had a 25% relative reduction in major cardiovascular events (the primary endpoint of the study), as well as 31% relative reduction in cardiovascular and all-cause mortality with continued treatment. In contrast, those patients with a less robust response (hs-CRP levels ≥2 mg/L at 3 months) derived no significant benefit.

These findings have important relevance for clinicians for a number of reasons. First, these results show that as for LDL-C,2,3 lower on-treatment concentrations of hs-CRP (indicative of lower inflammation), are associated with greater clinical benefit. Second, these findings were independent of baseline LDL-C levels. Third, given the need for judicious use of expensive treatments, such as monoclonal antibody therapy, a practical means for defining those patients most likely to derive maximum benefit from such treatments is highly attractive both to clinicians and payers. As shown by this analysis, assessing response to a single dose of canakinumab by the use of a simple test, measurement of hs-CRP levels at 3 months, can be readily adopted in routine practice. Importantly, such an approach is also consistent with the growing call for personalized medicine, also relevant for management of residual cardiovascular risk.

CANTOS and FOURIER have helped to categorize residual cardiovascular risk, as related to inflammation or LDL-C, respectively. In the future, will PROMINENT, with pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator,4 define the role of atherogenic dyslipidaemia in residual cardiovascular risk?

References

1. Ridker PM, Everett BM, Thuren T et al for the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–3.

2. Cannon CP, Braunwald E, McCabe CH et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–504.

3. Sabatine MS, Giugliano RP, Keech AC et al, for the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.

4. Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol. 2017 Oct 4;16(1):124.

Key words

residual cardiovascular risk; CANTOS; inflammation; major adverse cardiovascular events; cardiovascular mortality; all-cause mortality