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The secondary endpoint was reduced
by 17% in groups taking 150 or 300 mg of
canakinumab. Corresponding hazard ratios
in the 50, 150, and 300 mg groups were
0.90 (95% confidence interval 0.78–1.03;
P = .12); 0.83 (95% confidence interval 0.73–
0.95, P = .005); and 0.83 (95% confidence
interval 0.72–0.94; P = .004), respectively.
Due to multiplicity testing, only the 150-mg
dose met statistical significance for both the
primary and secondary endpoints.
The benefit of the 150-mg dose was driven
by a significant, 24% reduced risk of nonfa-
tal stroke or cardiovascular death observed.
Treatment with canakinumab did reduce
the risk of hospitalization for unstable
angina leading to urgent revascularization
(odds ratio 0.64; 95% confidence interval
0.44–0.94) and the need for any coronary
revascularization (odds ratio 0.68;95% con-
fidence interval 0.58–0.81).
Dr. Ridker explained that the relative reduc-
tion in clinical events ranged from 5% to
30%, depending on C-reactive protein and
interleukin-6 levels.
Overall, the drug was found to be safe, but
approximately one in every 1000 patients
suffered a potentially fatal infection. A small
but significantly increased risk of death
caused by infection or sepsis was observed
when all three treatment arms were com-
bined and compared with events in the
placebo arm (0.31 vs 0.18 events per 100
patient years; P = .02). Neutropenia and
thrombocytopenia were more common in
patients treated with canakinumab.
In contrast, cancer mortality was significantly
lower in patients treated with canakinumab
than those treated with placebo, which Dr.
Ridker said was “remarkable.” Treatment
with canakinumab 150 mg and 300 mg
reduced the risk of death from any cancer
by 22% and 51%, respectively. The reduc-
tion was driven primarily by a reduction in
the risk of lung cancer. In addition, treatment
with canakinumab resulted in a reduction in
the risk of arthritis, osteoarthritis, and gout.
Dr. Ridker said, “We found that in high risk
patients, a drug that lowers inflammation but
exerts no effect on cholesterol reduced the
risk of major adverse cardiovascular events.
In my lifetime, I’ve seen three broad eras
of preventative cardiology. First, we rec-
ognized the importance of diet, exercise,
and smoking cessation. Then we saw the
tremendous value of lipid-lowering drugs
such as statins. Nowwe’re cracking the door
open on the third era. This is very exciting.”
“As an inflammatory biologist and cardiol-
ogist, my primary interest is heart disease
but CANTOS was a good setting to explore
a previously observed link between can-
cer and inflammation,” said Dr. Ridker. “The
data on cancer rates point to the possibility
of slowing the progression of certain can-
cers, but these are exploratory findings that
need replication.”
“Maybe we don’t want everybody on this
drug,” Dr. Ridker explained, speculating on
how treatment might be managed for the
still investigational canakinumab. “Maybe
we give patients the first dose for free to see
if they respond? If they respond, with a 25%
or 30% risk reduction, that’s pretty good.
If they do not respond, we don’t want you
exposed to the toxicity, and we want you to
stay away from the drug. It’s a different way
of thinking about care.”
“This is the first time in 40 years where we
have something that’s not about lipid-low-
ering. We had no change in LDL cholesterol
– there was a 30% to 40% reduction in inter-
leukin-6 and C-reactive protein. Yet we had
an event rate identical to what you’d get
from being treated with a PCSK9 inhibitor.”
“This is about personalized medicine,”
he continued. “It’s saying not all second-
ary-prevention patients are the same. If
your problem is because your inflammatory
response has not been inhibited enough,
that your C-reactive protein is high, that’s
residual inflammatory risk.”
He added, “Now we have something to
offer those patients. If your LDL cholesterol
is high after a myocardial infarction, then you
can think about a PCSK9 inhibitor. You’re not
going to give both drugs to patients. We’re
trying to figure out how to give the right drug
to the right patient.”
PracticeUpdate Editorial Team
COMMENT
By Clyde W Yancy
MD, MSc, MACC, FAHA, MACP, FHFSA
CANTOS
T
he much-awaited CANTOS,
“Canakinumab anti-inflammatory
thrombosis outcomes study,” find-
ings were released. This is an important
study with positive results which define
new paths of thinking about cardiovascu-
lar disease but will not yet change clinical
practice. The hypothesis of CANTOS was
predicated on targeting inflammation in
those at risk for subsequent cardiovas-
cular events using hs-CRP as a surrogate
biomarker of inflammation and then initi-
ating therapy with a novel monoclonal
antibody against interleukin-1β. The
study included approximately 10,000
post–myocardial infarction patients on
guideline-directed high-dose statins who
were then randomized to canakinumab
versus placebo given subcutaneously
every 3 months and followed for 4 years.
A modest 15% relative risk reduction (CI,
0.74–0.98; P = .021) in the primary end-
point of nonfatal myocardial infarction,
nonfatal stroke, and cardiovascular death
was observed. The entirety of the effect
was on nonfatal myocardial infarction as
neither stroke nor cardiovascular death
was significantly reduced.
Two important treatment-related
observations:
•
Therewas a risk of infections, some fatal,
likely related to immunosuppression.
•
But, there was a peculiar signal on a
reduction of cancers, lung especially,
that will for certain require replication
before it can be incorporated in clinical
medicine; but, the possibilities are quite
intriguing.
What are the messages for the
PracticeUpdate Cardiology
community?
•
There is reason to now incorporate
inflammation in the genesis of future
ASCVD events in high-risk patients
(secondary prevention).
•
New “biologics” as treatments are on
the way. The protean effect of these
agents will firmly bring systems biology
into our discussion and will require that
we think much more broadly about the
impact of new agents.
•
Finally, exposing inflammation as a
now-confirmed participatory pathway in
the progression of cardiovascular dis-
ease introduces an exciting new path
of research and potentially important
new therapeutic considerations.
Nowwe have something to offer those patients. If your LDL
cholesterol is high after a myocardial infarction, then you can
think about a PCSK9 inhibitor. You’re not going to give both
drugs to patients. We’re trying to figure out how to give the
right drug to the right patient.
Paul M Ridker,
MD
ESC 2017
17
VOL. 2 • NO. 2 • 2017