Practice Update: Cardiology

ESC 2017 17

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.”

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

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. • 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. Two important treatment-related observations:

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.

PracticeUpdate Editorial Team

VOL. 2 • NO. 2 • 2017