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Caution urged over 'new frontier' anti-inflammatory that slashes CVD and cancer risk

HeartAttackA pioneering drug, currently used to treat juvenile arthritis, has been found in a trial to also to cut the risk of heart attack by 25%, as well halving the chances of dying from cancer. A New England Journal of Medicine editorial urges caution: the drug is very expensive and those taking it were at a higher risk of dying from infections.

Almost every drug on the market for heart disease targets cholesterol. So it was major news on August 27 when a group of cardiologists from around the world announced they’d discovered that the drug canakinumab, sold under the brand name Ilaris by the Swiss company Novartis, which funded the study, reduces inflammation and successfully prevented heart attacks, strokes, and other kinds of cardiac death.

The drug itself is not likely to be a miracle cure. In both papers, those taking canakinumab were at a higher risk of dying from infections—suggesting that there are risks associated with decreasing the body’s immune response. Canakinumab is also expensive: a year’s supply for heart disease treatment would cost $64,000. But, this trial opens the door for future treatments for patients for whom controlling cholesterol isn’t enough to improve heart health.

The IL-1β inhibitor canakinumab lowers the risk of cardiovascular disease and lung cancer risk by reducing inflammation, according to late-breaking results from the CANTOS trial presented at the ESC Congress. "These findings represent the end game of more than two decades of research, stemming from a critical observation that half of heart attacks occur in people who do not have high cholesterol," said principal investigator Dr Paul M Ridker, director of the Centre for Cardiovascular Disease Prevention at Brigham and Women's Hospital, Boston. "For the first time, we've been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. By leveraging an entirely new way to treat patients – targeting inflammation – we may be able to significantly improve outcomes for certain very high-risk populations."

The CANTOS trial aimed to test whether reducing inflammation in patients who had a prior heart attack can lower the risk of another cardiovascular event. The drug tested was canakinumab, a human monoclonal antibody that neutralises interleukin-1β signalling, thereby suppressing inflammation. It is used to treat rare inherited conditions associated with overproduction of IL-1β.

The study included 10,061 patients who had previously had a heart attack and had persistent, elevated levels of high sensitivity C-reactive protein (hsCRP), a marker of inflammation. All patients received aggressive standard care, which included high doses of cholesterol-lowering statins. In addition, participants were randomised to receive 50, 150 or 300 mg of canakinumab, or a placebo, administered subcutaneously once every three months. Patients were followed for up to four years.

The primary endpoint was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The secondary endpoint was the first occurrence of any of the above, or of hospitalisation for unstable angina requiring urgent re-vascularisation.

Canakinumab at doses of 150 or 300 mg reduced the risk of a cardiovascular event (the primary endpoint) by 15% and 14%, respectively. Hazard ratios (HRs) for the primary endpoint in the 50, 150, and 300 mg groups were 0.93 (95% confidence interval [CI], 0.80-1.07; p=0.30), 0.85 (95% CI, 0.74-0.98; p=0.021), and 0.86 (95% CI, 0.75-0.99; p=0.031), respectively.

The secondary endpoint was reduced by 17% in the groups taking 150 or 300 mg of canakinumab. The corresponding HRs in the 50, 150, and 300 mg groups were 0.90 (95% CI, 0.78-1.03; p=0.12), 0.83 (95% CI, 0.73-0.95; p=0.005), and 0.83 (95% CI, 0.72-0.94; p=0.004). Due to multiplicity testing, only the 150mg dose formally met statistical significance for both the primary and secondary endpoints. Overall, the drug was found to be safe, but approximately 1 in every 1,000 patients had a potentially fatal infection.

Exploratory analyses revealed that canakinumab dramatically cut rates of total cancer death, especially death due to lung cancer, as well as the incidence of lung cancer. The effects were dose dependent.

Ridker said: "We found that in high risk patients, a drug that lowers inflammation but has 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 recognised the importance of diet, exercise and smoking cessation. Then we saw the tremendous value of lipid-lowering drugs such as statins. Now we're cracking the door open on the third era. This is very exciting."

"As an inflammatory biologist and cardiologist, my primary interest is heart disease but CANTOS was a good setting to explore a previously observed link between cancer and inflammation," said Ridker. "The data on cancer rates point to the possibility of slowing the progression of certain cancers, but these are exploratory findings that need replication."


Dr Robert A Harrington at the department of medicine, Stanford University, writes in an accompanying editorial, however, “despite the scientific and clinical excitement associated with having a new mechanism of action to attack in the treatment of coronary artery disease, a better understanding of the risks and benefits of this form of therapy is needed. Given that there was no observed effect on cardiovascular mortality in this trial, more information about the details of the myocardial infarctions (infarct size, Q-wave vs non–Q-wave, and spontaneous or procedure-related) is needed to better assess the clinical benefit of canakinumab.

“We also need additional information about the fatal infections encountered in CANTOS. Furthermore, any discussion of the use of canakinumab in patients with a previous myocardial infarction must consider cost. Given monthly for approved indications, canakinumab is priced at approximately $200,000 per year in the US. Such pricing may be suitable for rare diseases, but not for a common indication such as coronary artery disease, even if given every 3 months.”

Harrington writes that CANTOS has helped move the inflammatory hypothesis of coronary artery disease forward scientifically. However, he says, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with previous myocardial infarction until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.
Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
Results: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).
Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.

Paul M Ridker, Brendan M Everett, Tom Thuren, Jean G MacFadyen., William H Chang, Christie Ballantyne, Francisco Fonseca, Jose Nicolau, Wolfgang Koenig., Stefan D Anker, John JP Kastelein, Jan H Cornel, Prem Pais, Daniel Pella, Jacques Genest, Renata Cifkova, Alberto Lorenzatti, Tamas Forster, Zhanna Kobalava, Luminita Vida-Simiti, Marcus Flather, Hiroaki Shimokawa, Hisao Ogawa, Mikael Dellborg, Paulo RF Rossi, Roland PT Troquay, Peter Libby, Robert J Glynn

[link url="https://www.sciencedaily.com/releases/2017/08/170827101551.htm"]European Society of Cardiology material[/link]
[link url="http://www.nejm.org/doi/10.1056/NEJMoa1707914"]New England Journal of Medicine abstract[/link]
[link url="http://www.nejm.org/doi/full/10.1056/NEJMe1709904"]New England Journal of Medicine editorial[/link]

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