“Anti-inflammatory drug ‘cuts heart attack risk’,” BBC News reports. A major study found canakinumab – an anti-inflammatory drug originally designed to treat rheumatoid arthritis – could also reduce the risk of having another heart attack in people who have already had one.
The study included more than 10,000 people who’d already had a heart attack. They were assigned to receive either injections of the drug canakinumab or a placebo.
Canakinumab is what’s known as a monoclonal antibody – an engineered antibody designed to modify the immune system. It turns off the process of inflammation, making it useful for serious inflammatory conditions like rheumatoid arthritis.
Not everyone who has a heart attack has raised cholesterol levels, so it’s unclear whether giving statins to these groups of patients would reduce the risk of another heart attack. The researchers wanted to see if a drug that reduces inflammation would be of more use.
After four years, researchers found people who received the higher doses of canakinumab (150mg or 300mg) were significantly less likely to have had another heart attack or a stroke, or to have died from cardiovascular disease.
But people taking the drug had a higher risk of developing fatal infections. Though this outcome was rare, it’s a serious risk that needs investigation.
We also need to see how the drug compares with other treatments currently used for people who’ve had a heart attack.
Where did the story come from?
The study was carried out by a large team of researchers from an extensive number of organisations worldwide, including Brigham and Women’s Hospital, Harvard Medical School, and Baylor College of Medicine in the US, Novartis in the US and Switzerland, and the Federal University of São Paulo and the University of São Paulo Medical School in Brazil.
It was funded by Novartis, the company that manufactures canakinumab. It was published in the peer-reviewed New England Journal of Medicine.
Overall, the media coverage of this story was well balanced, although the headlines didn’t mention that the study only looked at people who’d already had a heart attack.
Many newspapers claimed that canakinumab was “better than statins”, but this isn’t really a useful comparison and doesn’t reflect what was done in the study.
If canakinumab was licensed as a preventative medication, it’s likely it would be given to people who wouldn’t benefit from taking statins.
The papers acknowledged this treatment has potential downsides and more research is needed before it could be used in routine care.
What kind of research was this?
This placebo-controlled randomised clinical trial aimed to see whether the anti-inflammatory drug canakinumab (given at a specific dose of 50mg, 150mg or 300mg) could reduce the risk of further cardiovascular events in people who’d had a heart attack and had blood markers of inflammation.
Canakinumab is a monoclonal antibody given by injection. It’s currently licensed in the UK for the treatment of a selection of rare inflammatory conditions.
As prior research supports the role of inflammatory processes in the build-up of fatty deposits in the arteries (atherosclerosis), it’s thought anti-inflammatory drugs could affect the risk of heart attacks.
The study was very large, well-conducted and well reported. Its design, as a randomised controlled trial, is ideal for looking at how canakinumab might affect heart attacks.
What did the research involve?
Researchers enrolled people who’d previously had a heart attack (myocardial infarction) and lived in one of the 39 countries where the research took place.
The participants also had a raised blood level (2mg per litre or more) of an inflammatory marker called high-sensitivity C-reactive protein (hs-CRP). Raised levels of this protein may indicate people at risk of having further heart attacks.
People weren’t allowed to take part in the study if they had:
- a history of chronic or recurrent infections
- previous cancer (except basal cell skin cancer)
- suspected or known problems with their immune system
- a history or high risk of tuberculosis or diseases related to HIV
- been using other anti-inflammatory treatments
The 10,016 people recruited to the study were split into four groups to receive either a placebo (3,344 people) or canakinumab at either 50mg (2,170 people), 150mg (2,284 people) or 300mg (2,263 people) doses.
The placebo, 50mg and 150mg doses were given by injection every three months. People receiving the 300mg dose initially had two injections a fortnight apart before switching to every three months.
Participants were monitored over the next four years. The researchers were mainly interested in whether the participants had any further heart attacks or a stroke, or died from cardiovascular disease during this time.
Other outcomes of interest included hospitalisation for unstable angina and need for surgery to improve blood flow to the heart. The researchers also looked at any negative reactions to the treatment.
They analysed all participants in their assigned treatment groups, even if they stopped or changed treatment. This is known as an intention to treat analysis.
What were the basic results?
After four years, a total of 1,490 participants had experienced the main combined outcome of heart attack, stroke, or death from cardiovascular disease.
Overall, there was an average of 4.5 of these events per year per 100 people in the placebo group.
The risk in the treatment groups was:
- 50mg group – 4.11 events per year per 100 people (not statistically significant compared with placebo)
- 150mg group – 3.86 events per year per 100 people (a 15% lower risk compared with placebo, hazard ratio 0.85, 95% confidence interval 0.74 to 0.98)
- 300mg group – 3.90 events per year per 100 people (a 14% lower risk, hazard ratio 0.86, 95% confidence interval 0.75 to 0.99)
When combined with other outcomes, the 150mg dose was considered the best.
The researchers found people taking any dose of canakinumab were at higher risk of fatal infections like sepsis. The rate of death from infection was 0.31 per 100 people in the treatment groups, compared with 0.18 in the placebo group.
A low white blood cell count was far more common in the treatment group compared with the placebo group, which could make people vulnerable to infections.
A similar pattern was found with a reduction in platelets, the cells that help keep blood sticky and prevent excessive bleeding, though no increased bleeding risk was reported.
Consistent with the known effects of the drug, treatment was also linked with fewer reports of arthritis and gout.
How did the researchers interpret the results?
The researchers concluded that the 150mg dose every three months led to a significant reduction in recurrent cardiovascular events compared with placebo.
The drug also reduced the inflammatory marker hs-CRP, which the researchers suggest indicates a reduction of inflammation overall.
They also noted that treatment had no effect on cholesterol levels.
This well-conducted study shows promising signs that canakinumab may reduce the risk of future heart attacks and other cardiovascular events in people who’ve had them in the past.
But before any changes are made to the current licensing of this drug, further research is needed to confirm the beneficial effects and the optimal dose.
Most importantly, researchers will need to focus on the observation that the drug lowered white blood cell counts and increased the risk of fatal infection.
They estimated around 1 in every 300 people taking canakinumab would die of a fatal infection. This number, while low, is still a concern if you’re planning to potentially treat thousands of people.
It also remains to be seen how this drug compares with existing drugs used in the secondary prevention of heart attack.
Many people could potentially be eligible for this treatment, so we need to be sure that the benefits outweigh any risks.