The results are in. The conclusions, sadly, are not. The long-running and complex Cabana trial, pitting cardiac ablation devices from several manufacturers against drug therapy in patients with atrial fibrillation, has shown that use of the devices confers no benefit over the drugs on a composite endpoint of death and various cardiovascular events.
What that means for clinical practice, and therefore the sales of ablation catheters, depends on who is asked. Industry players say there is clear evidence of the utility of ablation, at least in certain patients, or that it is too early to predict Cabana’s likely effect on sales. But the trial failed, and with off-patent drug therapy cheaper – probably – than ablation, the data seem likely to cause use of the products to dwindle.
With forecast 2024 sales north of $3bn Johnson & Johnson is the leader in the fast-growing electrophysiology market. Electrophysiology broadly encompasses the catheter-based devices used to conduct ablation or to aid it, such as products to map the surface of the heart or to monitor patients during the procedure.
|The electrophysiology market|
|Global sales ($m)|
|Johnson & Johnson||Biosense Webster||1,925||3,050||+7%|
|Abbott Laboratories||Electrophysiology/core atrial fibrillation||1,382||2,612||+10%|
|Medtronic||AF & other cardiac rhythm & heart failure||950||1,918||+11%|
|Microport Scientific||Electrophysiology devices||9||15||+7%|
|St. Jude Medical*||Core atrial fibrillation||14||-||N/A|
|C. R. Bard**||Electrophysiology||3||-||N/A|
|*Acquired by Abbott. **Acquired by Becton Dickinson. Source: EvaluateMedTech.|
Ablation catheters from several groups were used in Cabana: J&J, via its subsidiary Biosense Webster, Medtronic, Boston Scientific, St. Jude Medical (now part of Abbott), and C. R. Bard (now part of Becton Dickinson) all supplied various devices. But other companies could be at risk too: if cardiologists find the data discouraging they will be put off ablation as a whole, not just the specific devices used in the trial.
The data do look discouraging. According to the intent-to-treat analysis a composite of all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest occurred in 8% of ablation patients and 9.2% of those on either rate control drugs – largely beta blockers – and/or antiarrhythmics, all of which were generic. There was no significant difference, with a p value of 0.3.
Analysed separately, there were still no differences in the individual components of the primary endpoint. The lack of mortality benefit is particularly important as Cabana started out with this as the primary: this was changed in 2014 owing to slow enrolment and event rates.
There were the usual crumbs: benefits for ablation in the rate of death or CV hospitalisation and in the rate of recurrence of AF. And a per-protocol analysis did suggest a benefit for ablation on the primary endpoint, with a nominal p value of 0.046. There was a great deal of crossover between the two arms: of the 1,108 patients randomised to ablation, 9.2% did not in fact undergo the procedure, while 27.5% of the 1,096 patients randomised to drug therapy were treated with ablation.
But the per-protocol analysis was not prespecified, and is obviously less rigorous than ITT. Moreover, the trial was open-label, which ought to have favoured ablation.
This has not prevented industry from taking an upbeat view.
“While the trial was negative for its primary endpoint according to the ITT analysis, there are some very positive signals within the data,” says Boston Scientific's Ken Stein to EP Vantage. Mr Stein is senior vice-president and chief medical officer of rhythm management and global health policy.
“Some people in the field are going to look at the headline and be discouraged,” he concedes, but says that “more people” will take heart from the positive subgroup findings, and points in particular to a benefit seen in patients with heart failure.
He also states, not unfairly, that technology has moved on in the eight years it has taken Cabana to conclude: “There’s been a huge evolution in the technology used for ablation, and even in our understanding of the best approaches to atrial fibrillation. In a lot of respects this is a worst-case analysis.”
Boston Scientific has been prioritising investment in its electrophysiology division in recent years. It has a number of novel catheters in development and has recently bought two companies with related technology.
Apama Medical, bought for $175m in October, has an irrigated multi-electrode radiofrequency balloon for cardiac ablation, though this is not yet approved in the US, and Securus Medical Group, maker of a device used to monitor oesophageal temperature during ablation procedures, was picked up last month for $40m.
“To the extent that people look at Cabana as having causative signals, anything that causes the atrial fibrillation market to continue to grow is something that’s going to be good for Boston Scientific as a company,” says Mr Stein. The flip side of that is true as well, of course – anything that drives customers away from ablation devices will be bad news for Boston.
Boston is not the only company for which this holds true. Doubtless all the makers of these devices will redouble their marketing efforts to try to hold off a sales slide, and future cost-effectiveness and quality of life analyses may yet come to their aid. But one of the possible outcomes from Cabana is that use of ablation will be restricted to the subgroups definitively shown to benefit from it, limiting the market.