John M. Mandrola, MD


March 17, 2019

Cardiac implantable device (CIED) infection is an important problem. Encasing the CIED in an  antibiotic-impregnated absorbable envelope (TYRX, Medtronic) has biologic plausibility for reducing such infection. Preexisting evidence for benefit from local antibiotic delivery in the pocket is suggestive but not convincing.

The only way to answer the question was to do a randomized controlled trial (RCT). WRAP-IT[1] was a large multicenter RCT that appears to be well conducted. It was presented today at the American College of Cardiology 68th Annual Scientific Session (ACC) 2019

The trialists asked a relevant question and measured a legitimate hard endpoint of major CIED infection. They also enrolled patients similar to those we see in practice.

Coauthor Edward J. Schloss, MD, from The Christ Hospital in Cincinnati, Ohio, wrote to me that Medtronic did not have to conduct this trial. "Since TYRX is already FDA approved, they could have taken the easy road and aggressively marketed it with available observational data.

"Instead," Schloss writes, "the company took an expensive risk to give us the data that we need to make decisions."

I agree with him. This is industry-physician collaboration done correctly.

The results reveal the challenge in clinical science today: namely, it's hard to make a dent in already good outcomes.

Major CIED infection occurred in 25 of 3495 (0.7%) patients in the envelope arm and 42 of 3488 (1.2%) in the control arm.
In a trial of almost 7000 patients, the envelope prevented 17 infections.

This is a classic case of a large relative risk reduction (40%) corresponding to a tiny absolute risk reduction of 0.5 percentage points.

Because prevention of a CIED infection is a one-time therapy, I think the number needed to treat (NNT) statistic is relevant.  Here it is 200. At the current $995* price of the envelope, the cost of preventing one CIED infection is nearly $200,000. (*According to our hospital pricing.)
That big number gets even bigger when one considers how many CIEDs get implanted. The authors write in the opening sentence of their paper that 1.5 million people receive CIEDs worldwide per year. Thus, for patients, hospitals, and society, this is a pricey therapy.

WRAP-IT also suffers from power issues. The researchers powered the trial expecting a 2% rate of infection in the control arm. The actual rate came out lower, at 1.2%. As such, the P value for the 0.5%-percentage point risk reduction in the primary endpoint barely met significance at .04.

This makes the results fragile. I calculated the fragility index[2]—the number indicating how many patients would be required to convert a trial from being statistically significant to not significant. The fragility index of WRAP-IT is 1. This is especially notable because each group had more than 60 patients lost to follow-up.

I think the TYRX envelope probably does reduce infection by a small amount. The question is, How do we translate this evidence to patient care?

The translation of WRAP-IT isn't about a P value; it's about cost.  Think about it: if the envelope cost next to nothing, we would use it in almost everyone. The lack of harm reported is reassuring.

But at its current price, the envelope lies on the flat part of the value curve: that is, for the small chance of benefit, the costs are extreme.

Doctors often shun opportunity costs. We say that we treat individual patients, not societies or populations. That is a cop-out. Of course, we consider costs in our decisions.

At the current price, we cannot use the envelope in the millions of patients who receive CIEDs. So we have to decide how to ration this device.

That's a tough call because balanced against the small absolute risk reduction and high costs are the devastating complications of a CIED infection.

Two closing comments: One is that at least we have data from which to make this decision. Good on all those who generated the data.

The other is that in the marketing blitz following this "positive" trial, I hope that doctors do not let their guard down on the seriousness of a CIED. This evidence should not be used to sway the benefit/risk calculus in favor of a CIED. An implanted device remains a potentially harmful therapy


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