PADIT: Aggressive Antibiotics Didn't Cut Already-Low CIED Infection Risk

May 18, 2018

BOSTON — A randomized trial with almost 20,000 patients didn't show an advantage to administering a "incremental" series of several antibiotics in patients getting a cardiac electronic implantable device (CIED) compared with a more conventional single-antibiotic, single-dose, approach.

The 1-year rate of hospitalization due to device-related infection edged lower but not significantly so after the incremental prophylactic regimen. With only 177 such events shared between the groups, the overall rate didn't reach even 1% in the analysis of patients treated only at centers in Canada.

That was about 40% below expected when the trial was designed, and possibly the reason the incremental regimen didn't perform better than the standard approach, said Andrew D. Krahn, MD, University of British Columbia, Vancouver, Canada, when presenting the Prevention of Arrhythmia Device Infection Trial (PADIT) here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions.

Although a broad subgroup analysis didn't show a preferential benefit in some types of patients, the incremental approach's effect consistently seemed to tip toward a reduced risk for hospitalization for infection, Krahn said.

"We looked at this in an immense number of ways, adjusted for every different parameter, and found a consistent effect no matter what," he said. "It does suggest a very modest effect across the board, as opposed to the missing subgroup where we should be applying most of the benefit." But the observation is only hypothesis-generating, Krahn noted.

"A Huge Amount of Passion"

Guidelines call for a single dose of cefazolin before CIED implantation, based more on judgment than a solid evidence base. And that antibiotic doesn't protect against "up to 30%" of organisms that cause CIED-related infections, Krahn observed.

In practice, said Bruce L. Wilkoff, MD, Cleveland Clinic, Ohio, antibiotic prophylaxis at CIED implantation varies widely, at least at centers in the United States.

There's little consistency across hospitals and clinics, and lacking much of an evidence base, the approaches are often borrowed from other medical specialties, Wilkoff said as assigned discussant for Krahn's presentation. Yet at those centers there is often "a huge amount of passion" for their preferred approaches.

In PADIT, the guidelines-based conventional approach consisted of a single preoperative intravenous cefazolin infusion (or vancomycin for patients allergic to peni­cillin). That provides protective coverage for little longer than the CIED insertions procedure itself, the researchers note.

The tested incremental approach took advantage of the wide-ranging half-lives of several antibiotics, given in stages to prolong their overall protective effect for several days and cover most of the time needed for the skin wound to heal.

It consisted of preoperative combined IV doses of cefazolin and vancomycin, plus a bacitracin wash of the subcutaneous pocket, along with postoperative oral cephalosporin for 2 days.

Partly to account for potential bias from institutional preferences, PADIT randomly assigned centers rather than patients by using a "prospective, randomized, unblinded, cluster crossover" design. All centers were randomly assigned to use the conventional or incremental strategy for 6 months, after which they would cross over to the other approach. The sequence was repeated for a total of 2 years, after which outcomes were followed for another year.

"If It Had Been 2% as Anticipated…"

Much PADIT discussion at the sessions centered on the few infections observed overall during the prespecified 12-month follow-up.

The "incredibly low" infection rate is testament to uniformity of practices across the Canadian healthcare system and in the study itself, Wilkoff said, but perhaps it "won't hold up around the world."

He also noted that about 50% of all infections seen in patients occurred after their own 12-month follow-up. "But then it gets a bit cloudier because there are other things that happen to those patients, and it's hard to assign those infections to the original intervention."

Wilkoff said that the incremental approach indeed seemed to have a consistently positive effect across subgroups; however, with such a low overall infection rate, any clinical advantage would be very small. "If it had been 2% as anticipated, I think it would have more impact."

Others agreed that infection rates are likely to be especially low in clinical trials. "When you are in a trial like this, and somebody's watching your infection rate, it's a process improvement, almost," said Christine M. Albert, MD, MPH, from Brigham and Women's Hospital, Boston, Massachusetts.

"They have a protocol that they will go to and everyone uses. It really potentially could have led to a lower infection rate across the board, which I think you saw," Albert, who co-chaired the session featuring PADIT, said at a media briefing on the trial.

Three Fourths at Tertiary Care Centers

The trial included 19,559 patients undergoing CIED implantations, including 12,842 with procedures considered high risk for infection. The high-risk cases were spread across all 28 trial sites; the lower-risk cases were limited to 6 sites.

About 62% of the high-risk cases involved generator change-outs, but the subgroup also included device upgrades, lead or pocket revisions, and implantation of biventricular devices.

The median annual device-placement volume was 150 at the 28 centers, which had an average of 5.5 operators and of which 75% were tertiary care centers.

The primary endpoint was assessed, by intention to treat, only in the subgroup with high-risk procedures. There were 99 hospitalizations due to device infection in the conventional prophylaxis group and 78 in the incremental group. The adjusted odds ratio for incremental vs conventional was 0.77 (95% CI, 0.56 - 1.05, P = .10).

There were no significant differences in need for antibiotics due to infection, all-cause mortality, or cardiac mortality.

The rate of antibiotic-related adverse events was "pretty trivial," said Krahn at the media briefing: 0.3% in the incremental group and 0.2% in the conventional management group (P = .77). These events included 18 and 6 cases of allergic reaction (P = .018), respectively, likely from the antibiotics, he said.

The likely message providers will hear from PADIT, he said, is that the incremental approach should be considered for the highest-risk patients, Krahn said. "The real question we have is, the literature doesn't actually have a very clear guidance on exactly who constitutes high risk."

For example, "I think, practically speaking, in my own practice last week I implanted somebody where it was the third procedure in a year, in a patient who was on dialysis, and the patient needed pacing," he said.

"There's a high-risk patient where I'd want to do everything in my power to try to prevent them from getting an infection. And I would give them incremental antibiotics until we have more clear guidance."

Krahn discloses receiving compensation for services for Medtronic and receiving research grants from Boston Scientific and Medtronic. Wilkoff chaired the PADIT data safety and monitoring board and discloses compensation for services or royalty income from Convatech, Medtronic, St Jude Medical/Abbott, and Spectranetics. Albert discloses receiving compensation from Myokardia and research grants from Roche Diagnostics and St Jude Medical.

Heart Rhythm Society (HRS) 2018 Scientific Sessions. Abstract B-LBCT01-01. Presented  May 10, 2018

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