Meeting NewsPerspective

Antibacterial envelope reduces rate of cardiac device infections in WRAP-IT

Khaldoun G. Tarakji
Khaldoun G. Tarakji

NEW ORLEANS — Wrapping cardiac implantable devices in an antibiotic-eluting envelope, in addition to standard infection prevention strategies, reduced the risk for major device-related infections by approximately 40%, researchers reported at the American College of Cardiology Scientific Session.

Researchers for the WRAP-IT study randomly assigned 6,983 patients undergoing a cardiac implantable electronic device (CIED) pocket revision, generator replacement or system upgrade or undergoing initial implantation of a cardiac resynchronization therapy defibrillator to a device wrapped in a bioabsorbable antibacterial envelope (Tyrx, Medtronic) or standard-of-care strategies to prevent infection.

Infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence or death occurred at a low rate of 1.2% in the standard-of-care group. However, at 0.7%, the rate was even lower in the envelope group (HR = 0.6; 95% CI, 0.36-0.98), whereas procedure-related or system-related complications were comparable in the two groups (envelope group, 6%; control group, 6.9%; P < .001 for noninferiority), Khaldoun G. Tarakji, MD, MPH, associate section head of cardiac electrophysiology at the Cleveland Clinic Heart and Vascular Institute, said during his presentation of the data.

“The results essentially show that the envelope is safe and effective and also did not increase complication rates,” he told Cardiology Today.

Effective across subgroups

For the study, Tarakji and colleagues defined infections as superficial cellulitis within the region of the pocket with at least one incidence of erosion, drainage, deep pocket infection, persistent bacteremia or endocarditis. For infections to be considered major, they had to lead to system removal, including the device and leads, or any invasive procedure, such as pocket revision or extended antibody suppressive therapy, which was mainly for patients who were not candidates for lead extraction. All other infections were classified as minor.

Wrapping cardiac implantable devices in an antibiotic-eluting envelope, in addition to standard infection prevention strategies, reduced the risk for major device-related infections by approximately 40%, researchers reported at the American College of Cardiology Scientific Session.
Source: Adobe Stock

The researchers found that approximately 75% of major infections were pocket infections. When looking at pocket infections alone, Tarakji said, there was a 61% RR reduction in major infections with use of the envelope over 12 months.

“We followed patients for a minimum of 12 months. However, we continued to follow-up all patients through the whole follow-up duration. Again, it seems like the effect of the envelope was sustained over time, with an event rate of 1.3% in the envelope group vs. 1.9% in the control arm at 36 months,” he said during his presentation. “However, after multiple comparison adjustment, the adjusted P value was not significant for this endpoint.”

In subgroup analyses, it appears the envelope’s effects were consistent across subgroups, including age, sex, comorbidities and device type, he added.

“This study provides comprehensive data on CIED-related infection and strong evidence for the use of the envelope for infection prevention in this patient population,” Tarakji said.

The study was not without limitations, he said, including that only one manufacturer’s device was used, which may have affected the nature of enrollment.

“The envelope itself has been commercially available and that may have led to some selection bias in participation with the trial,” Tarakji said.

Patients were enrolled from 2015 to 2017. The mean age was 70 years and 28% were women. Notably, patients were excluded if they were at exceptionally high risk for infection due to special circumstances, such as patients on dialysis or those who had an infection within the previous 12 months.

Challenge of device-related infections

Major device-related infections in patients undergoing device implantation procedures, including pacemakers and implantable cardioverter defibrillators, occur in 1% to 4% of these procedures, based on prior data, according to Tarakji.

“While the rate is small, the consequences could be serious and sometimes catastrophic,” he said during his presentation. “When you have a diagnosis of device infection, the management requires removal of the device and the leads, in addition to extended antibiotic therapy and longer hospitalization. And, despite going through all of the proper management steps, estimated 30-day mortality is still about 4% to 5% and 12-month mortality can be up to 15% to 18%.”

The antibacterial envelope, which is designed to wrap around an implantable cardiac device and keep it stable in the pocket while also decreasing infection risk, is constructed of a multifilament mesh with an absorbable polymer mixed with two antibiotics — minocycline and rifampin — that are released in the pocket for 7 days, and it is fully absorbed after 9 weeks.

“In order to determine whether the envelope could reduce major device-related infection rates, we conducted a global study that included nearly 7,000 patients from 181 centers in 25 countries performed by 776 implanting physicians. We wanted to be as inclusive of all types of practices as possible,” Tarakji told Cardiology Today.

Future considerations

Tarakji said the electrophysiology community is excited about the WRAP-IT results because given the size of the size, it represents an opportunity to learn more about device infection in general.

“We’re going to look into all of the clinical variables that we have, in addition to all procedural characteristics,  to see if we can develop models to predict which patients are likely to develop infection,” Tarakji said.

Cost is another area of concern, he added.

“With the small event rate, the cost of the envelopes is going to come up, and that’s a healthy discussion to have. It’s difficult to have a discussion about cost-effectiveness if you don’t have evidence that an intervention is actually effective and safe. So now that we know the envelope is effective and safe, it’s natural and expected to have that discussion about cost,” Tarakji said. “That’s something else that WRAP-IT will have provided us with — an opportunity to prospectively assess as accurately as we can the true cost of infection.”

For now, though, Tarakji and colleagues said they remain enthusiastic about the trial’s success.

“In other subspecialties in cardiology, mega-trials involving thousands and thousands of patients is normal, but it’s not like that for the electrophysiology community, so we’re very proud. We’re a smaller society, but this shows we can do it if we want to,” Tarakji told Cardiology Today. – by Melissa Foster with additional reporting by Darlene Dobkowski

References:

Tarakji KG. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.

Tarakji KG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1901111.

Disclosures: The study was funded by Medtronic. Tarakji reports he receives nonfinancial support from Cleveland Clinic C5 and Medtronic; personal fees from Medtronic; and personal fees from AliveCor.

Editor’s Note: This article was updated on March 19, 2019 to correct some data-related errors. The Editors regret the errors.

Khaldoun G. Tarakji
Khaldoun G. Tarakji

NEW ORLEANS — Wrapping cardiac implantable devices in an antibiotic-eluting envelope, in addition to standard infection prevention strategies, reduced the risk for major device-related infections by approximately 40%, researchers reported at the American College of Cardiology Scientific Session.

Researchers for the WRAP-IT study randomly assigned 6,983 patients undergoing a cardiac implantable electronic device (CIED) pocket revision, generator replacement or system upgrade or undergoing initial implantation of a cardiac resynchronization therapy defibrillator to a device wrapped in a bioabsorbable antibacterial envelope (Tyrx, Medtronic) or standard-of-care strategies to prevent infection.

Infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence or death occurred at a low rate of 1.2% in the standard-of-care group. However, at 0.7%, the rate was even lower in the envelope group (HR = 0.6; 95% CI, 0.36-0.98), whereas procedure-related or system-related complications were comparable in the two groups (envelope group, 6%; control group, 6.9%; P < .001 for noninferiority), Khaldoun G. Tarakji, MD, MPH, associate section head of cardiac electrophysiology at the Cleveland Clinic Heart and Vascular Institute, said during his presentation of the data.

“The results essentially show that the envelope is safe and effective and also did not increase complication rates,” he told Cardiology Today.

Effective across subgroups

For the study, Tarakji and colleagues defined infections as superficial cellulitis within the region of the pocket with at least one incidence of erosion, drainage, deep pocket infection, persistent bacteremia or endocarditis. For infections to be considered major, they had to lead to system removal, including the device and leads, or any invasive procedure, such as pocket revision or extended antibody suppressive therapy, which was mainly for patients who were not candidates for lead extraction. All other infections were classified as minor.

Wrapping cardiac implantable devices in an antibiotic-eluting envelope, in addition to standard infection prevention strategies, reduced the risk for major device-related infections by approximately 40%, researchers reported at the American College of Cardiology Scientific Session.
Source: Adobe Stock

The researchers found that approximately 75% of major infections were pocket infections. When looking at pocket infections alone, Tarakji said, there was a 61% RR reduction in major infections with use of the envelope over 12 months.

“We followed patients for a minimum of 12 months. However, we continued to follow-up all patients through the whole follow-up duration. Again, it seems like the effect of the envelope was sustained over time, with an event rate of 1.3% in the envelope group vs. 1.9% in the control arm at 36 months,” he said during his presentation. “However, after multiple comparison adjustment, the adjusted P value was not significant for this endpoint.”

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In subgroup analyses, it appears the envelope’s effects were consistent across subgroups, including age, sex, comorbidities and device type, he added.

“This study provides comprehensive data on CIED-related infection and strong evidence for the use of the envelope for infection prevention in this patient population,” Tarakji said.

The study was not without limitations, he said, including that only one manufacturer’s device was used, which may have affected the nature of enrollment.

“The envelope itself has been commercially available and that may have led to some selection bias in participation with the trial,” Tarakji said.

Patients were enrolled from 2015 to 2017. The mean age was 70 years and 28% were women. Notably, patients were excluded if they were at exceptionally high risk for infection due to special circumstances, such as patients on dialysis or those who had an infection within the previous 12 months.

Challenge of device-related infections

Major device-related infections in patients undergoing device implantation procedures, including pacemakers and implantable cardioverter defibrillators, occur in 1% to 4% of these procedures, based on prior data, according to Tarakji.

“While the rate is small, the consequences could be serious and sometimes catastrophic,” he said during his presentation. “When you have a diagnosis of device infection, the management requires removal of the device and the leads, in addition to extended antibiotic therapy and longer hospitalization. And, despite going through all of the proper management steps, estimated 30-day mortality is still about 4% to 5% and 12-month mortality can be up to 15% to 18%.”

The antibacterial envelope, which is designed to wrap around an implantable cardiac device and keep it stable in the pocket while also decreasing infection risk, is constructed of a multifilament mesh with an absorbable polymer mixed with two antibiotics — minocycline and rifampin — that are released in the pocket for 7 days, and it is fully absorbed after 9 weeks.

“In order to determine whether the envelope could reduce major device-related infection rates, we conducted a global study that included nearly 7,000 patients from 181 centers in 25 countries performed by 776 implanting physicians. We wanted to be as inclusive of all types of practices as possible,” Tarakji told Cardiology Today.

Future considerations

Tarakji said the electrophysiology community is excited about the WRAP-IT results because given the size of the size, it represents an opportunity to learn more about device infection in general.

“We’re going to look into all of the clinical variables that we have, in addition to all procedural characteristics,  to see if we can develop models to predict which patients are likely to develop infection,” Tarakji said.

Cost is another area of concern, he added.

“With the small event rate, the cost of the envelopes is going to come up, and that’s a healthy discussion to have. It’s difficult to have a discussion about cost-effectiveness if you don’t have evidence that an intervention is actually effective and safe. So now that we know the envelope is effective and safe, it’s natural and expected to have that discussion about cost,” Tarakji said. “That’s something else that WRAP-IT will have provided us with — an opportunity to prospectively assess as accurately as we can the true cost of infection.”

For now, though, Tarakji and colleagues said they remain enthusiastic about the trial’s success.

“In other subspecialties in cardiology, mega-trials involving thousands and thousands of patients is normal, but it’s not like that for the electrophysiology community, so we’re very proud. We’re a smaller society, but this shows we can do it if we want to,” Tarakji told Cardiology Today. – by Melissa Foster with additional reporting by Darlene Dobkowski

References:

Tarakji KG. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.

Tarakji KG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1901111.

Disclosures: The study was funded by Medtronic. Tarakji reports he receives nonfinancial support from Cleveland Clinic C5 and Medtronic; personal fees from Medtronic; and personal fees from AliveCor.

Editor’s Note: This article was updated on March 19, 2019 to correct some data-related errors. The Editors regret the errors.

    Perspective
    Joseph A. Hill

    Joseph A. Hill

    This study is interesting because it was a large, multinational, randomized controlled trial in the electrophysiology space, which is rare. Moreover, the researchers demonstrated the benefit of this antibacterial envelope in a terrible event that occurs rarely — about 1% of the time — and yet they enrolled nearly 7,000 patients and were able to show a 40% decline. To see a robust signal when you are starting with a small probability is impressive.

    In light of these data, I see little downside to using this envelope in practice. The researchers appropriately avoided enrolling high-risk patients because they wanted to target infection at the site of device implantation rather than another infection that is circulating from elsewhere in the body. In practice, we, of course, would have to target the use of this envelope to patients who fall into the same categories as the those included in this trial.

    Another impressive aspect of this trial is the low device infection rate, even though it was conducted at 181 centers in 25 countries. It speaks to the kind of care that these providers offer and the rigor with which they operate. We have seen in many cases across cardiology subspecialties where what goes on in one country is a little different than what goes on in another.

    There are still a few questions about the data. For instance, in terms of the infections that did occur, were they resistant to the antibiotics that were impregnated into the envelope? That answer is unknown at this point. Also, cost is important. It is commercially available, but I am uncertain of how expensive it is, and that could be a potential barrier to its increased use in this space.

    • Joseph A. Hill, MD, PhD
    • Chief of Cardiology, UT Southwestern Medical Center
      Director, UT Southwestern Medical Center's Harry S. Moss Heart Center
      Professor, Department of Molecular Biology, UT Southwestern Medical Center
      Editor-in-Chief, Circulation

    Disclosures: Hill reports no relevant financial disclosures

    Perspective
    Arnold H. Seto

    Arnold H. Seto

    This was a 6,983-patient study using Medtronic’s Tyrx antibiotic envelope, in a population of patients felt to be at increased risk for CIED infection, including patients undergoing CIED generator replacement, lead revision or CRT-D system. The primary outcome, infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence or death within 12 months, occurred in 0.7% of the antibiotic envelope group compared with 1.2% of control group (P = .04).

    The WRAP-IT study is important, especially considering the recent inability of the large 19,000-patient PADIT trial (Krahn AD, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.09.068) to show a statistically significant difference in CIED infection rates with an aggressive antibiotic regimen including vancomycin with cefazolin, bacitracin and oral cefalexin. For patients at high risk, there are, thus, limited evidence-based options for prevention of infection. Fortunately, the rates of infection are quite low, generally around 1% or less, even in higher-risk populations.

    Like other studies with low event rates, the study results are statistically fragile with a low incidence of the primary endpoint — an increase of just one infection in the experimental group would make the results statistically nonsignificant. The supplementary appendix indicates the same since the “as-treated” analysis has a nonsignificant P value of .052. The lack of blinding among the investigators risks miscounting of events, and miscounting just one event would suffice to make the results nonsignificant.

    Finally, although prior cost-effectiveness studies have suggested that the Tyrx envelope would be cost-effective in patients with estimated infection rates of greater than 1.4%, both the WRAP-IT and PADIT trials have shown that the actual rate of infection is less than that for most patients. Even for the high-risk patients in the WRAP-IT study, the number needed to treat was 200. At an acquisition cost of $800 to $1,000, the $200,000 needed to prevent one device infection exceeds most estimates of treatment cost of $44,000 to $83,000 for such infections.

    The WRAP-IT study demonstrates a benefit of the Tyrx antibiotic envelope to prevent device infection, but unless the cost decreases, device implanters should reserve it for patients at even higher risk of device infection than the patients in the WRAP-IT trial. Such patients might include those with dialysis, chronic indwelling catheters, prior infection or other risks for infection on top of the known risks of multiple leads, ICD implant, generator change and device revision.

    • Arnold H. Seto, MD
    • Chief of Cardiology Tibor Rubin VA Medical Center
      Long Beach, California

    Disclosures: Seto reports no relevant financial disclosures.

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