According to the National Inpatient Sample database of 4,144,683 device-related procedures, cardiovascular implantable electronic device (CIED) procedures due to related infections increased 135% (from 1.45% to 3.41%) in the United States over the 12 years spanning 2000-2012.¹ As such, we considered WRAP-IT (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial) with interest.

Tarakji et al. reported results from WRAP-IT,² a prospective, randomized, controlled, clinical trial that evaluated 6,983 patients, of whom, 3,495 were randomized to an absorbable, multi-filament mesh antibacterial envelope and 3,488 to a control group. The study included 646 implanting physicians at 181 study locations. There were 30 major infections in 25 patients in the envelope group and 45 major infections in 42 patients in the control group (confidence interval 0.36-0.98; p = 0.04). Thus, 0.7% in the envelope group and 1.2% in the control group reached the primary endpoint of a major CIED infection related solely to localized pocket infections within 12 months versus a paradoxical, numerically larger, number of bacteremia and endocarditis cases in the envelope versus the control group.

So, is it now time to consider the antibacterial envelope touted to prevent CIED infections? We do not think so. We find the results from WRAP-IT insubstantial, unconvincing, clinically meaningless, financially bereft, and diversionary.

A Glaring Weakness of WRAP-IT

A key issue, clear to any rational clinician involved with patients who have CIED implants, is that the 40% relative risk reduction utilizing the envelope is a canard that overemphasizes the potential importance of the envelope. The absolute risk reduction was only 0.5%, meaning that the number needed to treat to reduce 1 pocket infection was 200. Thus, 199 would derive no benefit from their implanted envelope. A large population was needed to power the trial properly, and even then the study barely squeaked by as significant with a confidence interval nearly spanning 1.0 and a p-value of 0.04. This weakness barely uncovers issues of major concern with WRAP-IT.

The Outcome Measure Is Questionable

Although notable, the primary endpoint—a major CIED infection within 12 months after implant that resulted in system removal, treatment with long-term antibiotic therapy, or death—ultimately may not be that important. The only reported, substantiated true measure of infection—endocarditis or bacteremia—was not reduced. This endpoint included an invasive procedure (i.e., the pocket opening without system removal and treatment with antibiotic therapy), but the severity of the infections that actually occurred during this procedure remain unknown. A pocket revision does not equate to infection. Importantly, there was no significant difference in death between groups (hazard ratio for death was 0.96; confidence interval 0.83-1.11). A pocket infection can be treated and, although potentially harmful, does not occur very often. There were no differences in risk of death between the 2 groups (only 3 in each group thought due to device-related infection), so what was the real value? Reduction in days in the hospital?

Was It Really a Major Infection?

Even if a major infection was thought to be present, was it? Was device removal or revision necessary? The decision was not necessarily based on culture results. There may be a bias in favor of those with envelopes implanted because the study was not blinded. Because we cannot determine the cumulative severity of the infections in both groups, adjudication of an extra patient or two sways the barely significant study results. Thus, the information is simply not compelling. Only a small number of outcome measures were present in a very large population. Further, the envelope could have masked and/or facilitated a more serious bacteremia event. As such, it may create harm.

Envelopes Cannot Prevent All Infections and Cannot Stop Infections Due to Sloppy Technique

The pouch cannot affect all CIED-associated infections. Device-related infections are due to device factors (e.g., plastic polymers), microbial factors (e.g., biofilm formation and microbial persistence), and host factors (e.g., renal failure, diabetes, and hematoma), among others.³

Fundamentally, CIED infections comprise the following types:

1. Metastatic hematologic spread of non-pocket infection to the leads (i.e., bacteremia from dialysis or other procedures)
2. Pocket erosion and subsequent infection
3. Pocket infection (acute vs. indolent)

There is no reason to believe type A or B infections would benefit from an antibiotic envelope. Regarding type C infections, risk for pocket infection is multifactorial and defined by the following:

• Poorly controlled diabetes and obesity
• Poor hygiene
• Poor surgical technique (postoperative hematoma, suture choice, staples vs. no staples, pocket cleansing, postoperative antibiotic infusions, incision site, and draping)
• Improper prophylactic antibiotic, either not properly infused or improper antibiotic selection (such as for methicillin-resistant staphylococcus aureus)
• Anticoagulant and antiplatelet use
• Time to first shower
• Wound closure (Steri-Strips, sulfadiazine bandages, op-site dressing)
• Skin prep (chlorohexidine vs. betadine)
• Hand washing (surgical scrub vs. catheterization laboratory scrub)
• Implantation location (catheterization laboratory vs. electrophysiology laboratory vs. operating room)

Prolonged time to complete an implant and improper and sloppy technique are potential causes of CIED infections. In a controlled clinical trial, less sloppiness may be present. Perhaps that is why the risk of infection in the control group is less than in the National Inpatient Sample database. Thus, the data may not be applicable to the general population of implanters and patients in need of a CIED. There is no reason to suspect that results from WRAP-IT apply to patients and implanters in general. Counting on an envelope to help when the skin is not cleansed properly is nonsensical and potentially dangerous.

Clustering of Infections

The study does not provide information about clustering of infections that may occur in specific users not based on the population being considered. It is clear, based on the number of centers involved and the number of investigators, the overwhelming majority did not have infections at all. Therefore, the envelope was useless for those centers and implanters. It is possible that clustering of infections occurred at centers in which scrupulous care was not taken to reduce the risk of infection by using proper techniques such as sterile procedures.

Although WRAP-IT may fail to identify benefit of the envelope at specific sites, it may identify risk factors for infection if they compare the centers with infection with those without infection.

A Diversionary Tactic

This study diverts attention from potential obvious causes for infection that may occur at select sites based on poor technique, including improper draping, prepping, handwashing, gloving, antibiotic utilization, and other technologies that are important for pristine surgical technique. Although data on these issues are scant, it is surprising that there is so much effort focused on an envelope that provides so little benefit when one does not address obvious issues that could be causing infection to improve or reduce infections markedly.

The presence of a pocket infection is not necessarily a justification to put an antibiotic envelope in a huge number of individuals who will not need it.

The envelope may divert our attention away from much more serious infections (bacteremia and endocarditis) that could be missed if an envelope reduces obvious localized pocket infections that could be treated earlier and more simply.

What About the Highest Risk Population?

The study does not address the highest-risk population. Patients undergoing generator replacement, system upgrade, with or without new leads, pocket or lead revision, or an initial procedure were included, but many high-risk patients were not, including those on hemo or peritoneal dialysis, those who had a heart transplant or ventricular assist device, those requiring long-term vascular access or immunosuppressive therapy, and those with prosthetic or endovascular infections. And yet those are the patients who may benefit the most. Also excluded were those who had their CIED pocket accessed within the past 365 days. Those at greatest risk for infections whom the envelope might actually help were specifically excluded. The results do not apply to excluded high-risk populations and must be considered only in the population tested. One way to limit the need for pulse generator replacement, and thus risk of infection, is to manufacture devices that last longer. Such devices are already on the market.

Cherry Picking

The population may have been cherry-picked. Besides excluding the highest-risk patients, the authors do not report how many patients had CIED implants at the various investigative centers excluded even in the lower-risk group.

The Control Group Is Suspect

Those randomized to the envelope were randomized before surgical implantation. This means that the implanting team may have intentional or unintentional bias affecting outcomes because the study was not placebo-controlled or blinded. This may have led to differences in implantation technique, pocket cleansing and antibiotic utilization before the procedure, as well as other specific features that can help reduce risk. Further, bias resulting in intervention on a pocket for drainage, wound dehiscence, hematoma, or erythema without culture data may have occurred. Thus, infection scrutiny after implant may have occurred.

For patients with no history of bacteremia or endocarditis, an adopted therapy must successfully reduce long-term risk of these most serious CIED infections. WRAP-IT did not show this with use of the envelope and may have shown just the opposite. Further, it cannot be assumed that the envelope will reduce the minimal long-term risk of these serious outcomes in "real-life" patients not entered into the study. More is not always better.

Subgroup Analysis

Subgroup analysis is difficult because the number of patients with specific medical problems such as renal dysfunction and diabetes was limited. Notably, however, women did not benefit from the envelope. It is also true that patients undergoing "low-power" CIED implants did not benefit from the envelope. Any claim that the study was underpowered is plain silly. The data simply are not compelling or even indicative of any value for this low-risk group. This is especially true for women.

A Financial Catastrophe

One must also consider the cost and the return from utilizing an envelope to help minimize pocket infections. Proper sterile technique, preoperative antibiotic use, speed of implantation, prevention of pocket hematomas and other known instigators of infection were completely ignored in this study, but proper technique does not cost much. Use of improper technique with a concomitant envelope will not necessarily reduce many (if any) infections, and yet the envelope's cost is inordinate enough to completely eliminate any profit for the hospital and/or ramp up extraordinary costs to the health care system. Doesn't health care cost enough already?

The incremental benefit of the envelope is minuscule, especially in light of other aspects of implantation technique that may be of much greater importance. Responsible scientific scrutiny, debate, and commentary can clarify benefit of a therapy, but early release publications like WRAP-IT might lead to widespread media coverage and endorsement and open the doors to exponentially ramping up the cost of care without providing real, substantial benefit. We are further concerned that there is inherent bias when the one that profits from a study like this is the company that sponsored the study. We are concerned that publication of these data may spur medical-legal suits if an infection occurs in a patient undergoing a CIED implant without an envelope. Publishing these data does a disservice to the medical community at large.

Let's Get Back to Reality

The clinical reality is that with or without an envelope, a careful implantation performed efficiently, effectively, and with pristine surgical technique will occasionally, but rarely, lead to an infection. The outcome much more likely will be excellent without an antibiotic envelope. Even if an infection ensues, antibiotic envelopes were not shown to make a difference in hard outcome measures such as death. The authors have not shown that patients who did not receive antibiotic patches had worse long-term outcomes other than the need for a new implantable device. The authors have not shown that patients who received antibiotic envelopes had fewer lead extractions, shorter infection-related hospitalizations when infections occurred, or lower cost overall.

To Sum It Up

WRAP-IT² compared an antibacterial envelope to no envelope in patients undergoing CIED implants. The results were barely statistically significant for major device-related infections but clinically insignificant. An astounding number of envelope implants are needed to reduce one major pocket infection, but other major outcomes do not favor the envelope. The data cannot be extrapolated to high-risk patients who were excluded. These data from WRAP-IT are not compelling and should not change practice. Scrupulous technique during implantation and in follow-up is far more important than use of an antibacterial envelope. Based on data from WRAP-IT, we do not recommend antibacterial envelope implants as a routine adjunct to CIED implantation.

References

1. Joy PS, Kumar G, Poole JE, London B, Olshansky B. Cardiac implantable electronic device infections: Who is at greatest risk? Heart Rhythm 2017;14:839-45.
2. Tarakji KG, Mittal S, Kennergren C, et al. Antibacterial Envelope to Prevent Cardiac Implantable Device Infection. N Engl J Med 2019;380:1895-905.
3. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458-77.

Keywords: Anti-Bacterial Agents, Anticoagulants, Antibiotic Prophylaxis, Bacteremia, Biofilms, Catheterization, Device Removal, Diabetes Mellitus, Drainage, Endocarditis, Endocarditis, Bacterial, Electrophysiology, Erythema, Health Care Costs, Heart Transplantation, Heart-Assist Devices, Hematoma, Inpatients, Methicillin, Methicillin-Resistant Staphylococcus aureus, Hospitalization, Follow-Up Studies, Obesity, Numbers Needed To Treat, Peritoneal Dialysis, Outcome Assessment, Health Care, Povidone-Iodine, Operating Rooms, Prospective Studies, Renal Dialysis, Renal Insufficiency, Research Personnel, Risk Factors, Sulfadiazine, Sutures, Risk, ACC Annual Scientific Session, ACC19

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