Antibiotic envelope worldwide trial for prevention of CIED infections trial Device - TYRX Medtronic NEJM March, 2019

1. WRAP IT
(Worldwide Randomized Antibiotic
Envelope Infection Prevention Trial)
Presented by:
Dr. Himanshu Rana

2. This article was published on March 17, 2019, at NEJM.org.

3. BACKGROUND
 Infections after placement of cardiac implantable
electronic devices (CIEDs) are associated with
substantial morbidity and mortality.
 There is limited evidence on prophylactic
strategies, other than use of preoperative
antibiotics, to prevent such infections.

4.  In a trial of 1000 consecutive CIED procedures at
a single center, iv administration of cefazolin
before procedure reduced the risk of infection by
81%.
 Unblinded, cluster-randomized, crossover trial
(Prevention of Arrhythmia Device Infection Trial
[PADIT]) was conducted to assess the effect of
incremental prophylaxis antibiotics before,
during, and after CIED procedure. The rates of
hospitalization due to infection were not
significantly reduced with incremental antibiotics

5. Trial device:
TYRX Absorbable Antibacterial Envelope,
Medtronic

6.  Multifilament knitted mesh
 coated with an absorbable polymer
 mixed with minocycline and rifampin,
 elutes the antibiotics into the local tissue for a
minimum of 7 days
 fully absorbed in approx. 9 wks.

7. Aim
To evaluate the safety & effectiveness of envelope
in reducing CIED infection as adjunctive therapy to
standard infection-prevention strategies

8. Trial design
 Multicenter, randomized, controlled, prospective,
singleblind, postmarketing, interventional clinical
trial.
 It compared the incidence of major CIED
infections through 12 months after implantation
among patients with/without absorbable
antibacterial envelope.
 Standard-of-care infection-prevention strategies
(preprocedure iv antibiotics & sterile technique)
used in all.

9.  Patients were randomly assigned in 1:1 ratio,
with stratification according to trial site & device
type (pacemaker or CRT-P vs. ICD or CRT-D)
 Patients were followed at hospital discharge & at
6-month intervals till all patients completed a
min. of 12 months follow-up.

10. Inclusion Criteria:
 Patient is planned to undergo at least one of the
following:
a) Patient having CIED & undergoing pacemaker
(including CRT-P), ICD or CRT-D replacement or
upgrade with a new Medtronic generator
i. Subjects planned to have leads added, or extracted &
added for upgrades can be enrolled OR
b) Patient will undergo a de novo Medtronic CRT-D system
implant per approved indications OR
c) Patient has existing study eligible Medtronic CIED & the
pocket was not accessed in last 365 days, and is
undergoing pocket or lead revisionNote:
Pacemaker (including CRT-P) randomizations were capped
at 25% of target sample size

11. Exclusion Criteria
 Known allergy to minocycline or rifampin or any other known
contraindications to TYRX envelope.
 Current therapy with chronic oral immunosuppressive agents or ≥
20mg/day of Prednisone or equivalent.
 Hemodialysis or peritoneal dialysis.
 Prior Cardiac transplantation or existing Ventricular Assist Device (VAD).
 Require long-term vascular access for any reason.
 Prior history of a CIED infection, other prosthetic device infection, or
endovascular infection, including endocarditis, in the past 12 months.
 Physical, clinical, or laboratory signs or symptoms consistent with an
active infection (including but not limited to pneumonia, urinary tract,
cellulitis, or bacteremia)
 Systemic lupus erythematous (SLE), because minocycline known to
aggravate this condition
 Female patient who is pregnant, or of childbearing potential and not
on a reliable form of birth control.
 Participation in another study that may confound the results of this study.

12. Definitions:
 CIED infection was defined as superficial cellulitis with
◦ wound dehiscence, erosion, or purulent drainage;
◦ deep incisional or pocket surgical-site infection that met the CDC and
Prevention criteria, independent of time from surgery;
◦ persistent bacteremia; or
◦ endocarditis.
 Major CIED infections were defined as infections that
resulted in
◦ CIED system removal,
◦ an invasive CIED procedure (e.g., pocket revision without removal),
◦ treatment with long-term antibiotic therapy (if the patient was not a
candidate for system removal) with infection recurrence after
discontinuation of antibiotic therapy, or
◦ death.
 CIED infections that did not meet one or more of the
criteria for major infection were classified as minor CIED
infections.

13. END POINT
 Primary end point
◦ Major CIED infection within 12 months after the
CIED procedure.
 Secondary end points were
◦ CIED procedure/system-related complications
within 12 months after the procedure,
◦ Major/minor CIED infection within 12 months, &
◦ Maj. CIED infection regardless of time of
occurrence.
 Death from any cause was a ancillary end
point of interest.

16. Procedure Characteristics
 The mean procedure time did not differ
significantly between the two groups (56.3±46.2
minutes in the envelope group and 55.0±48.0
minutes in the control group; between-group
difference, 1.3 minutes
 Though the envelope was not successfully
implanted in 10 procedures owing to limited
pocket space (successful in 99.7%).

17. Patient follow up
 During the 12-month follow-up, 181 system
revisions occurred in 153 patients in the
envelope group and 229 in 186 patients in the
control group

18.  Within 12 months after the index CIED
procedure, there were 30 major infections in 25
patients in the envelope group and 45 major
infections in 42 patients in the control group.

21. Subgroup Analysis
 Subgroup analysis was conducted to test for
interaction among various baseline variables for
the primary end point through 12 months.
 None of the differences between subgroups,
inclusive of age, sex, or baseline characteristics,
or high power v/s low power device were
significant.

23. Disscussion:
 Population of patients who were at increased risk for
CIED pocket infection, envelope was significantly
more effective at preventing infection than standard
care alone.
 efficacy objective was met, with 40% fewer patients
in the envelope group than in the control group
having a major infection.
 envelope was successfully implanted in 99.7% of
procedure attempts.
 The safety objective was met as envelope group did
not have a higher incidence of procedure/system-
related complications

24.  the use of the envelope may require dissection of
a slightly larger CIED pocket
 The beneficial effects of the envelope in
preventing major CIED infection in 12 months
were more pronounced in patients with high-
power than in low-power devices or an initial
CRT-D.

25. Limitations of this trial
 Use of immunosuppressive agents was not
balanced between the trial groups
 Periprocedure and postprocedure infection-
prevention strategies including antibiotic use
were not controlled
 Higher incidence of bacteremia and endocarditis
in the envelop group was not properly evaluated.
 This also further raises the concern about the
antibiotic resistance, the data for which is lacking

26. Thank you…!