(Circulation. 1995;92:2935-2939.)
© 1995 American Heart Association, Inc.
Articles |
Steroid Elution Improves the Stimulation Threshold in an Active-Fixation Atrial Permanent Pacing Lead
A Randomized, Controlled Study
From the Cardiology Section, Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC (G.H.C.); Johns Hopkins University, Baltimore, Md (J.A.B.); The University of Oklahoma, Oklahoma City (D.R.); Baylor College of Medicine, Houston, Tex (W.S.); Mercy Hospital, Des Moines, Iowa (W.B.J.); Washington University, St Louis, Mo (H.H.); and Medtronic Inc, Minneapolis, Minn (L.T., M.Z.).
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Abstract |
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Background Prior work suggests that the addition of a steroid-eluting reservoir to a passive-fixation permanent pacemaker lead improves the stimulation threshold; however, no large randomized study has addressed this issue. Over the last several years, there has been an increase in enthusiasm for the use of active-fixation permanent pacemaker leads for various reasons in spite of the generally accepted notion that active-fixation leads have higher stimulation thresholds.
Methods and Results This multicenter, randomized, controlled study examined the difference in performance between a standard active-fixation atrial lead (Medtronic model 4058) and a steroid-eluting lead (Medtronic model 4068). Stimulation thresholds were obtained in a four-point strength-duration fashion. Evaluations of sensing and impedance were performed as well. These evaluations were performed at implantation, at weeks 1 through 4, and at weeks 6, 12, 24, and 52. Stimulation thresholds were significantly better in the steroid lead than in the nonsteroid lead at each measurement point from 1 week to 12 months. The mean 1.6-V stimulation threshold at 12 months was 0.19±0.2 ms in the steroid lead and 0.41±0.30 ms in the control lead. No acute peaking was observed with the steroid lead, whereas significant peaking was observed with the control lead. There was no difference in long-term sensing or impedance.
Conclusions Inclusion of a steroid-eluting reservoir in an active-fixation permanent pacing lead improved stimulation thresholds in both the subacute and chronic periods and therefore should extend pulse-generator longevity.
Key Words: pacemakers • electrical stimulation • trials
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Introduction |
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Performance of the leads is the most important factor determining the safety and longevity of permanent pacemaker systems. Two types of transvenous leads are currently in use: those with a passive-fixation mechanism and those with an active-fixation mechanism. It is generally accepted that active-fixation leads have higher stimulation thresholds than do passive-fixation leads because of the trauma associated with implantation of the active-fixation leads.1 However, over the past several years, there has been an increase in enthusiasm for the use of active-fixation permanent pacemaker leads for several reasons. Passive-fixation leads generally require placement in the atrial appendage, which may be technically difficult in patients with prior cardiac surgery or congenital heart disease. The use of active-fixation leads allows atrial mapping and placement in areas that are unsuitable for passive-fixation leads.2 Use of the lateral atrial wall for lead implantation has become routine in many centers, and some centers use active-fixation leads exclusively.3 Others have suggested that active-fixation leads reduce the incidence of dislodgments.1 Pediatric cardiologists and those physicians caring for adults with congenital heart disease have found active-fixation leads to be indispensable.4 In many cases, they allow patients who otherwise would have required epicardial systems to undergo transvenous implantation.5 6 These and other factors have supported the use of active-fixation atrial leads despite the generally accepted notion that these leads have poorer stimulation thresholds than passive-fixation leads.
Although there are no large randomized studies on this subject, several small studies have suggested that steroid elution improves the subacute and chronic thresholds of passive-fixation electrodes.7 8 9 10 11 These leads have become available generally and have widened the gap in performance between passive-fixation and active-fixation leads. Given the beneficial effect on stimulation threshold with the use of passive-fixation leads, a novel active-fixation steroid-eluting lead was developed (Medtronic model 4068). In a multicenter, randomized, controlled trial, we compared this lead (used in the atrium) with a similar active-fixation lead (Medtronic model 4058) that did not contain a steroid-eluting reservoir. This is the first report of a multicenter randomized trial comparing a steroid-eluting lead with a similar control lead.
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Methods |
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Devices
The investigational lead (Medtronic model 4068) was a bipolar, transvenous, extendable/retractable, screw-in lead with a steroid-eluting reservoir included in the fixation apparatus. The insulation material was polyurethane. The fixation mechanism was a Bisping-type screw that was electrically active.12 A reservoir in the tip of the lead contained dexamethasone sodium phosphate (1 mg). The control lead (Medtronic model 4058) was a similarly constructed active-fixation lead without a steroid-eluting reservoir. A variety of pulse generators capable of performing pulse-width thresholds at or near 0.8, 1.6, 2.5, and 5.0 V were used.
Study Design
This study was a randomized, controlled study using a 3:1 ratio
between the investigational lead and the control lead. Randomization
was performed at the time of implantation by use of the blinded
envelope method. A center-based, variable-sized,
balanced-block randomization scheme was used, which resulted in
each center having similar ratios of investigational versus control
leads throughout the study period. The study was approved by the
Institutional Review Board of each of the participating centers.
Patients
The study group comprised 254 patients (101 [40%] female, 153
[60%] male) who were undergoing either atrial or dual-chamber
pacemaker implantation. Mean age was 67.3 years. Each subject gave
written informed consent in accordance with the requirements of the
local Institutional Review Board. Indications for pacing were typical
for a dual-chamber pacemaker population. Seventy-seven percent
of the leads were implanted via the subclavian vein, 23% via the
cephalic vein, and none via a jugular approach. Implantation began in
February 1992. All data acquired by August 1994 are included in the
present report.
Lead Function Analysis
Evaluations of lead function were performed at the time of
implantation; 1, 2, 3, 4, and 6 weeks after implantation; 3 and 6
months after implantation; and every 6 months thereafter.
Four-point strength-duration curves were obtained by
measuring pulse-width stimulation thresholds at 5.0, 2.5, 1.6, and
0.8 V. Analysis of sensing function and impedance was also
performed. Notations of complications or medical events were made.
Effect on Pulse-Generator Longevity
Estimation of the effect of programming changes on longevity is
easily quantifiable in pulse generators that report battery current.
The current is reported in microamperes, and if one knows the
deliverable battery capacity (in ampere-hours), the expected life
span of the pulse generator can be calculated easily. Using the mean
data from the study, one can model the energy consumption in a typical
pulse generator and estimate the effect on longevity. Two separate
analyses were conducted for the study. The single-chamber
analysis used a Medtronic model 8416 single-chamber,
rate-responsive pacemaker. It was assumed that the pulse generator
could deliver 85% of its battery capacity. It was also assumed that
patients would pace 100% of the time at 70 beats per minute in the
AAIR mode at the base rate. The pulse generator used for the
dual-chamber model was the Medtronic model 7950 dual-chamber,
rate-responsive pacemaker. For dual-chamber calculations, the
same assumptions were used, substituting the DDDR mode.
Ventricular output was set to 2.5 V at 0.4 ms, a setting
that is achieved easily with a considerable safety margin by use of
passive-fixation steroid leads.13 The voltage settings
used on the atrial channel for both models were a pulse width of 3
times the stimulation threshold.14 A 600-
noninductive
impedance source was used to simulate the patient load.
Statistical Analysis
The pulse-width strength-duration curves, impedances,
and P-wave amplitudes were measured at each evaluation and expressed as
mean±SD. Figs 1
and 2 display the
mean±SEM. To accommodate different follow-up schedules of the
patients (ie, intensive phase versus general phase), Student's
t tests were conducted at each follow-up point.
Analysis of the pulse-width threshold was evaluated at
settings of 1.6 and 2.5 V. The Hochberg multiple comparison procedure
was used to account for multiple inference.15 Atrial
dislodgment rate was compared by use of a 
2
test.
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Results |
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Sensing Function
For the steroid lead, the mean P-wave amplitude was 4.12±2.53 mV at implantation and 3.50±1.75 mV at 12 months. The control lead displayed a mean implantation P wave of 4.04±2.31 mV and was 3.78±1.33 mV at 12 months. Although there were no significant differences in the P wave at implantation or chronically, the P wave was significantly stronger in the steroid lead in weeks 1 and 2 (P
.006). This was due to the diminution of the P wave in
the nonsteroid leads and the steady P wave in the steroid group.
Impedance
The mean impedance of the steroid-eluting lead at implantation
was 623±125 compared with 589±92 for the control lead
(P=.03). At 12 months, mean impedance of the steroid lead
was 669±107 and of the control lead was 633±132
(P=NS).
Stimulation Function
Fig 1
displays pulse-width thresholds over time for the
steroid lead versus the nonsteroid lead at 1.6 V. At implantation, mean
stimulation threshold was 0.12±0.12 ms for the steroid lead and
0.13±0.11 ms for the control lead (P=NS). At 12 months,
mean threshold was 0.19±0.20 ms for the steroid lead and 0.41±0.3 ms
for the control lead (P<.007). At each measurement point
after implantation, the steroid lead had a significantly lower
stimulation threshold than did the control lead (P<.007).
Similar data for measurements at 2.5 V are displayed in Fig 2. Again,
there was a significantly better stimulation threshold observed in the
steroid group compared with the nonsteroid group at each measurement
point after implantation. Statistical comparisons between the two leads
are difficult at 5.0 V and 0.8 V because at 5.0 V many of the leads did
not lose capture at the minimum pulse width of the pulse generators
used (0.06 ms) and at 0.8 V some of the leads failed to capture at a
maximum pulse width (1.5 ms).
Acute Peaking
The most striking difference between the stimulation thresholds of
the control lead and those of the investigational lead was the lack of
an acute increase in threshold with the use of the steroid lead. At 2.5
V, the mean stimulation threshold of the control lead increased from
0.07±0.04 ms at implantation to 0.31±0.29 ms at 1 week, whereas the
steroid lead only increased from 0.09±0.12 to 0.13±0.16 ms. Fig 3 displays the mean ratio of peak stimulation threshold
to the threshold at implantation by use of the 2.5-V stimulation
thresholds. This ratio is significantly lower for the steroid lead. The
duration of peaking was strikingly different as well. At 2.5 V, the
steroid lead threshold increased to 0.13 ms at 1 week but returned to
chronic values by week 2, whereas the control lead threshold remained
significantly above the chronic level until week 12.
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Complications
Complication rates did not differ significantly between the
steroid and control leads. The dislodgment rate was 2% in the steroid
group and 0% in the control group (P=.58). There were no
atrial perforations.
Hypothetical Energy Savings
Using the mean data from the study, one can model the energy
consumption in a typical pulse generator and estimate both energy
savings and longevity improvement. The mean chronic 2.5-V
pulse-width threshold was 0.11 ms in the steroid lead. This
suggests that a setting of 0.30-ms volts would provide for an adequate
safety margin.14 Given these voltage settings and our
previously mentioned assumptions, the battery current for the steroid
lead would be 8.6 µA. Since the mean threshold for the nonsteroid
lead was 0.19 ms, a setting of 0.60 was chosen. The battery current at
these settings was 10.2 µA. Estimated longevity based on our
assumptions would be 18.0 years for the steroid group and 15.2 for the
control group, a difference of 2.8 years. With use of the dual chamber
model noted above, the following battery currents are obtained: 12.4
µA for the steroid atrial lead and 13.6 µA for the control atrial
lead. This results in predicted longevity of 14.4 years for the steroid
lead and 13.1 years for the control lead control, a difference of 1.3
years.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Since the development of transvenous electrodes, there have been a number of important advances. Various fixation mechanisms have made leads less likely to dislodge. New electrode materials have improved performance in both stimulation and sensing functions. This has allowed the use of lower energy for stimulation, and therefore pulse generator size has decreased while an acceptable longevity has been maintained. The development of active-fixation leads has facilitated the placement of transvenous lead systems in many patients in whom passive-fixation lead placement would have been difficult or impossible.
Steroid Leads
Although there are no prior large-scale, randomized,
controlled trials examining the efficacy of steroid elution in
permanent pacemaker leads, several small, randomized, controlled trials
have demonstrated that the subacute and chronic thresholds of leads
that include a steroid-eluting reservoir are significantly improved
over similar leads without steroid.7 8 9 Other large,
nonrandomized studies have suggested similar results.10 11
An uncontrolled study of permanent epicardial leads yielded similar
results.16 17 It has been demonstrated that an adequate
safety margin for capture can be achieved in the majority of patients
with passive-fixation, steroid-eluting endocardial electrodes
with a modest pulse width at 1.6 V, resulting in substantial
improvement in longevity.17 Before this study, however, no
large, multicenter, randomized trial had compared the use of steroid
elution with a similar lead without steroid.
Comparison With Passive-Fixation Steroid Leads
Although there are no large studies of passive-fixation atrial
leads, reasonable studies are available on the use of such leads in the
ventricle. One study suggested that the typical thresholds are 
0.21
ms at 0.8 V.13 Although these thresholds are lower than
those seen in the present study, they are similar for practical
purposes. Using standard safety margins,14 one would
program the typical patient in the present study to receive 2.5 V
and 0.3 ms or 1.6 V and 0.6 ms. To take full advantage of the
passive-fixation steroid lead, the pulse generator would have to be
programmed to 1.6 V and 0.4 ms. This is lower than the "comfort
level" of most physicians and for practical purposes, it is rare
that output settings are decreased to below 2.5 V and 0.5 ms.
Study Limitations
This study was performed in centers with considerable experience
in pacing and particularly in the placement of active-fixation
electrodes. The possibility exists that the stimulation thresholds
achieved will not be generalizable to the pacing population in general;
however, this should not affect the relative performance of the
steroid versus the nonsteroid lead. The battery longevity calculations
are somewhat arbitrary but represent easily obtainable values.
These values would be very much affected by the type of
ventricular lead chosen and by efforts made to conserve
energy through reprogramming. It is likely that much better results
would be seen if a steroid lead was used and the output was programmed
to twice the voltage threshold at a given pulse width. It is also
likely that the use of a nonsteroid lead would result in significantly
poorer longevity.
Conclusions
These data provide compelling evidence that the inclusion of a
steroid-eluting reservoir in an active-fixation permanent
pacing lead improved stimulation thresholds in both the subacute
and chronic periods. Furthermore, the data suggest that if the steroid
lead were substituted for the control lead and the device programmed
accordingly, a significant increase in pulse generator longevity could
be expected.
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Acknowledgments |
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This study was sponsored and supported by a grant from Medtronic Inc, Minneapolis, Minn.
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Footnotes |
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Reprint requests to George H. Crossley, MD, Cardiology Section, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1045. E-mail gcrossle@isnet.is.wfu.edu.
G.H.C. is an investigator and consultant to Medtronic Inc on this and other projects. J.A.B. serves as Chairman, Food and Drug Administration Panel on Cardiac Devices. D.R. is an investigator and consultant to Medtronic Inc on other projects. L.T. and M.Z. are employees of Medtronic Inc.
1 A complete list of the investigators and coordinators for the study is provided in the "Appendix." 
Investigators and Coordinators for the Medtronic 4068
Study
Yale-New Haven Hospital, New Haven, Conn: Bill Batsford, MD;
Gini Elwood.
Mount Sinai Medical Center, New York, NY: Jorge L. Camunas, MD; Unsoon Shagong, RN.
Thomas Jefferson University Hospital, Philadelphia, Pa: Arnold Greenspon, MD; Michelle Romash, RN.
Baystate Medical Center, Springfield, Mass: James Kirchhoffer, MD; Laura Liucci, RN.
Brigham & Women's Hospital, Boston, Mass: Gary Mitchell, MD; Bernadette Stanton-Mayor, RN; and Anne Spector, RN.
Children's Hospital, Boston, Mass: Walter J. Gamble, MD.
Blake Hospital, Bradenton, Fla: Robert Batey, MD; Steve Erickson (follow-ups); Mark Sweesy; Debby Bunton; and Beth McHargue.
Johns Hopkins University, Baltimore, Md: Jeffrey Brinker, MD; Billie-Jo Kreps.
NC Baptist Hospital/Bowman Gray School of Medicine, Winston-Salem, NC: George H. Crossley, MD; Tony W. Simmons, MD; Wesley K. Haisty, Jr, MD; David M. Fitzgerald, MD; Kathleen D. O'Brien, RN; and Lisa Kiger, RN.
Baptist Montclair Medical Center, Birmingham, Ala: Russell Reeves, MD; William R. Harrison, MD; Nancy Self, RN; and Melisa Lail, RN.
Illinois Masonic Medical Center, Chicago: Marilyn Ezri, MD; Susan Donahue, RN.
Barnes Hospital, St Louis, Mo: Bruce Ferguson, MD; Dennis Fogarty, PA.
Mercy Hospital, Des Moines, Iowa: W. Ben Johnson, MD; Amy Leiserowitz, RN.
William Beaumont Hospital, Royal Oak, Mich: James Stewart, MD; Lori Bell, RN.
Seton Medical Center, Austin, Tex: Gerald A. Baugh, MD; and Corinne Wise.
St Francis Hospital, Tulsa, Okla: James Higgins, MD; Michelle Raby, RN; Martha Thompson, RN.
Methodist Hospital, Lubbock, Tex: Howard Hurd, MD; Melanie Quijada.
University of Oklahoma Hospital, Oklahoma City: Dwight Reynolds, MD; Roberta Kendall, RN.
Methodist Hospital, Houston, Tex: William Spencer, MD; Mary Freeman; and Cindy Kirkpatrick.
Mercy Hospital San Diego, Calif: Jerrold Glassman, MD; Fred McDonald.
Long Beach Memorial Hospital, Calif: John Messenger, MD; Arlene Rylaarsdam.
Central Cardiology Medical Clinic, Bakersfield, Calif: Peter Nalos, MD; Marilyn Williams.
Sacred Heart Medical Center, Spokane, Wash: David Oakes, MD; Steve Edwards, RN.
Received May 30, 1995; accepted July 7, 1995.
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