Abstract
Background:
A global study designed to demonstrate the safety and efficacy of a transcatheter pacing system included 38 Japanese patients enrolled at 4 sites. Subgroup analysis to evaluate the performance of the leadless intracardiac transcatheter pacing system in Japanese patients was performed.
Methods and Results:
Safety and efficacy outcomes, patient and implant procedure characteristics, and patient and physician acceptability from the Japanese population were compared with those from outside Japan. Differences in patient characteristics, implant procedure characteristics and patient acceptability were observed. There were no major complications in Japanese patients and pacing thresholds remained low and stable throughout follow-up. There were no observable differences between Japanese patients and patients from outside Japan in the freedom from major complication rate at 12-months post-implant (100.0% vs. 95.7%, P=0.211) or physician acceptability.
Conclusions:
Although some differences in specific baseline characteristics, such as body size and pacing indication, and in implant procedure characteristics, including anticoagulation strategy and hospitalization period, were observed in the Japanese patients, transcatheter pacemaker performance was similar to that in the global trial. (Clinical Trial Registration: ClinicalTrials.gov ID NCT02004873.)
Permanent cardiac pacing is the only effective treatment for symptomatic bradycardia, and over 50,000 patients receive pacemakers in Japan annually.1
Traditional pacemakers consist of an electrical generator and one or more transvenous leads and have a history of over half a century; however, 1 in 8 patients experiences a complication.2,3
Complications include lead-related complications (2.4–5.5%), pocket-related complications (0.4–4.8%), pneumothorax (0.9–2.2%), or device infection (0.3–0.8%).2,3
Recently, the Transcatheter Pacing System (TPS, Medtronic plc, MN, USA) was introduced to overcome these lead- and pocket-associated problems. In a prospective global clinical study, including Japanese centers, the TPS was successfully implanted in 99.2% of 725 patients, and met prespecified safety and efficacy criteria.4
The freedom from major complications at 6-month post-implant among the 725 patients with a TPS implant attempt was 96.0%. The percentage of patients with a low and stable pacing capture threshold measured at 6 months post-implant was 98.3%. Similarly, through the 12 months post-implant, the freedom from major complications rate was 96.0% and pacing thresholds remained low and stable throughout the follow-up period.5
No significant inter-regional differences have been reported in traditional leaded pacing therapy, but the TPS is a novel device and requires a new implant procedure. The purpose of this study was to compare outcomes in the global study results between Japan and outside Japan.
Editorial p 1576
Methods
Study Design
The TPS global study was a prospective, non-randomized, single-arm, multi-site, international clinical study to evaluate the safety and efficacy of the TPS. The study design and primary results have been published previously.4–6
Patients
Enrolled patients met a class I or II guideline-based indication7–9
for de novo ventricular pacing with no restriction by comorbidity. All patients provided written informed consent. The protocol was approved by the institutional review board at each participating site and was also approved by associated national and local regulatory agencies.
Study Device
The TPS consists of single-use delivery catheter and pacemaker. The pacemaker is a miniaturized single-chamber ventricular pacemaker with a volume of 0.8 mL, a length of 25.9 mm, an outer diameter of 6.7 mm, and a weight of 2.0 g. It sits in a steerable delivery catheter and is inserted through a femoral vein using a 23-Fr introducer (Figure 1).
Follow-up and Endpoints
Successfully implanted patients had scheduled study visits at hospital discharge, 1, 3, and 6 months post-implant, and every 6 months thereafter. Adverse events and device function were evaluated at each follow-up visit. The primary safety endpoint was freedom from system-related or procedure-related major complications at 6 months, though for this report we also provide the safety data through 12 months as all the 12-month study visits were completed at the time of this analysis. Major complications were defined as events resulting in death, permanent loss of device function as a result of mechanical or electrical dysfunction, hospitalization, prolongation of hospitalization by at least 48 h, or system revision. The primary efficacy endpoint was the combination of a low (≤2 V at a pulse width of 0.24 ms) and stable (increase ≤1.5 V from the implant) pacing capture threshold at the 6-month visit; however, for this analysis, we focused on electrical performance through 12 months. Secondary and ancillary endpoints included accuracy of ventricular capture management feature, implant procedure characteristics, estimation of battery longevity and electrical performance. Additional endpoints included reporting on device-handling questionnaire responses by implanting physicians and satisfaction questionnaire responses by patients. For the device-handling questionnaire, the implanting physician selected one of the response choices (extremely difficult, difficult, neutral, easy, and extremely easy) for each question: (1) navigation of the delivery system to the right ventricle, (2) device deployment, (3) pull and hold test (used to verify device fixation, as previously described10
and (4) overall impression, following each implant procedure. For the satisfaction questionnaire, evaluated at the 3-month visit, the patient selected one of the response choices (very satisfied, satisfied, neutral, dissatisfied, and very dissatisfied) for each question: (1) recovery, (2) cosmetic appearance and (3) level of activity.
Statistical Analysis
The study protocol and sample size allowed for up to 3 planned interim analyses of the 2 primary endpoints when 300, 450, and 600 patients completed the 6-month visit. The study also had a prespecified long-term safety objective that occurred when all patients had the opportunity to complete the 12-month visit. Because the long-term safety assessment has been completed,5
the 12-month major complication free rates are reported. Baseline demographics, medical history, implant procedure characteristics, device-handling questionnaire, and the patient satisfaction questionnaire were compared between patients at the Japanese centers (Japan patients) and those outside Japan (“Outside of Japan” patients) using t-tests or the Wilcoxon rank-sum test (continuous variables) or Fisher’s exact test (discrete variables). The major complication rates through 12 months were compared between the Japan and Outside of Japan patients using a log-rank test. The accuracy of Micra’s ventricular capture management feature was compared between the Japan and Outside of Japan patients using Fisher’s exact test. The analysis cohort for the long-term safety endpoint included all patients with a Micra implant attempt. The analysis cohort for the secondary endpoint of ventricular capture management feature accuracy included all patients with pacing thresholds measured both manually and using Micra’s ventricular capture management feature at the 6-month visit. Electrical parameters were summarized at each study visit using means and standard deviations. Battery longevity was projected using Monte Carlo methods by combining bench-measured static current drain distributions combined with actual-use conditions obtained via 12-month device interrogation files, plus 6 half-hour telemetry sessions per year.
Results
Patients
A total of 745 patients were enrolled at 56 centers in 19 countries worldwide, and 726 patients underwent an implantation attempt. In Japan, 38 patients were enrolled at 4 centers and 36 patients underwent an implant attempt by 6 operators. The 2 patients left the study before pacemaker implantation was attempted because they did not meet eligibility criteria; 1 was likely to relocate during the follow-up and the other had a narrow femoral vein. The analysis included 726 patients (including 36 Japanese patients) who underwent pacemaker implantation, 695 patients (including 35 Japanese patients) who completed the 3-month visit, 684 patients (including 36 Japanese patients) who completed the 6-month visit, and 656 (including 36 Japanese patients) who completed the 12-month visit (Figure 2).
Baseline characteristics of the Japan and Outside of Japan patients are shown in
Table 1
and
Table 2. Japan patients were significantly shorter and smaller than the Outside of Japan patients (P<0.001). Pacing indication associated with atrial fibrillation (AF) was lower in Japan patients compared with Outside of Japan patients (42% vs. 65%, P=0.007). Of the Japan patients, 21 (58.3%) had indications unrelated to AF and included: sinus node dysfunction (n=15, 41.7%), atrioventricular (AV) block (n=5, 13.9%), and trifascicular block with presyncope (n=1, 2.8%). The rationales for single-chamber pacemaker selection in the Japan patients, which were not mutually exclusive, were: infrequent pacing (66.7%), old age (61.1%), persistent AF (41.7%), low activity (16.7%), post- or planned AV node ablation (5.6%), anatomical difficulty with atrial lead insertion (2.8%), serious comorbidity that affected prognosis (2.8%), and possible high risk of complications with a dual-chamber system (2.8%). None of the Japan patients had a history of cardiomyopathy and more Japan patients presented with congestive heart failure caused by bradycardia (39% vs. 17%, P=0.003). Fewer Japan patients had coronary artery disease compared with the Outside of Japan patients (11% vs. 29%, P=0.021).
Table 1.
Characteristics of the Patients at Baseline
| |
Japan
(n=36) |
Outside of Japan
(n=690*) |
P value† |
| Age (years) |
| Mean±SD |
78.2±10.0 |
75.7±11.0 |
0.19 |
| Min.−max. |
31–91 |
19–94 |
|
| Sex |
| Male, n (%) |
24 (66.7) |
403 (58.4) |
0.39 |
| Height (cm) |
| Mean±SD |
159.1±11.1 |
169.2±10.4 |
<0.001 |
| Min.−max. |
138–177 |
140–203 |
|
| Weight (kg) |
| Mean±SD |
58.8±12.5 |
80.0±18.1 |
<0.001 |
| Min.−max. |
39–84 |
37–155 |
|
| BMI |
| Mean±SD |
23.1±3.3 |
27.8±5.3 |
<0.001 |
| Min.−max. |
18–31 |
14–57 |
|
*Height and weight for 2 patients not available. †Calculated using Fisher’s exact test for discrete variables and t-test for continuous variables. BMI, body mass index; max., maximum; min., minimum; SD, standard deviation.
Table 2.
Characteristics of the Patients’ Medical Histories
| |
Japan
(n=36) |
Outside of Japan
(n=690) |
P value* |
| Pacing indication associated with AF |
41.7% |
65.1% |
0.007 |
| Cardiomyopathy |
0.0% |
11.7% |
0.026 |
| Congestive heart failure |
38.9% |
17.0% |
0.003 |
| Coronary artery disease |
11.1% |
29.1% |
0.021 |
| Hypertension |
69.4% |
79.1% |
0.21 |
| Myocardial infarction |
8.3% |
10.7% |
1.00 |
| Pulmonary hypertension |
2.8% |
11.7% |
0.11 |
| Valve dysfunction, tricuspid |
19.4% |
26.5% |
0.44 |
| COPD |
8.3% |
12.9% |
0.61 |
| Diabetes |
25.0% |
28.7% |
0.71 |
| Renal dysfunction |
30.6% |
20.0% |
0.14 |
| Chronic lung disease |
33.3% |
29.4% |
0.58 |
*Calculated using Fisher’s exact test for discrete variables and t-tests for continuous variables. AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease.
Procedural characteristics of the Japan and Outside of Japan patients are shown in
Table 3. All attempts at Micra implant were successful in the 36 (100%) Japan patients. Procedure time from introducer placement to introducer removal was longer in the Japan patients compared with the Outside of Japan patients (39.3±16.9 vs. 34.5±24.4 min, P=0.007). The location of the device was similar, and was positioned with £5 deployments in the majority of patients (88.9% vs. 95.8%; P=0.08) in both groups. Most patients were anticoagulated prior to the implant, and all Japan patients received intraprocedural anticoagulation, whereas only 49.9% of the Outside of Japan patients received anticoagulation during the procedure (P<0.001). Prior to sheath removal and hemostasis, an anticoagulation antagonist was used more frequently in the Japan patients (63.9% vs. 6.7%; P<0.001). Hemostasis with suture and manual pressure was the only closure method used in Japan patients, but was used less frequently in the Outside of Japan patients (100.0% vs. 51.8%; P<0.001). Time to ambulation and days of hospitalization for the implant were longer in Japan patients (18.6± 6.2 vs. 10.1±6.9 h; P<0.001 and 5.1±1.8 vs. 2.0±2.7 days; P<0.001, respectively).
Table 3.
Characteristics of the Implant Procedure
| |
Japan
(n=36) |
Outside of Japan
(n=684) |
P value* |
| Implant success rate, % |
100.0 |
99.1† |
|
| Procedure time, min‡ |
| Mean±SD |
39.3±16.9 |
34.5±24.4 |
0.007** |
| Median |
39.0 |
27.0 |
|
| Device location, n (%) |
| Apex |
23 (63.9%) |
452 (66.1%) |
0.68 |
| Septum/mid-septum |
13 (36.1%) |
214 (31.3%) |
|
| Other |
0 (0.0%) |
18 (2.6%) |
|
| No. of deployments ≤5, n (%) |
32 (88.9%) |
655 (95.8%) |
0.08 |
| Preprocedure OAC/antiplatelet use, n (%) |
28 (77.8%) |
446 (65.2%) |
0.15 |
| Intraprocedure anticoagulation, n (%) |
36 (100.0%) |
341 (49.9%) |
<0.001 |
| Anticoagulation antagonist, n (%) |
23 (63.9%) |
46 (6.7%) |
<0.001 |
| Closure method: manual pressure+suture, n (%) |
36 (100.0%) |
354 (51.8%) |
<0.001 |
| Time to ambulation (h), mean±SD |
18.6±6.2 |
10.1±6.9 |
<0.001 |
| Days of hospitalization for implant, mean±SD |
5.1±1.8 |
2.0±2.7 |
<0.001 |
*Calculated using Fisher’s exact test for discrete variables and t-test for continuous variables; **calculated using Wilcoxon rank-sum test. †Denominator: 690 patients outside of Japan with implant attempt. ‡Procedure time: from the beginning of introducer placement to the end of introducer removal. OAC, oral anticoagulant.
There were 5 complications related to the system or procedure experienced by 5 of the Japan patients (presyncope, incision site hematoma, incision site hemorrhage, pericardial effusion, and hypotension). None of these complications met the criteria for a major complication which was defined as an event resulting in death, permanent loss of device function, hospitalization, prolongation of hospitalization, or system revision. Presyncope occurred during the implant procedure, possibly caused by vagal reflex. Incision site hematoma and hemorrhage were related to the implant procedure and introducer. Pericardial effusion was classified as a complication because it required an invasive intervention (pericardiocentesis) for resolution. Hypotension was observed during the implant procedure and was an adverse effect of the sedative agent. The freedom from system- or procedure-related major complications through 12 months was 100.0% (95% confidence interval (CI) 90.3–100.0%) in the Japan patients and was not significantly different from Outside of Japan (95.7%, 95% CI 93.9–97.0%, P=0.211).
Electrical Performance
The average pacing capture threshold among Japan patients at both implant and the 12-month visit was 0.54 V compared with 0.63 V and 0.61 V for patients outside Japan (Figure 3A). The average R-wave amplitude among Japan patients at implant was 11.3 mV and 14.2 mV at 12-month visit compared with 11.2 mV and 15.1 mV, respectively, in patients outside Japan (Figure 3B). The average pacing impedance among Japan patients was 753 ohms at implant and 566 ohms at the 12-month visit compared with 722 ohms and 597 ohms, respectively, among patients outside of Japan (Figure 3C). Based on the use conditions of the 36 Japan patients through 12 months, mean estimated battery longevity was 12.5 years with a range of 8.1–14.5 years.
Responses to Device-Handling Questionnaire by Implant Physicians
Physicians’ responses to the questionnaire were similar in both groups (Table 4). The majority of physicians felt the navigation delivery was extremely easy/easy (91.6% vs. 89.0% for Japan patients vs. Outside of Japan patients, P=0.173), device deployment was extremely easy/easy (94.4% vs. 94.6% for Japan patients vs. Outside of Japan patients, P=0.557), pull and hold test was extremely easy/easy (91.7% vs. 77.8% for Japan patients vs. Outside of Japan patients, P=0.153), and overall impression was extremely easy/easy (91.7% vs. 88.4% for Japan vs. Outside of Japan patients, P=0.638).
Table 4.
Physicians’ Responses to Device-Handling Questionnaire
| Device-handling questions |
Japan
(n=36) |
Outside of Japan
(n=683) |
P value* |
| Navigation of delivery system to RV |
|
|
0.173 |
| Extremely difficult/difficult |
3 (8.3%) |
32 (4.7%) |
|
| Neutral |
0 (0.0%) |
43 (6.3%) |
|
| Extremely easy/easy |
33 (91.6%) |
608 (89.0%) |
|
| Device deployment |
|
|
0.557 |
| Extremely difficult/difficult |
0 (0.0%) |
13 (1.9%) |
|
| Neutral |
2 (5.6%) |
24 (3.5%) |
|
| Extremely easy/easy |
34 (94.4%) |
646 (94.6%) |
|
| Tug test |
|
|
0.153 |
| Extremely difficult/difficult |
0 (0.0%) |
36 (5.3%) |
|
| Neutral |
3 (8.3%) |
116 (17.0%) |
|
| Extremely easy/easy |
33 (91.7%) |
531 (77.8%) |
|
| Overall impression |
|
|
0.638 |
| Extremely difficult/difficult |
2 (5.5%) |
30 (4.4%) |
|
| Neutral |
1 (2.8%) |
49 (7.2%) |
|
| Extremely easy/easy |
33 (91.7%) |
604 (88.4%) |
|
*Calculated using Fisher’s exact test for discrete variables and t-tests for continuous variables. RV, right ventricle.
All 35 Japan patients and 658 of 660 Outside of Japan patients with a 3-month visit at the time of the primary analysis completed satisfaction questionnaires (Table 5). Patients’ responses were similar for cosmetic appearance and level of activity. However, more patients outside of Japan were very satisfied or satisfied with their recovery than Japan patients (74.3% vs. 91.8%, P=0.002).
Table 5.
Patient Satisfaction at 3 Months
| Satisfaction questions |
Japan
(n=35) |
Outside of Japan
(n=658) |
P value* |
| Recovery |
|
|
0.002 |
| Very dissatisfied/dissatisfied |
2 (5.7%) |
20 (3.0%) |
|
| Neutral |
7 (20.0%) |
34 (5.2%) |
|
| Very satisfied/satisfied |
26 (74.3%) |
604 (91.8%) |
|
| Cosmetic appearance |
|
|
0.254 |
| Very dissatisfied/dissatisfied |
0 (0.0%) |
3 (0.5%) |
|
| Neutral |
3 (8.6%) |
22 (3.3%) |
|
| Very satisfied/satisfied |
32 (91.4%) |
633 (96.2%) |
|
| Level of Activity |
|
|
0.090 |
| Very dissatisfied/dissatisfied |
2 (5.7%) |
35 (5.3%) |
|
| Neutral |
12 (34.3%) |
131 (19.9%) |
|
| Very satisfied/satisfied |
21 (60.0%) |
492 (74.9%) |
|
*Calculated using Fisher’s exact test for discrete variables and t-tests for continuous variables.
Discussion
In this study, there were no significant differences in long-term safety, electrical performance, or patient and physician acceptability observed between patients inside and outside Japan, except in patient satisfaction with recovery. This is despite there being differences in specific baseline characteristics and implant procedure characteristics between the 2 groups. These findings suggested that the favorable safety and efficacy results from the global study may be extended to Japanese patients, despite Japan-specific medical practices and environments.
Implantation
There were 5 events in 5 patients (13.9%) that were considered complications requiring invasive intervention such as intravenous medications to resolve the event. None were considered major complications, and no dislodgements or systemic infections were observed. There was 1 case of pericardial effusion that occurred in a Japanese patient during an implant procedure. The patient was an 81-year-old male with a history of chronic obstructive pulmonary disease, emphysema, and pleural effusion. The pericardial effusion was classified as a minor complication because it required pericardiocentesis, but it did not meet the definition of a major complication because the event did not result in death, hospitalization, prolongation of hospitalization, loss of device functionality, or system revision.
Because the TPS only has one size and shape and the catheter requires a large-bore introducer, the adaptability of the system to small or short patients was a major concern prior to starting the study. Although the Japanese patients enrolled in the study were considerably smaller than patients from the rest of the world, TPS implantation was successful in all of them and there were no procedure-related major complications, including groin puncture site major complications. In addition, all Japanese patients had low and stable pacing threshold, sensitivity, and impedance. The most common device location was the apex, and the distribution of placement location was similar in patients inside and outside of Japan.
One Japanese patient left the study prior to implant attempt because a narrow femoral vein confirmed by preoperative CT scan. Preoperative imaging, such as MRI, CT scan or venogram, is thought to be useful to confirm if the femoral vein’s size and anatomy can accommodate a 23-Fr introducer, especially in patients with small stature. The TPS is ideal for elderly and thin patients, as it does not require a subcutaneous pocket. It is expected that Japanese patients, who tend to be thin, will receive more benefit from the TPS.
For Japanese patients, implant procedure time was longer, most likely because of anticoagulation, monitoring of the activated clotting time during the procedure, and reversing anticoagulation prior to sheath removal. Also, hemostasis with figure-of-eight suture and manual pressure was used for all Japanese patients. These findings suggested that there was more concern surrounding potential bleeding complications in the Japanese patients. Time before ambulation and length of hospital stay were longer for Japanese patients, which might be explained by the use of the same clinical pathway that is used for conventional pacemaker implantation. However, given the physician satisfaction survey results and patient condition following the implant, hospital stays could be shortened, which will have additional benefit, especially for elderly and frail patients.
Satisfaction Survey
A total of 9 of 35 Japanese patients were not satisfied with their recovery and there was a significant difference in patient response regarding recovery between Japan and outside Japan. It is plausible that the medical history of the patients and adverse events associated with the implant procedure had a negative effect on their satisfaction with recovery. In fact, 6 of the 9 Japanese patients, including 2 patients who were very dissatisfied or dissatisfied with recovery, had congestive heart failure. The remaining 3 patients were experiencing an adverse event: worsening of AF or epilepsy at their 3-month visit. One Japanese patient who was very dissatisfied with recovery had congestive heart failure and reported cardiac failure deterioration at the 3-month visit. None of the Japanese patients developed pacemaker syndrome.
Study Limitations
The TPS global study was not designed to evaluate inter-regional differences between Japan and outside Japan. The number of Japanese patients who underwent an implant attempt with the TPS was only 36, accounting for approximately 5% of the entire study cohort. However, the study was conducted simultaneously around the globe following a single protocol. This makes it easier to generalize the study results to individual geographic regions.
Conclusions
TPS was successfully implanted in 100% of Japanese patients. Despite some differences in baseline characteristics and implant procedure characteristics in Japanese patients, safety and efficacy performance were favorable and similar to the global trial performance. Further, the TPS was favorably accepted by implanting physicians and patients.
Disclosures
K. Stromberg and J.L. work for Medtronic. W.T. was an employee of Medtronic.
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