Abstract
Background:
Thromboembolism (TE) is one of the most serious complications after pacemaker implantation. It has been demonstrated that several patient characteristics and different pacing modes are related to an increased risk of TE events during long‐term follow‐up.
Hypothesis:
We propose that TE events occurring during the perioperative period of pacemaker implantation may be associated with certain clinical characteristics.
Methods:
The potential risk factors of TE events were analyzed in 406 consecutive patients who underwent pacemaker implantation.
Results:
We identified TE events in 11 patients (2.7%) within 7 days after pacemaker implantation. Four of the 11 (36.4%) patients died of complications of TE. Univariate analysis revealed that an age of >75 years (4.56 odds ratio [OR], P = 0.031), hypertension (3.59 OR, P = 0.028), diabetes (8.89 OR, P < 0.001), coronary heart disease (4.8 OR, P = 0.005), atrial fibrillation (AF) (5.68 OR, P = 0.006), persistent AF (10.36 OR, P < 0.001), and a history of stroke or transient ischemic attack (5.62 OR, P = 0.002) were associated with an increased risk of TE events. Multivariate logistic analysis showed that persistent AF (9.8 OR, P < 0.001) was independently associated with TE. The incidence of perioperative TE was not significantly different between patients with single‐ and dual‐chamber pacemakers.
Conclusions:
We found TE events during the perioperative period in patients undergoing pacemaker implantation were not uncommon. Because persistent AF during the perioperative period was the only independent risk factor for perioperative TE, appropriate anticoagulation therapy may be necessary in those patients. © 2012 Wiley Periodicals, Inc.
J. Liu, MD, is co‐first author. The authors have no funding, financial relationships, or conflicts of interest to disclose.
Introduction
Thromboembolic (TE) events, including stroke, peripheral artery embolism, venous thrombosis, and pulmonary embolism (PE), are regarded as common and serious complications in patients undergoing permanent pacemaker (PPM) implantation.1, 2, 3 It has been demonstrated that several clinical characteristics are related to an increased risk of latent TE events in paced patients after long‐term follow‐up, such as old age (>75 years), atrial fibrillation (AF), hypertension, diabetes mellitus (DM), pacing mode, intracardiac shunts, and so on.3, 4, 5, 6, 7, 8 To date, however, few data about perioperative TE events in paced patients are available. Evaluating the incidence and risk factors of TE events during the perioperative period is of clinical significance. It potentially provides us with useful information in improving subsequent patient management during device implantation. Accordingly, this clinical observational study was performed in PPM implantation patients to evaluate the incidence and risk factors of TE events during the perioperative period.
Methods
Study Patients
From February 2006 to February 2007, a total of 406 consecutive patients who underwent PPM implantation were enrolled. Patients implanted with an implantable cardioverter defibrillator and/or cardiac resynchronization therapy device were excluded. Indications for pacemaker implantation were sick sinus syndrome (n = 140), second‐ and third‐degree atrioventricular block (n = 181), AF with RR intervals >3 seconds or with QRS rate <40 beats/min (n = 79), and others (n = 6). Established risk factors for TE events, such as history of AF, stroke or transient ischemic attack (TIA), deep vein thrombosis/PE, and anticoagulation and antiplatelet medication, were evaluated in detail for all patients before PPM implantation. Echocardiography data and cardiac functional grading (New York Heart Association class) were also recorded.
Pacemaker Implantation
Standard single‐ or dual‐chamber pacemakers were implanted when it was indicated. The atrial leads, used only for dual‐chamber pacemakers, were implanted in the right atrial appendage with passive fixation. The ventricular leads were implanted in the right ventricular apex with passive fixation. The location of lead implantation was confirmed by electrocardiography and chest X‐ray to exclude inadvertent placement in the left ventricle or the coronary sinus. Anticoagulation therapy was discontinued until the International Normalized Ratio (INR) was less than 1.3 (generally 3–5 days) before pacemaker implantation. Antiplatelet therapy was discontinued 1 to 3 days before the procedure. Two days after implantation, the anticoagulation or antiplatelet therapy was restarted if no moderate or severe bleeding had occurred.
Confirmation of TE Events During the Perioperative Period
After the implantation procedure, out‐of‐bed activity was encouraged as soon as possible. All patients were observed in hospital for 7 days, at which time stitches were removed. Patients with clinical symptoms indicating a potential TE event were referred to the radiology department for further examination to confirm location and severity. When no TE events were found, patients underwent routine observation and radiology examination performed 24 hours later as necessary. Treatment was given individually according to the manifestation of the TE. Those patients with TE events during the perioperative period were defined as the TE group and those without TE events as the control group.
Statistical Analysis
Continuous variables were expressed as the mean ± standard deviation. Discrete variables were presented as percentages. Comparisons among variables were made by means of the Fisher exact test or χ 2 test for categorical variables and the unpaired Student t test for continuous variables. Univariate and multivariate logistic regression analysis was performed to determine the potential risk factors of a TE. An additional subgroup analysis was done to determine the risk factors for TE events in AF patients. All tests were 2‐tailed. P < 0.05 was considered statistically significant. SPSS 17.0 software (SPSS Inc., Chicago, IL) was used for statistical analysis.
Results
A total of 406 patients (192 male; mean age, 73.4 ± 10.3 years) were enrolled in this observational study. In the study population, TE events during the perioperative period were clinically manifested and confirmed in 11 of 406 patients (2.7%) (TE group; 3 males; mean age, 77.3 ± 10.1 years). The clinical characteristics of these patients are summarized in Table 1. There were 9 strokes, 1 PE, and 1 renal infarction. No pocket hematoma or bleeding complications were observed.
Table 1.
Clinical Characteristics of Patients With Thromboembolic Events During the Perioperative Period
| Case | Sex | Age (y) | Leads | LA (mm) | LVEF (%) | NYHA Class | Combinations | Onset Time (Days Postoperation) | TE Events | Outcome (Days Postoperation) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 84 | Single | 40 | 56 | II | HTN | 1 | Stroke | Discharged (14) |
| 2 | F | 77 | Dual | 39 | 59 | I | DM, CAD | 1 | Stroke | Discharged (13) |
| 3 | F | 86 | Single | 58 | 55 | II | HTN, DM, CAD, stroke, PsAF | 1 | Stroke | Died (80) |
| 4 | F | 84 | Single | 56 | 55 | II | HTN, DM, CAD, stroke, PsAF | 6 | Stroke | Discharged (15) |
| 5 | M | 79 | Single | 28 | 59 | II | DM, CAD | 3 | Stroke | Discharged (16) |
| 6 | M | 80 | Single | 50 | 62 | I | HTN, CAD, stroke, PsAF | 1 | Stroke | Died (33) |
| 7 | F | 80 | Single | 42 | 60 | I | HTN, DM, stroke, PaAF | 3 | Stroke | Discharged (15) |
| 8 | F | 82 | Single | 45 | 69 | I | HTN, stroke, PsAF | 4 | Stroke | Died (56) |
| 9 | F | 79 | Dual | 39 | 50 | III | DM, CAD | 2 | Stroke | Died (32) |
| 10 | F | 50 | Single | 50 | 73 | I | PsAF | 4 | Renal infarction | Discharged (11) |
| 11 | F | 69 | Single | 45 | 65 | I | PsAF | 4 | Pulmonary embolism | Discharged (13) |
Abbreviations: CAD, coronary artery disease; DM, diabetes mellitus; F, female; HTN, hypertension; LA, left atrium; LVEF, left ventricular ejection fraction; M, male; NYHA, New York Heart Association; PaAF, paroxysmal atrial fibrillation; PsAF, persistent atrial fibrillation; TE, thromboembolism.
Four patients with stroke died of complications of pulmonary infection and respiratory failure 50.2 ± 22.7 days after operation. The other 7 patients were discharged at 13.9 ± 1.7 days after the procedure. Of those, 5 patients with stroke were discharged with little neurologic sequelae, and the patients with PE or renal infarction recovered without any sequelae. The mortality related to stroke during the perioperative period was therefore 44.4%, and mortality related to TE events was 36.4%. The length of postoperative hospitalization was longer in the TE group than in the control group (27.1 ± 22.2 days vs 7.1 ± 0.6 days; P = 0.014).
The potential risk factors for TE events are summarized in Table 2. None of the patients with TE events had a history of deep vein thrombosis/PE or prosthetic heart valves. Univariate analysis demonstrated that an age >75 years (4.66 odds ratio [OR], 95% confidence interval [CI]: 1.00–21.85, P = 0.032), hypertension (3.59 OR, 95% CI: 1.07–12.01, P = 0.038), DM (8.89 OR, 95% CI: 2.61–30.26, P = 0.001), coronary artery disease (4.80 OR, 95% CI: 1.43–16.12, P = 0.013), history of AF (5.68 OR, 95% CI: 1.63–19.84, P = 0.006), persistent AF (10.36 OR, 95% CI: 3.03–35.45, P = 0.001), and history of stroke or TIA (5.62 OR, 95% CI: 1.65–19.09, P = 0.010) were associated with an increased risk of TE events. Multivariate analysis showed that persistent AF (9.8 OR, 95% CI: 2.83–34.16, P < 0.001) was the only independent predictor of TE events.
Table 2.
Comparisons Between the Control Group and the Thromboembolic Events Group
| Factors | Control Group, n = 395 | TE Group, n = 11 | OR | P Value |
|---|---|---|---|---|
| Sex, male/female | 189/206 | 3/8 | 0.41 | 0.178 |
| Age, y | 73.3 ± 10.3 | 77.3 ± 10.1 | 1.05 | 0.210 |
| Older than 75 y, no. (%) | 194 (49.1) | 9 (81.8) | 4.66 | 0.032 |
| Hypertension, no. (%) | 99 (25.1) | 6 (54.5) | 3.59 | 0.038 |
| Diabetes mellitus, no. (%) | 47 (11.9) | 6 (54.5) | 8.88 | 0.001 |
| Coronary artery disease, no. (%) | 79 (20.0) | 6 (54.5) | 4.80 | 0.013 |
| AF, no. (%) | 93 (23.5) | 7 (63.6) | 5.68 | 0.006 |
| Persistent AF, no. (%) | 41 (10.4) | 6 (54.5) | 10.36 | 0.001 |
| Paroxysmal AF, no. (%) | 52 (13.2) | 1 (9.1) | 0.66 | 0.741 |
| History of stroke or TIA, no. (%) | 51 (12.9) | 5 (45.5) | 5.62 | 0.010 |
| NYHA class II‐III, no. (%) | 82 (20.8) | 5 (45.5) | 3.18 | 0.063 |
| Leads, single/dual | 291/104 | 9/2 | 1.61 | 0.735 |
| LA diameter, mm | 42.4 ± 7.6 | 44.7 ± 8.6 | 1.04 | 0.315 |
| LVEF, % | 63.1 ± 9.1 | 60.3 ± 6.7 | 0.97 | 0.309 |
| Preoperation anticoagulation, no. (%) | 36 (9.1) | 2 (18.2) | 0.45 | 0.275 |
| Preoperation antiplatelet therapy, no. (%)a | 77 (19.5) | 2 (18.2) | 1.09 | 1.000 |
Abbreviations: AF, atrial fibrillation; LA, left atrium; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OR, odds ratio; TE, thromboembolism; TIA, transient ischemic attack.
91.1% with aspirin 100 mg every day, 4.2% with aspirin 50 mg every day, 4.7% with clopidogrel 75 mg every day.
A subgroup analysis was then performed for patients with persistent AF, whereby patients with and without TE events were compared (Table 3). The proportion of preoperation antiplatelet therapy was higher in non‐TE patients than in the TE patient subgroup (51.2% vs 0.0%, P = 0.026). Other clinical characteristics, including CHADS2 score, CHA2DS2 VASc score, or preoperative anticoagulation therapy, were not significantly different between the persistent AF patients with and without TE events.
Table 3.
Subgroup Analysis of Persistent Atrial Fibrillation Patients
| Factors | Without TE, n = 41 | TE, n = 6 | P Value |
|---|---|---|---|
| Sex, male/female | 24/17 | 1/5 | 0.085 |
| Age, y | 78.2 ± 9.0 | 75.2 ± 13.7 | 0.474 |
| Older than 75 y, no. (%) | 28 (68.3) | 4 (66.7) | 1.000 |
| CHADS2 score | 2.39 ± 1.86 | 3.00 ± 2.37 | 0.471 |
| CHA2DS2VASc score | 4.17 ± 2.44 | 5.17 ± 2.99 | 0.368 |
| Hypertension, no. (%) | 11 (26.8) | 4 (66.7) | 0.072 |
| Diabetes mellitus, no. (%) | 24 (58.5) | 2 (33.3) | 0.386 |
| Coronary artery disease, no. (%) | 21 (51.2) | 3 (50) | 1.000 |
| History of stroke or TIA, no. (%) | 15 (36.6) | 4 (66.7) | 0.204 |
| NYHA class II‐III | 16 (39.0) | 2 (33.3) | 1.000 |
| LA diameter, mm | 52.9 ± 7.6 | 50.7 ± 5.4 | 0.485 |
| LVEF, % | 59.2 ± 10.1 | 63.2 ± 7.3 | 0.362 |
| Preoperation anticoagulation, no. (%) | 19 (46.3) | 2 (33.3) | 0.678 |
| Preoperation antiplatelet therapy, no. (%) | 21 (51.2) | 0 | 0.026 |
Abbreviations: LA, left atrium; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; TE, thromboembolism; TIA, transient ischemic attack.
Discussion
After long‐term follow‐up, the actuarial incidence of stroke after PPM implantation was 3% at 1 year, 5% at 5 years, and 13% at 10 years.3 However, the incidence of TE events during the perioperative period was lower than that reported in long‐term follow‐up, which was reported as 0.2% to 1.0%.9, 10 In the present patient population, the incidence of TE events during the perioperative period was 2.7%, slightly higher than that reported by other authors.9, 10 The mortality caused by TE events during the perioperative period in the present study was about 1.0%, similar to that reported by Michaud et al.10 Nine of the 11 (88.9%) patients with TE events experienced a stroke during the perioperative period, and 4 of them (36.4%) died. Therefore, more attention should be paid to reduce the incidence and mortality of TE events (particularly stroke) during the perioperative period.
In this study, an age >75 years, hypertension, DM, coronary artery disease, AF (particularly persistent AF), and a history of stroke or TIA were clear contributors to an increased risk of TE event in paced patients; these findings are similar to results from previous studies.3, 11 Furthermore, persistent AF was the only independent risk factor for perioperative TE events. However, pacing modes were not found to be a risk factor for TE events during the perioperative period in our study population.
The influence of pacing mode on latent TE events has been reported by several studies.3, 4, 12 The risk of developing AF, the underlying cause of latent TE events, has been shown to be greater with VVI pacing than with DDD pacing.12 AF, however, takes time to develop and may have done so outside the scope of our evaluation period. Moreover, the detrimental effects of ventricular desynchronization or LV dyssynchrony produced by long‐term, nonphysiologic RV pacing were supported by data from Nielsen et al.13 Therefore, it is understandable that the pacing mode or the number of leads did not increase the risk of TE events during the perioperative period.
The relationship between AF (including paroxysmal and chronic AF) and TE events has been confirmed by many previous studies.14, 15 The incidence of AF in nonpacing patients with TE events has been reported at 6% to 24% and at up to 50% in those with cardiogenic thrombosis.14, 15 Therefore, the risk of TE events in AF patients was significantly elevated independent of PPM implantation. Capucci et al found that the risk of TE, adjusted for known risk factors, increased by 3.1 times in patients with device‐detected AF episodes longer than 1 day during follow‐up.11 Our data showed that patients with persistent AF were 9.8 times more likely to have TE events during the perioperative period. One reason for the high risk of TE may be that anticoagulation with warfarin was discontinued or even not previously prescribed before the procedure in those patients with a history of AF or previous stroke.
Based on the results of the present study, antithrombotic therapy should be considered in patients with AF, especially persistent AF. However, the optimal anticoagulation approach during device implantation is still controversial. Current guidelines state that interruption of oral anticoagulation is mandatory before intervention in patients with an elevated risk of bleeding.16 Several studies have investigated the effect with or without the interruption of anticoagulation in patients at high risk of TE who underwent PPM implantation. In a prospective study, Hammerstingl and Omran found that oral anticoagulation could be safely interrupted before pacemaker implantation with use of enoxaparin for bridging.17 However, other data indicate that an elevated risk for pocket hematoma exists in patients who undergo pacemaker implantation without interruption of oral anticoagulation.18 It also has been demonstrated that use of heparin initiated 6 or 24 hours after implantation or use of high doses of heparin may significantly increase the risk of bleeding.10, 18 In a meta‐analysis study,18 the perioperative management of patients with a high risk of TE event was not established. Managing patients with a high risk for TE events continues to be difficult and requires further study to establish a recommendation.
In the present study, we found that the preoperative utility of antiplatelet therapy was associated with less risk of TE event in persistent AF patients. This finding is of interest, as consensus exists that the antithrombotic effect of warfarin is better than that of aspirin in AF patients. There may be several reasons for this finding. First, the percentage of preoperative anticoagulation was relatively low in the persistent AF patients in our study (46.3% in patients without TE and 33.3% in patients with TE), diluting the protective effect of warfarin. Second, the protective effect of warfarin was reduced due to its discontinuation (until the INR was <1.3) before PPM implantation and the delayed postoperative onset. Although there was a relative low antiembolism efficacy19, 20 and antiplatelet therapy was discontinued 1 to 3 days before implantation, the antiplatelet effect may still have existed during the perioperative period as the antithrombotic effect of antiplatelet drugs commonly lasts for 7 to 10 days.21 Finally, in persistent AF patients implanted with a VVI pacemaker, the platelet activation was increased.22, 23, 24 Therefore, in accordance with the results of our study, it was postulated that preoperative antiplatelet therapy may have some effect for the prevention of TE events during the perioperative period in persistent AF patients whose oral anticoagulation was discontinued or not prescribed before implantation.
Conclusion
TE events during the perioperative period in patients undergoing PPM implantation was not uncommon and was followed by a high mortality rate. Persistent AF was the only independent risk factor for perioperative TE events in patients who underwent PPM implantation. Lack of anticoagulation with warfarin was the most likely explanation for these TE events. Appropriate anticoagulation therapy may therefore be necessary in patients with a high risk for TE events during the perioperative period, but the optimal management strategy remains to be determined.
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