A randomized trial comparing heparin initiation 6 h or 24 h after pacemaker or defibrillator implantation

Patient characteristics

The subjects of this prospective study were 192 consecutive patients at the University of Michigan Medical Center who received an implantable defibrillator or a permanent pacemaker between February 1997 and July 1998. Patients undergoing replacement of a pacemaker or implantable defibrillator generator were excluded. The patients consisted of 136 men and 56 women with a mean age of 64 ± 14 years and mean ejection fraction of 0.40 ± 0.17. Forty-seven percent of patients had coronary artery disease, 25% had no structural heart disease, 14% had nonischemic dilated cardiomyopathy, 9% had aortic or mitral valve disease, 3% had received a heart transplant, 1% had hypertrophic cardiomyopathy and 1% had congenital anomalies. Seventy-eight patients received a dual-chamber pacemaker, 35 patients received a single-chamber pacemaker, 60 patients received a single-chamber implantable defibrillator, 12 patients received a dual-chamber implantable defibrillator, and 7 patients received both a pacemaker and implantable defibrillator. All pacemakers and defibrillators were implanted in a prepectoral pocket.

Forty-nine patients had an indication for intravenous anticoagulation and were randomized to receive intravenous heparin 6 h or 24 h postoperatively. Among these 49 patients, 18 had a mechanical heart valve, 30 had chronic AF and 1 had a deep venous thrombosis within the previous month. Twenty-eight patients received warfarin long term but did not have an indication for immediate postoperative anticoagulation with heparin. One hundred fifteen patients did not receive intravenous heparin or warfarin following the surgical procedure.

Aspirin therapy was not altered for surgery. Overall, 50% of patients (97/192) were treated with aspirin (mean daily dosage of 228 ± 120 mg/d) at the time of the surgical procedure. Twenty-nine percent of patients (14/49) who received postoperative heparin, 36% of patients (10/28) who received warfarin alone starting the evening of the procedure and 63% of patients (73/115) who did not receive anticoagulation were receiving aspirin at the time of the surgical procedure (p < 0.001). Only three patients were receiving both ticlopidine and aspirin.

There were no identifiable differences in clinical characteristics among patients treated with the two heparin dosing schedules. There were also no identifiable differences in clinical characteristics or type of implanted device between patients treated with heparin, warfarin or no anticoagulation. However, patients with a mechanical heart valve were more likely to receive intravenous heparin (p < 0.001), and patients who did not receive intravenous heparin or warfarin were more likely to receive aspirin (p < 0.001).

Study protocol

The study was approved by the Human Research Committee at the University of Michigan Medical Center. Patients who were not randomized to receive heparin therapy were entered into the study registry. Treatment with warfarin and heparin was discontinued at least three days and 6 h, respectively, before the pacemaker or defibrillator implantation procedure. All patients had an international normalized ratio (INR) <1.5 on the day of surgery. Patients with an indication for postoperative intravenous anticoagulation were randomized to receive intravenous heparin starting either 6 h or 24 h following device implantation. Postoperative intravenous heparin was infused at 1,000 U/h without a bolus dose or at a previously identified infusion rate that maintained the partial thromboplastin time between 1.5 and 2.0 times the control value. The partial thromboplastin time was measured 6 h after the initiation of heparin therapy and after dosage adjustments, which were made according to a standardized nomogram used at the University of Michigan Medical Center. Warfarin therapy was reinstituted the night of the surgical procedure in all patients in whom it was discontinued preoperatively. Infusion of heparin was discontinued when the INR reached ≥2.0. Patients were examined daily until hospital discharge, and then one week and two months after implantation. Systemic thromboembolic events were assessed over the same time period. A pocket hematoma was defined by two investigators as a palpable mass that protruded ≥2 cm anterior to the pulse generator and lead(s).

A pocket hematoma was evacuated if tense swelling caused poor capillary perfusion of the overlying skin or severe pain or if the hematoma enlarged progressively. Patients were instructed to contact one of the investigators if a hematoma developed after hospital discharge.

Statistical analysis

Continuous variables are expressed as mean ± 1 SD. Continuous variables were analyzed using a t test or analysis of variance with repeated measures, as appropriate. Nominal variables were compared using a chi-square analysis. A Mann-Whitney U nonparametric test was used to evaluate data that did not have a normal distribution. A probability value <0.05 was considered statistically significant. Kaplan-Meier log-rank analysis was performed to assess freedom from postoperative pocket hematoma formation for patients grouped by anticoagulation status.

Evacuation of a pocket hematoma

Evacuation of a pocket hematoma was necessary in 2 of 49 (4%) patients treated with heparin, 1 of 28 (4%) patients treated with warfarin (Coumadin) and 1 of 115 (1%) patients who received no anticoagulation (p = 0.4).

Prevalence of pocket hematomas

A pocket hematoma developed in 6 of 26 patients (23%) who received intravenous heparin 6 h postoperatively and warfarin the evening of surgery, as compared with 4 of 23 patients (17%) who received intravenous heparin 24 h postoperatively and warfarin the evening of surgery (p = 0.7). Among the 49 patients treated with intravenous heparin, 10 (20%) developed a pocket hematoma, compared with 1 of 28 patients (4%) treated with warfarin alone and 2 of 115 patients (2%) who did not undergo anticoagulation (p < 0.001). Figure 1 shows the time course of freedom from postoperative pocket hematoma formation in patients grouped by anticoagulation status. The mean time to hematoma formation was 5.1 ± 5.8 days (median, 3 days; range, 1 to 20 days) and did not differ among groups (p = 0.4). Pocket hematoma formation was not associated with age (p = 0.7), gender (p = 0.4), left ventricular ejection fraction (p = 0.6), type of heart disease (p = 0.3), type of device implanted (p = 0.1), number of leads implanted (p = 0.3), subclavian vein puncture or cephalic vein dissection for lead placement (p = 0.4), concomitant aspirin therapy (p = 0.6) or the maximum partial thromboplastin time value (p = 0.7). None of the patients taking ticlopidine alone or ticlopidine and aspirin developed a postoperative pocket hematoma.

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Figure 1

Kaplan-Meier analysis showing a statistically significant difference in freedom from pocket hematoma formation among patients treated with heparin, warfarin or no anticoagulation postoperatively (p < 0.0001).

Postoperative days in the hospital

Patients who were treated with heparin remained in the hospital a mean of 3.6 ± 2.9 postoperative days compared with a mean of 2.3 ± 1.1 postoperative days in patients treated with warfarin alone and a mean of 2.5 ± 2.5 postoperative days in patients receiving no anticoagulation (p = 0.02). The 13 patients who developed a pocket hematoma remained in the hospital a mean of 5.1 ± 4.6 postoperative days, compared with a mean of 2.6 ± 2.2 days in the 179 patients who did not develop a pocket hematoma (p = 0.02). The 10 patients treated with heparin who developed a pocket hematoma stayed in the hospital a mean of 5.9 ± 5.0 postoperative days, compared with a mean of 3.6 ± 2.9 postoperative days in the 39 patients treated with heparin who did not develop a pocket hematoma (p = 0.02).

Thromboembolic complications

A patient with dilated cardiomyopathy and chronic AF who received warfarin alone developed a stroke two days postoperatively. No other patients had symptoms or signs of an arterial or venous thromboembolic event. One patient who did not receive anticoagulation died of pulmonary edema one day after a pacemaker implantation.

Major findings

The risk of requiring a pocket hematoma evacuation following pacemaker or defibrillator implantation did not differ significantly with regard to anticoagulation status. Nevertheless, patients who received heparin after pacemaker or defibrillator implantation had a 5-fold and 10-fold greater risk of pocket hematoma formation than did patients treated with warfarin alone or no anticoagulation, respectively. The risk was the same (17% to 23%) whether heparin therapy was initiated 6 h or 24 h after surgery. Aspirin therapy did not affect the risk of hematoma formation in patients undergoing pacemaker or defibrillator implantation.

Patients treated with intravenous heparin following pacemaker or defibrillator implantation had a longer postoperative hospital stay than patients treated with warfarin alone or no anticoagulation. Additionally, patients who developed a pocket hematoma stayed longer after the implantation than patients who did not develop a hematoma. Even among those treated with heparin, patients with a pocket hematoma stayed in the hospital more postoperative days than patients without a hematoma.

Mechanism of pocket hematoma formation

The only identifiable risk factor for pocket hematoma formation was the use of intravenous heparin. The partial thromboplastin time did not correlate with pocket hematoma formation, as might be expected, since the partial thromboplastin time value is an indicator of the degree of anticoagulation afforded by intravenous heparin. The use of warfarin alone conferred a much lower risk of pocket hematoma formation, perhaps because warfarin therapy usually requires at least three days to achieve a therapeutic level of anticoagulation.

Previous studies

To our knowledge, these are the first published data demonstrating the high risk of developing a pocket hematoma in patients receiving heparin after pacemaker or defibrillator implantation. Pocket hematomas may require surgical drainage and are associated with discomfort and an increased risk of infection (2–4). In the present study, the incidence of pocket hematoma formation among patients who did not receive anticoagulation was 2%, and was similar to that observed in previous reports (5,6).

The risk of an arterial thromboembolic event with a prosthetic heart valve in the absence of anticoagulation is 8% per year (7,8). The average risk for an arterial thromboembolic event in a patient with nonvalvular atrial fibrillation is 4.5% per year (9). This risk may be as high as 20% if hypertension, prior stroke, advanced age or congestive heart failure is present (9,10). Based on these figures, the calculated daily risk ranges from 0.01% to 0.05%. Heparin would be expected to reduce venous and arterial thromboembolic risk by 66% to 80% (1). Patients who have experienced a deep venous thrombosis or arterial thromboembolism within the past month, however, have a much higher monthly risk of recurrence, 50% and 15%, respectively (1).

Limitations

Because of the small number of end point events and small sample sizes, the risk-benefit ratio of postoperative heparin use, that is, pocket hematoma formation versus prevention of thromboembolic complications, could not be assessed.

Right atrial pressure was not determined in this study. Hence, right atrial pressure cannot be addressed as a risk factor for hematoma formation.

Only two postoperative time intervals for heparin therapy initiation were chosen for randomization to minimize the exposure period without anticoagulation. Other intervals such as 36 h or 48 h may have been associated with fewer pocket hematomas.

Clinical implications

The use of heparin after pacemaker or defibrillator implantation is associated with a 20% risk of pocket hematoma formation and a longer postoperative hospital stay, but it is not associated with an increased risk of hematoma evacuation when compared to patients treated with warfarin alone or no anticoagulation. Additionally, a pocket hematoma is independently associated with an increased postoperative hospital stay. These risks, and the risk of infection and discomfort associated with a pocket hematoma, must be weighed against the small, increased risk of arterial thromboembolism during the few days it takes to achieve therapeutic anticoagulation with warfarin. Since an increased risk of infection, longer hospital stay and greater postoperative discomfort are trivial compared with a debilitating stroke, patients at the highest risk of thromboembolism should have postoperative heparin therapy initiated 6 h to 24 h after pacemaker or defibrillator implantation. Further studies are needed to elucidate the role of newer anticoagulation agents, such as low-molecular-weight heparin, and the use of drains to prevent hematoma formation.