ABSTRACT: Background. The role of different anticoagulants in reducing in-hospital complications in patients undergoing closure of interatrial septal defects (IASD) is unknown. In this study, we review our own experience with IASD closure data to determine if in-hospital complications and ambulation time are influenced by the use of various anticoagulants. Methods. Fifty-five consecutive patients with a history of unexplainable stroke or transient ischemic attacks (TIA), with the exception of the presence of an IASD, were included in this study. Multiple variables were collected including age, gender, history of smoking, hypertension, diabetes, hypercholesterolemia, ejection fraction, anticoagulants used pre- and postprocedure, anticoagulants used during the closure procedure, shunt grade across the IASD pre- and postprocedure, defect size, and right-sided filling pressures. Descriptive analysis was performed on all variables including complications frequency and ambulation time, and compared between bivalirudin and indirect thrombin inhibitors. Results. Of 55 consecutive patients included in this study, 22 patients received bivalirudin and 33 patients received unfractionated heparin (UFH) (n = 26) or enoxaparin (n = 7). The bivalirudin patients were older (60.1 vs 50.8 years; p = 0.028), with a higher incidence of interatrial septal aneurysm (75% vs. 40.7%; p = 0.037). In-hospital complications included 1 (5%) patient with a minor bleed (groin hematoma) in the bivalirudin group, and 3 patients with minor bleed (1 GI bleed, 1 groin hematoma, and 1 transient ischemia on electrocardiogram) in the non-bivalirudin group (9.1%). No patient had a major bleed that required a transfusion or prolonged hospital stay. Ambulation time was not significantly different between the two groups (7.7 ± 5.9 hours for bivalirudin and 6.9 ± 5.1 hours for other anticoagulants; p = NS). Conclusion. We conclude that bivalirudin is safe during IASD closure, with a statistically nonsignificant trend toward fewer minor complications than UFH and enoxaparin. No major bleeding occurred in either group. This could be due to the fact that IASD closure is performed via venous access that generally carries a low bleeding complication rate and allows safe early ambulation, irrespective of the anticoagulant utilized and despite the use of 10 and 11 Fr sheaths. Given that major differences do not appear to exist in this exploratory study between the anticoagulants studied, patent foramen ovale closure is currently being performed in our laboratory with UFH. J INVASIVE CARDIOL 2007;19:309–312

       Interatrial septal defects (IASD) have been associated with an increased incidence of cryptogenic strokes.^1–7 Percutaneous closure of these defects is now widely performed and the safety of this procedure has been established. It is unclear, however, which is the best anticoagulant to use during IASD closure. Bivalirudin has been shown to have lower bleeding complication rates in patients undergoing percutaneous coronary intervention.^8–12 These patients involved primarily an arterial access in contrast to percutaneous closure of IASD that primarily involves venous access, but larger venous sheath sizes. In this study, we retrospectively reviewed our own experience with the use of various anticoagulants in IASD closure and its relationship to in-hospital frequency of major adverse events.

Methods

       Fifty-five consecutive patients with a history of unexplainable stroke or TIA, with the exception of the presence of an IASD, were included in this retrospective study that was approved by our center’s Institutional Review Board. Patients were included in this study if they had a clinically or neuroradiologically confirmed ischemic stroke with no other identifiable cause, with the exception of an IASD. Patients were ruled out for cerebrovascular disease, arrhythmias and coagulation disorders. All patients had a documented IASD by saline contrast injection and had undergone closure of this defect per cut aneously using either the Amplatz^® occluder (AGA Medical Corp., Golden Valley, Minnesota) for atrial septal defect (ASD), or the CardioSEAL^® occluder (NMT Medical, Inc., Boston, Massachusetts) for patent foramen ovale (PFO).

       Multiple variables were collected including age, gender, history of smoking, hypertension, diabetes, hypercholesterolemia, ejection fraction, anticoagulants used pre- and postprocedure (including bivalirudin, enoxaparin and unfractionated heparin), shunt grade across the IASD pre- and postprocedure, defect size, size of IASD, degree of shunt, presence of atrial septal aneurysm and right-sided filling pressures.

       Bivalirudin REPLACE-2 dosing was utilized.¹¹ Enoxaparin was given as an intravenous bolus of 0.7 mg/kg. Unfractionated heparin was administered per the operator’s discretion (typically as an initial bolus of 5,000 units) and to keep the activated clotting time (ACT) greater than 300 seconds. The choice of the anticoagulant was left tothe operator’s discretion. ACTs were measured only in the UFH group, as prior data validated the reliability of anticoagulation with bivalirudin using REPLACE-2 dosing and the inadequacy of the ACT to measure the level of anticoagulation with enoxaparin. UFH gives an unpredictable ACT response, and in our laboratory the ACT target during PFO closure is 300 seconds.

       In-hospital complications were defined as major bleeding (Hb drop by ≥ 3 gm/dl with a source of bleed, retroperitoneal hematoma or hemorrhagic stroke), death, embolic stroke and vascular complications. Minor bleeding was defined as any non major bleed including hematoma or gastrointestinal bleed that did not meet the definition above.

       Descriptive analysis was performed on all variables. Continuous and dichotomous variables were compared using the Student’s t-test and the chi-square test of statistical significance, respectively.

Results

       Of the 55 patients enrolled, 22 (40%) received bivalirudin, 26 (47.3%) received UFH and 7 (12.7%) received enoxaparin. Demographic, clinical and procedural variables are described in Tables 1 and 2, respectively.

Table 2

Table 1

Patients receiving bivalirudin were older and had a higher rate of interatrial septal aneurysm than patients in the combined enoxaparin-unfrac tionat ed group. Also, the bivalirudin patients had a higher right ventricular pressure, and all of their procedures were performed under intracardiac echocardiography (ICE). ICE was performed via the insertion of a second venous line in the common femoral vein. Of the patients receiving heparinenoxaparin, 69% were performed under transesophageal echocardiography (TEE) when ICE was not yet available at our laboratory. All patients who underwent TEE had only one venous line in the common femoral vein. The remainder of all clinical and procedural variables was not statistically different between the two groups. The average ACT with UFH was 312 ± 52 seconds. In-hospital complications included 1 (5%) patient with a minor bleed (groin hematoma) in the bivalirudin group, and 3 patients with minor complications (1 GI bleed, 1 groin hematoma and 1 transient ischemia on electrocardiogram, none of which required transfusion or prolonged hospital stay) in the non-bivalirudin group (9.1%). No patient had a major bleed that required a transfusion or prolonged hospital stay. Ambulation time was not significantly different between the 2 groups (7.7 ± 5.9 hours for bivalirudin, and 6.9 ± 5.1 hours for other anticoagulants; p = NS).

Discussion

       Bivalirudin was shown to reduce bleeding complications and was more effective than UFH in the treatment of patients with coronary artery disease undergoing percutaneous intervention.^8–12 Data on the optimal anticoagulant in PFO or ASD closure is not available at present. Enhancedthrombogenicity, rather than platelet activation, was noted in patients undergoing percutaneous closure of IASD,¹³ and therefore the choice of the anticoagulant intraprocedurally and following the procedure might be of importance to reduce procedural complications.

       In this study of 55 consecutive patients, various anticoagulants were used based on the operator’s preference. Patient groups were mostly similar in procedural and clinical characteristics. The bivalirudin group had a higher right ventricular pressure, more bilateral venous sheaths and included older people, conditions that actually can be associated with an increase in complications. Despite this, patients receiving bivalirudin experienced a statistically nonsignificant reduction in minor bleeding compared to the heparin-enoxaparin group. None of the groups experienced major bleeding, death, vascular complications or embolic stroke. Furthermore, the small hematoma that was experienced by 2 patients in this study (1 in each group) could have been the result of an inadvertent arterial stick during the attempt to engage the common femoral vein. Finally, ambulation time appears similar in the two groups. In this study, the time to ambulation was left to the operator’s discretion. It is unclear whether a predetermined, more aggressive ambulation time would have demonstrated a significant difference among the various anticoagulants.

       Despite an initial interest at our laboratory to use bivalirudin during PFO closure, we are currently using UFH, given its significantly lower cost and the associated lack of major complications with its use. Despite a lower minor bleeding rate with bivalirudin, both heparin and bivalirudin appear safe, with no major bleeding complications, and this is probably related to the fact that IASD closure is performed via venous rather than arterial access, and inherently carries a lower rate of bleeding and complications. We believe that a large, randomized study with predefined ambulation time and a larger number of patients is needed to determine whether bivalirudin has an advantage over UFH prior to recommending the use of bivalirudin routinely during PFO closure procedures.

       Study limitations. This study is exploratory and is limited by its small number of patients and retrospective design. However, consecutive patients that met predefined inclusion criteria were all included. The groups were comparable, with the exception of the bivalirudin group that had more venous access, an older population and higher right-sided filling pressure. Despite these differences that could actually be disadvantageous to bivalirudin, there was a statistically nonsignificant trend toward less minor bleeding in the bivalirudin group compared to the heparin-enoxaparin group. It is possible that with large and more balanced groups, bivalirudin might show a more convincing, statistically significant safer profile than hepar in. Further studies are needed before bivalirudin can be recommended as a first-line anticoagulant in IASD closure.