Closure Device or Manual Compression in Patients Undergoing Percutaneous Coronary Intervention: A Randomized Comparison

ABSTRACT: Aims. Although closure devices may be comfortable for patients, the clinical benefits in patients with moderate-to-high risk of bleeding are not yet clear. We compared a closure device with manual compression in moderate- to high-risk bleeding patients undergoing percutaneous coronary intervention (PCI). Methods and Results. A randomized study was performed to compare a closure device (Angio-Seal, St. Jude Medical, Inc.) with manual compression in 627 patients treated with aspirin, clopidogrel, a glycoprotein IIb/IIIa inhibitor and heparin during PCI. The primary endpoint was the in-hospital combined incidence of: 1) severe hematoma > 5 cm at the puncture site or groin bleeding resulting in prolonged hospital stay, transfusion and/or surgical intervention at the puncture site; 2) arteriovenous fistula formation and/or surgical intervention at the puncture site. A total of 313 patients (49.9%) were randomized to the closure device and 314 patients (50.1%) to manual compression. The combined primary endpoint was 2.6% in the closure device group compared to 4.5% in the manual compression group (p = 0.195). In the predefined subgroup of patients with a history of hypertension, however, the combined primary endpoint (0.8% vs. 7.2%; p = 0.008) was significantly reduced after use of the closure device. Conclusion. This trial did not show the superiority of using a closure device over manual compression in patients treated with triple antiplatelet therapy who underwent PCI. The fact that patients with a history of hypertension had a benefit from a closure device merits further investigation. J INVASIVE CARDIOL 2010;22:562–566 Key words: Angio-Seal, closure device, manual compression, triple antiplatelet therapy, PCI ———————————————————— Vascular complication rates after cardiac catheterization or percutaneous coronary intervention (PCI) range from 1.5–9%, and 20–40% of patients who experience such complications require surgical intervention.^1,2 The identified risk factors for femoral puncture-site complications include age > 75 years, female gender, hypertension, diabetes mellitus, low body mass index, location of puncture site, sheath size, duration of the procedure and intensive use of antithrombotic drugs.^3–9 Because both manual compression after removal of the catheter sheath and bed rest are associated with discomfort to the patient and may have cost implications, arterial puncture closing devices have been developed to avoid manual compression and shorten bed rest. However, although it was shown that use of a closure device resulted in less reported pain,¹⁰ two meta-analyses concluded that many of the randomized trials had a limited sample size and were of poor methodological quality, and that there is only marginal evidence that closure devices are more effective than manual compression.^11,12 Furthermore, although some reports showed very low bleeding risks with the use of a closure device in patients treated with intensive antiplatelet medication, this has not been evaluated in a randomized clinical trial.^13,14 The aim of the present study was to compare a closure device with manual compression in moderate- to high-risk bleeding patients undergoing PCI.

Methods

Study design. The ANGIO-Seal or manual Compression After coRonary intervention Evaluation (ANGIOCARE) study was a single-center, prospective, randomized trial which compared the Angio-Seal closure device with manual compression in a moderate- to high-risk patient population. The randomization was 1:1 to receive or not a closure device. All patients were treated with aspirin, high-dose clopidogrel, glycoprotein IIb/IIIa inhibitor (GPI) and unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) during PCI. Data concerning primary and secondary endpoints were analyzed for subgroups defined by age > 75 years, female gender, history of hypertension and duration of the procedure. The study was registered with number ISRCTN22655249 (www.controlled-trials.com). Written informed consent was obtained from all patients. Study approval was obtained from the medical ethics committee of our hospital. Procedures. A modified Seldinger technique was used to cannulate the common femoral artery.¹⁵ Vascular access sheaths were used in every patient. All angiograms were made with 6 Fr guiding catheters in a standardized fashion. Randomization was performed by means of a computer program in blocks (randomly changing block size) to achieve a balanced allocation. The randomization was done after arterial puncture of the femoral artery. After the PCI, the sheath in the femoral artery was removed immediately. Closure device deployment (6 Fr) was performed without routine fluoroscopy of the femoral artery according to catheterization laboratory and nursing department protocol (bandage for 4 hours followed by immediate ambulation). Manual compression was also performed in the catheterization laboratory immediately after the procedure by compression for at least 15 minutes until leakage had stopped, with further treatment according to our local nursing protocol (bandage for 6 hours, ambulation after 8 hours). During bandaging, the patient was instructed to lie in bed, with the leg remaining straight. Population. Inclusion criteria were PCI via the femoral artery and treatment with aspirin, clopidogrel (600 mg preloading dose), UFH and a GPI. Patients routinely received weight-adjusted UFH (60 U/kg) and tirofiban (25 µg/kg bolus and 0.15 µg/kg/min maintenance infusion) according to the guidelines.¹⁶ In patients pretreated with UFH in the ambulance, additional heparin was only given when the activated clotting time was Measurements (endpoints, definitions). The primary endpoint was the combined incidence of: 1) severe hematoma > 5 cm at the puncture site or groin bleeding resulting in prolonged hospital stay, transfusion and/or surgical intervention at the puncture site; 2) arteriovenous fistula formation at the puncture site and/or surgical intervention at the puncture site. The indication for transfusion was defined according to our local hospital protocol as a measured hemoglobin 75 years, female gender, history of hypertension and prolonged procedure time. A history of hypertension was defined as patients who used antihypertensive drugs for the indication of hypertension or those with blood pressure > 140/90 mmHg on more than two occasions prior to the PCI. Data collection and follow-up. We collected the following variables from the patient files: age, gender, history of hypertension, diabetes, previous myocardial infarction, height, weight, angiographic variables, laboratory measurements, procedure variables and hospital duration. Clinical data were collected prospectively by research nurses. Follow-up information was obtained from medical hospital records, the patient’s general physician and by direct telephone interview with the patient. A blinded independent clinical endpoint committee adjudicated all clinical endpoints. Statistical analysis. The sample size was calculated to demonstrate increased efficacy of the use of a closure device compared to manual compression. The estimated incidence of the primary endpoint was 7% in the manual compression group based on the occurrence of bleeding in our previous large single-center observational study in consecutive ST-elevation myocardial infarction patients who underwent primary PCI.¹⁷ A sample size of 614 patients, with 307 patients in each treatment group, was planned. A trial of this size has an 80% power at an alpha level of 0.05 to show a decrease in the incidence of the primary endpoint of 7% in the manual compression group compared to 2% in the closure device group. All analyses were by intention-to-treat. An interim analysis was performed according to the probability stopping rules of Snapinn after inclusion of 430 patients. Statistical analysis was performed with the Statistical Package for the Social Sciences, version 15.0.1 (SPSS, Inc., Chicago, Illinois). Continuous data were expressed as mean ± standard deviation and categorical data as percentage, unless otherwise denoted. Differences between continuous data were performed by the student’s t-test and the chi-square or Fisher’s exact test was used as appropriate for dichotomous data. For all analyses, statistical significance was assumed when the two-tailed probability value was Results Baseline characteristics. Figure 1 shows the trial profile. A total of 627 patients were enrolled in the study between 2006 and 2008, 313 patients were randomly assigned to a closure device and 314 patients to manual compression (no closure device). Baseline characteristics of the patients were comparable between the groups, except for previous coronary artery bypass graft surgery (CABG), which was higher in the closure device group, whereas previous PCI tended to be higher in the manual compression group (Table 1). There were no significant differences in medication use (LMWH, UFH) before or during the procedure between the groups. In 3 patients the closure device could not be placed. One patient was randomized to manual compression, but a closure device was placed. Table 2 shows all clinical outcomes and serious events. There were no significant differences in death, bleeding and transfusion between the two groups. The rate of (retroperitoneal) bleeding was very low in both groups. The combined rate of groin bleeding, hematoma, arteriovenous fistula, surgical intervention, need for transfusion and prolonged hospitalization due to puncture site problems was 2.6% in the closure device group compared to 4.5% in the manual compression group (p = 0.195). We found a trend toward a lower incidence of severe hematoma at the puncture site in the closure device group compared to the manual compression group (1.6% vs. 3.5%; p = 0.134). Duration of hospital admission (secondary endpoint) and hemoglobin decrease were not significantly different between the groups. The frequency of the primary endpoint in the 4 predefined subgroups: age > 75 years, female gender, history of hypertension and prolonged procedure time are summarized in Figure 2 and Table 3. In patients with a history of hypertension, the closure device group was associated with a significantly larger benefit with regard to the combined primary endpoint. Aggregation of the prespecified subgroups did not show a significant difference in the primary endpoint between the two groups (Table 3).

Discussion

This trial, the largest randomized comparison of a closure device versus manual compression in patients treated with antiplatelet/antithrombotic therapy, including aspirin, clopidogrel, UFH and GPI, shows that closure device use did not reduce the combined primary endpoint significantly. Therefore, the main advantage of a closure device may be patient comfort with shorter bedrest and immobilization. However, in patients with a history of hypertension the combined primary endpoint was significantly reduced, a finding that merits further investigation. Previous studies. Exaire et al showed no difference in bleeding between manual compression and suture-based (Perclose) or collagen-based (Angio-Seal, Vasoseal) closure devices in patients treated with aspirin, clopidogrel and GPIs who underwent PCI.¹³ However, this study was not randomized and the patient groups were not balanced, with a lower risk in the closure device group. Two other large studies also revealed similar risks of access-site related complications between closure devices (Angio-Seal and Perclose) and manual compression in moderate- to high-risk bleeding patients.^18,19 However, retroperitoneal hemorrhage occurred significantly more often among patients treated with closure devices.¹⁸ A meta-analysis by Nikolsky et al showed a similar risk of access site-related complications for closure devices (Angio-Seal, Perclose, Vasoseal) compared with manual compression, although in the PCI setting, the Vasoseal device had more complications.²⁰ Limitations of several studies included in this meta-analysis were evaluation of first-generation devices, significant baseline differences in patient characteristics, inclusion of very select patients and limited operator and institutional experience with device use. Chevalier et al reported a superior safety and efficacy with an 8 Fr Angio-Seal device in a population at high bleeding risk compared to manual pressure.²¹ This was mainly related to a dramatic decrease in the need for prolonged compression. In our study, all procedures were performed by cardiologists with extensive Angio-Seal deployment experience (> 500 Angio-Seal deployments per cardiologist) before the start of the trial. Procedures and clinical outcome. Inappropriate location of the femoral artery puncture may influence the incidence of complications.²² However, routine fluoroscopy prior to sheath placement does not reduce complications²³ and is therefore not routinely performed at our hospital. Also, because there has been a lengthy debate regarding the merits of femoral artery angiography prior to sheath removal, the guidelines are unclear.^24–26 Little evidence exists regarding the optimal activated clotting time before arterial sheath removal, or the optimal duration of bedrest following sheath removal.^27,28 We removed the sheath immediately after PCI at the catheterization laboratory, partly to facilitate patient transfer. Our trial showed lower-than-anticipated access-site complications as compared to another previous trial.9 Potential reasons may be smaller guiding catheters (6 Fr instead of 7 Fr or 8 Fr) or use of a weight-adjusted heparin bolus (60 U/kg) instead of a standard dose.19 Also, we could have missed complications because duplex sonography to identify arteriovenous fistula or false aneurysms was not routinely performed. According to the protocol, we analyzed four prespecified subgroups (known risk factors for vascular complications). Our study revealed that patients with a history of hypertension had a significant decrease in the primary endpoint when a closure device was used. Antihypertensive medication may be protective in preventing access-site complications.²⁹ Also, a trend toward a benefit with the use of a closure device was found in elderly patients. These observations merit further investigation. Furthermore, the rate of bleeding was higher in female patients compared to the total population, however, no beneficial effect for the use of a closure device was found in females. Study strengths and limitations. The study could not be blinded. However, the primary endpoint was objective (as need for transfusion or need for surgery). Our follow-up period was until discharge and we recorded bleeding for only 24 hours after PCI. We had no data on previous history of bleeding, numbers of prior PCIs, other medications that could have influenced bleeding or renal failure and activated clotting time measurement and blood pressure at the time of sheath removal. We observed only a nonsignificant difference in the primary endpoint between the two treatment groups. Possibly, with a larger sample size, we might have found a significant difference. Efficacy of a closure device in nonselected patients is unknown and requires a much larger trial.

Conclusion

This trial did not show the superiority of using a closure device over manual compression in patients treated with triple antiplatelet therapy, who underwent PCI. The fact that patients with a history of hypertension derived a benefit from closure device placement merits further investigation.

References

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———————————————————— From the Isala Klinieken, Location Weezenlanden, Department of Cardiology, Zwolle, the Netherlands. Disclosure: This work was partly supported by an unrestricted grant from St. Jude Medical (St. Paul, Minnesota). Manuscript submitted July 28, 2010, provisional acceptance given August 27, 2010, final version accepted September 7, 2010. Address for correspondence: Jan Paul Ottervanger, MD, PhD, FESC, Isala Klinieken, Department of Cardiology, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands. E-mail: v.r.c.derks@isala.nl