Low-Dose Unfractionated Heparin Administration During Intravascular Ultrasound Studies is Safe Even Shortly After Endomyocardial Biopsy in Cardiac Transplant Patients
Abstract: Background. Full therapeutic heparin doses ranging from 5000-10,000 units or weight based (70-100 units/kg) have been recommended during percutaneous coronary interventions. However, there are currently no data available in regards to the appropriate dosing of unfractionated heparin during intravascular ultrasound (IVUS) studies without therapeutic coronary interventions. The goal of this study was to evaluate the safety of low dose unfractionated heparin during IVUS studies, shortly after endomyocardial biopsy in cardiac transplant patients. Methods. At the University of Arizona Medical Center, transplant patients routinely undergo diagnostic IVUS studies for the detection of early cardiac allograft vasculopathy (CAV) shortly after endomyocardial biopsy. A low-dose heparin (2000 to 3000 Units) is given before coronary wire and IVUS catheter advancement without checking activated clotting time. We evaluated the occurrence of any thromboembolic event or any other adverse outcomes in this population. Results. A total of 108 cardiac transplant patients, who had underwent routine IVUS studies between 2004-2008 were identified retrospectively. The average heparin dose used was 2528 ± 501 units. The left anterior descending artery was studied in 93% of cases. There was no thromboembolic event. Only one catheter-induced coronary dissection occurred treated with percutaneous coronary intervention. An endomyocardial biopsy was performed 10-15 minutes before the administration of low-dose heparin. There were no other major adverse cardiac events in this population during the procedure. Conclusion. This is the first study showing the safety of low-dose heparin use during diagnostic IVUS studies in cardiac transplant patients, even shortly after endomyocardial biopsy.
J INVASIVE CARDIOL 2012;24(4):154-156
Key words: heparin, anticoagulation, transplant, transplantation, myocardial biopsy, cardiac transplant, rejection, IVUS
The prevalence and incidence of heart failure continues to grow leading to cardiac transplantation as the last resort in many patients with end-stage heart failure.1-2 Significant advances have been made over the last 30 years in heart transplant management, with marked improvement in overall prognosis.3 Despite the overall improvement in survival, patients often face many complications during the post-transplant period. The post-transplant period can be broken up into two distinct stages, specifically, early and late. The early post-transplant stage is defined as the period within 1 year of transplantation, while the late stage is defined as 1 year after transplantation and beyond. Mortality in the early stage is associated with such entities as infection, multi-organ failure, and acute rejection.4 On the other hand, the leading cause of mortality after the first year of transplantation is cardiac allograft vasculopathy (CAV) and cancers.4,5 Endomyocardial biopsy has traditionally been utilized during the post-transplant period to provide morphological index of acute rejection.6-9 CAV is an accelerated form of intimal hyperplasia that affects the transplanted heart. CAV consists of a diffuse endothelial thickening that is secondary to the accumulation of smooth muscle cells.10 While the exact etiology of CAV is unknown, it has been postulated that both immune and non-immune mechanisms may play a role. The diagnosis of CAV is often difficult to establish based upon clinical evaluation. Despite continued advances in noninvasive techniques, the gold standard remains yearly angiography. Yet, the concept of intravascular ultrasound (IVUS) as a screening tool is gaining popularity. It allows for quantification of intimal wall thickness and has been shown to have prognostic value in predicting overall mortality, cardiac mortality, and need for re-transplantation.11-13
Full therapeutic heparin doses ranging from 5000-10,000 U or weight-based (70-100 U/kg) have been recommended during percutaneous coronary interventions.14,15 However, there are currently no data available about the appropriate dosing of heparin during IVUS studies only without therapeutic coronary interventions. The goal of this study is to retrospectively evaluate the safety of low-dose heparin (2000-3000 U) used during IVUS studies in this population shortly after endomyocardial biopsy.
At the University of Arizona Medical Center, routine annual surveillance endomyocardial biopsy and IVUS studies are performed to evaluate for acute rejection and CAV. In addition, symptom-based biopsy and IVUS studies are performed on more frequent intervals if clinically indicated. At our center, transplant patients undergo annual right heart catheterization, endomyocardial biopsy, coronary angiography, and IVUS via femoral approach. Following hemodynamic measurements using 7 Fr thermodilution Swan-Ganz catheter, the 7 Fr venous sheath is exchanged for an 8 Fr Mullins sheath. The Mullins sheath is advanced into the right ventricle over a 0.032˝ J-wire, under fluoroscopic guidance. Using a 6 Fr bioptome forceps, multiple endomyocardial biopsies are obtained and sent to the laboratory for evaluation. Following serial biopsies, the Mullins sheath is pulled back into the inferior vena cava. Next, routine coronary angiography is performed in multiple projections. Following angiography, 2000-3000 U of unfractionated heparin is administered. Patients who weigh less than 100 kg routinely receive 2000 U of heparin and those who weigh greater than 100 kg receive 3000 U of heparin. Subsequently, IVUS is performed in the vessel of choice using standard techniques (Volcano IVUS catheter and Boston Scientific 40 mHz rotational IVUS catheter) using manual pullback. The cardiac vessel chosen for IVUS examination was determined on a case-to-case basis by the interventional cardiologist performing the study. Intracoronary nitroglycerin was routinely administered prior to IVUS examination. The left anterior descending artery was the primary target in the majority of cases. If wiring of the LAD was difficult, the circumflex artery was used for IVUS studies initially and thereafter. Upon completion of IVUS, final angiographic images are obtained and all catheters are removed. Protamine was administered in all cases prior to sheath removal. Following the procedure, the patients are observed for 4 hours for any evidence of bleeding, arrhythmias, electrocardiographic changes, or significant hemodynamic changes.
In our study, we retrospectively evaluated cardiac transplant patients who underwent endomyocardial biopsy followed by routine IVUS examination using low-dose heparin (2000-3000 U) at our institution between the years 2004-2008. Patients under the age of 18 at the time of transplantation were excluded from the study. The outcome data for all patients were abstracted from medical records to evaluate for occurrence of major adverse cardiac events (MACE), including myocardial infarction, need for percutaneous intervention, coronary artery bypass grafting, re-transplantation, and death, up to 30 days post procedure. In addition, we examined the incidence of major complications associated with administration of anticoagulation following endomyocardial biopsy, including pericardial tamponade requiring pericardiocentesis, hemothorax, urgent cardiac surgery, or death.
A cohort of 108 patients had an endomyocardial biopsy and IVUS study performed for diagnosis of acute rejection and CAV between 2004 and 2008 at our institution. A total of 179 IVUS studies were performed during that time period. The patient’s baseline characteristics are listed in Table 1. The average age was 51 years old. The left anterior descending artery was the vessel studied in 93% of cases. Based on angiographic findings, 10% of patients had mild luminal irregularities and 3% had moderate stenosis. The average heparin dose used during the procedure was 2522 ± 497 U. No thromboembolic events occurred during the procedure. There was one catheter-induced coronary dissection requiring percutaneous coronary intervention. There were no deaths in our cohort. In addition, there were no other procedure-related MACE following low-dose heparin administration shortly after performance of endomyocardial biopsy.
The safety of endomyocardial biopsy via both femoral and jugular approach has been well established, with major complications defined as cardiac tamponade requiring pericardiocentesis, hemothorax, pneumothorax, need for urgent surgery, and permanent complete AV block requiring permanent pacemaker occurring in less than 1/1000 cases.9,16 However, in these prior studies evaluating the safety of endomyocardial biopsy, the patients were not anticoagulated and most of the biopsies were performed in native hearts. CAV remains one of the leading causes limiting long-term success of cardiac transplantation.The use of IVUS in addition to coronary angiography has been shown to have prognostic value.13,17,18 This has led to increasing popularity in using IVUS in cardiac transplant patients for early diagnosis of CAV. Anticoagulation is routinely administered prior to percutaneous cardiac interventions (PCI) to decrease the likelihood of thrombotic complications. Unfractionated heparin is often administered during PCI and its effects are routinely monitored by measuring activated clotting time (ACT). The recommended dose of unfractionated heparin in the absence of adjunctive glycoprotein IIb/IIIa is 70-100 IU/kg.14 However, there are currently no data available about the appropriate dosing of heparin during IVUS studies only without therapeutic coronary interventions. The current guidelines for administration of anticoagulation for IVUS is similar to other PCI procedures, with full therapeutic unfractionated heparin doses ranging from 5000-10,000 U or weight-based (70-100 U/kg) being utilized.14,15 This practice can lead to unnecessary high levels of anticoagulation with higher risk of bleeding complications. Stabile and colleagues previously demonstrated that the PCI procedure could safely be performed without the use of systemic anticoagulation in low-risks patients, who were treated with dual-antiplatelet therapy only. IVUS studies can be safely and rapidly performed without direct injury to the arterial wall, in non-tortuous, non-calcified vessels, without evidence of high-grade obstruction. Based on our study, IVUS could safely be performed in low-risk patients using low-dose unfractionated heparin (2000-3000 U) without the occurrence of any thromboembolic events. Low-risk patients are defined as those with intermediate de novo lesion in non-calcified, non-tortuous coronary arteries, without acute coronary syndrome, evidence of active thrombus, or hypercoagulable state. This low-risk population is similar to patients studied by Stabile and colleagues, who safely underwent PCI with dual-antiplatelet therapy in absence of systemic anticoagulation.19 Furthermore, based on our study, low-dose anticoagulation could be safely administered shortly after endomyocardial biopsy in transplant patients without occurrence of major complications such as cardiac tamponade or hemothorax. However, these data cannot be easily extrapolated to non-transplanted patients undergoing endomyocardial biopsy. The combination of dilated, thinned-out myocardium and anticoagulation could increase the risk of complications associated with endomyocardial biopsy, although this remains unclear.
To our knowledge, this is the first study to evaluate the safety of low-dose unfractionated heparin for anticoagulation during routine diagnostic IVUS study in transplant patients without significant flow-limiting obstruction.
Study limitations. Our study was a retrospective, single-center study, with its inherent limitations. Therefore, larger randomized trials are needed in order to definitively identify appropriate dose of unfractionated heparin during routine diagnostic IVUS study. Our study evaluated the safety of IVUS use in combination with low-dose heparin only in post-transplant patients without angiographic presence of high-grade obstruction or high plaque or thrombus burden. Furthermore, all our IVUS studies were performed in patients without clinical history of acute coronary syndrome. In addition, the time period ranging from introducing the guidewire into the coronary artery until final pullback of the IVUS catheter into the guide catheter was very short; therefore, we cannot extrapolate our finding to patients with high-grade obstructive or thrombus containing lesions, in patients presenting with acute coronary syndrome, or time-intensive procedures. Finally, due to low rates of IVUS-related complications in diagnostic cases, the lack of complications could be related to our sampling size. Future studies are needed to evaluate the safety of low dose heparin during diagnostic IVUS studies in high risk, non-transplanted patients.
- Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics — 2010 update: a report from the American Heart Association. Circulation. 2010;121(7):948-954.
- McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: public and private health burden. Eur Heart J. 1998;19(Suppl P):P9-P16.
- Taylor DO, Stehlik J, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult heart transplant report-2009. J Heart Lung Transplant. 2009;28(10):1007-1022.
- Bieber CP, Hunt SA, Schwinn DA, et al. Complications in long-term survivors of cardiac transplantation. Transplant Proc. 1981;13(1 Pt 1):207-211.
- Kapadia SR, Nissen SE, Ziada KM, et al. Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis: comparison by serial intravascular ultrasound imaging. Circulation. 1998;98(24):2672-2678.
- Winters GL, Marboe CC, Billingham ME. The International Society for Heart and Lung Transplantation grading system for heart transplant biopsy specimens: clarification and commentary. J Heart Lung Transplant. 1998;17(8):754-760.
- Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24(11):1710-1720.
- Stehlik J, Starling RC, Movsesian MA, et al. Utility of long-term surveillance endomyocardial biopsy: a multi-institutional analysis. J Heart Lung Transplant. 2006;25(12):1402-1409.
- Holzmann M, Nicko A, Kühl U, et al. Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation. 2008;118(17):1722-1728.
- Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant. 1992;11(3 Pt 2):S38-S44.
- Kapadia SR, Nissen SE, Tuzcu EM. Impact of intravascular ultrasound in understanding transplant coronary artery disease. Curr Opin Cardiol. 1999;14(2):140-150.
- Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol. 2005;45(9):1532-1537.
- Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee SR. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant. 1995;14(4):632-639.
- Baim DS. Grossman’s Cardiac Catheterization, Angiography, and Intervention. Seventh edition. Lippincott Williams & Wilkins; 2005.
- Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation. 1995;91(6):1676-1688.
- Huang J, Yang Y-jin, Yin D, et al. [Safety analyses from 439 patients underwent endomyocardial biopsy via the right internal jugular vein approach]. Zhonghua Xin Xue Guan Bing Za Zhi. 2010;38(1):43-46.
- Rickenbacher PR, Pinto FJ, Lewis NP, et al. Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation. 1995;92(12):3445-3452.
- Tuzcu EM, Kapadia SR, Sachar R, et al. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol. 2005;45(9):1538-1542.
- Stabile E, Nammas W, Salemme L, et al. The CIAO (Coronary Interventions Antiplatelet-based Only) study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. J Am Coll Cardiol. 2008;52(16):1293-1298.
From the University of Arizona School of Medicine and the Southern Arizona VA Health Care System & University of Arizona Sarver Heart Center, Tucson, Arizona.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted December 20, 2011, provisional acceptance given February 7, 2012, final version accepted February 16, 2012.
Address for correspondence: Dr. Mohammad Reza Movahed, Professor, Southern Arizona VA Health Care System & Univ. of Arizona Sarver Heart Center, Department of Medicine, Division of Cardiology, 1501 N. Campell Avenue, Tucson, AZ 85724-5037. Email: firstname.lastname@example.org