LETTER TO THE EDITOR
Reply
Ulrike Krumsdorf, MD,
Stefan Ostermayer, MD,
Kai Billinger, MD,
Thomas Trepels, MD,
Elisabeth Zadan, MD,
Kathrin Horvath, MD and
Horst Sievert, MD, PHD
CardioVascular Center Frankfurt, Sankt Katharinen, Seckbacher Landstrasse 65, 60389 Frankfurt, Germany
(Email: horstsievertMD{at}aol.com).
We greatly appreciate the comments and suggestions by Drs. Landzberg and colleagues, Massimo and colleagues, Jux and Bertram, and Schräder regarding our recent paper (1).
First, we absolutely share the opinion of Landzberg and colleagues that randomized trials are superior to nonrandomized trials! Conversely, nonrandomized trials are better than no trials at all! And before a randomized trial can be initiated we have to have an idea about what we are looking for and what the incidence of a specific event like thrombus formation might be. Dr. Landzberg and his colleagues know very well how difficult it is to conduct a randomized trial in catheter closure of intracardiac defects. Although the first transcatheter atrial septal defect (ASD) closure was performed more than 25 years ago, until today no randomized trial has ever been started.
Regarding patent foramen ovale (PFO) closure, initial experience in nonrandomized trials in their centers and in our center provided the data to adequately plan and conduct randomized trials that have just been initiated. Results will probably not be available within the next three to five years. We are sure that Dr. Landzberg and colleagues acknowledge that this is the first study in which transesophageal echocardiography (TEE) follow-up was performed in a prospective way in a patient group large enough to detect significant numbers of rare adverse events like thrombus formation. Now we know that the incidence of thrombus formation is low. With this information one might consider randomized trials to investigate this issue further. However, it is not very likely that the occurrence of thrombi on different devices will ever be investigated in a randomized trial. Their criticism regarding preprocedural assessment of prothrombotic risks, intraobserver variability, interobserver variability, and so forth is well taken, but this has to be investigated in the next 1,000-patient study. Also, we totally agree that it is very difficult to define sensitivity and specificity of echocardiographically detected device-related thrombosis because there is apparently no other technique available to diagnose thrombus formation better than TEE. So how can we determine sensitivity and specificity?
Dr. Massimo and colleagues underlined the role of activated clotting time (ACT) during the procedure in their experience. We did not monitor anticoagulation by the ACT. In our patient population, we have no doubt that during the procedure the ACT was within therapeutic range because our standard dose of heparin was 20,000 U until Patient #817 and 10,000 U after Patient #818. Initially this was according to one of the study protocols. Later this high dose of heparin was also used in clinical practice owing to apparently good results. Nineteen of 20 patients with thrombus formation had received 20,000 U of heparin during the procedure. More important may be the fact that the first 817 patients (and accordingly 19 of 20 thrombus patients) received protamine at the end of the procedure to allow early sheath removal.
Dr. Massimo and colleagues also speculated that thrombus formation may have occurred immediately after the procedure. It is well known that, in adults, atrial thrombus formation after device closure can neither be diagnosed nor excluded with TEE. Recently, similar incidences of thrombus formation on closure devices have been reported without use of protamine (2). Furthermore, it is a fact that protamine is used routinely to reverse the anticoagulant effect of heparin following cardiac surgery, including valve replacement and ASD patch closure, other vascular procedures, and hemodialysis, apparently without causing thromboembolic complications (3–6). Protamine acts as a heparin antagonist, but it does not have any thrombogenic potential.
Conversely, excessive protamine administration or protamine administration in the absence of heparin has an anticoagulant effect and can result in a "paradoxical" bleeding diathesis (7,8). Protamine given before sheath removal was not a significant risk factor for thrombus formation in our patients, but this may be due to the small numbers of patients treated without protamine. In the last three decades there have been several prospective studies with cohorts ranging from 50 to 429 patients (9–14) and which tested the approach of reversing anticoagulation by protamine administration after percutaneous coronary intervention. Shorter compression times, lower incidence of bleedings, rapid mobilization, and significant reduction in the number of in-hospital days had been the main advantages. Reversal of anticoagulation by protamine even after stent implantation did not predispose to thrombotic complications (11–14).
We agree with Dr. Massimo and colleagues that a prolonged antiplatelet therapy may help to prevent late thrombus formation. One thrombus was detected five years after implantation. However, we do not know at what time these late thrombi develop. This event is so rare that it is an open question whether a prolonged (>6 months) antiplatelet therapy that has its own risks is justified.
Of course, all 593 PFO patients had an embolic event prior to the procedure. Otherwise a PFO closure would not have been indicated. On average, our 593 patients had 1.2 embolic events before the procedure.
We agree with Drs. Jux and Bertram that a routine follow-up by TEE should be performed for all intracardiac devices. As described on page 304 in our study (1), thrombus formation also occurred on an Amplatzer (AGA Medical Corp., Golden Valley, Minnesota) device. Age was not a risk factor for thrombus formation in our adult patient population, but of course this may be different if children are taken into consideration. We are aware of the fact that in some other series the incidence of thrombus formation, even with the CardioSEAL/STARflex (NMT Medical, Boston, Massachusetts) and the PFO-Star (Applied Biometrics Inc., Barnsville, Minnesota), was lower than in our patient population. In some of these series, children were included (obviously with a lower risk of thrombus formation); in some others it was not clear in how many patients and how long after implantation a TEE follow-up was actually performed (15–17).
Regarding the comments of Dr. Schräder, the thrombus on the Amplatzer device did not occur after four weeks but six months after implantation as described in our study on page 304 (1). Regarding the thrombus detected by Gaul et al. (18), 5.7 years after implantation of a Sideris occluder in our institution: this confirms our experience that late thrombus formation may occur. We are happy to hear that Dr. Schräder now shares our opinion that life-long follow-up after device closure is mandatory.
As Moore and Levi (19) noted in their editorial, our report offers reasonable assurance that the incidence of thrombi and related embolic events is low enough to justify continued use for ASD and PFO closure and that thrombus formation usually resolves under appropriate anticoagulation therapy. We would like to emphasize that, for the most part, PFO closure with a device is a safe and simple procedure. Every device offers some advantage over others, and indeed there is no "perfect" device on the market today. Like any new therapy, optimizing the treatment requires a certain degree of learning and risk. It is also important to note that other complications are associated with different devices not addressed in our report. Therefore, placing judgment and device selection on one attribute is not appropriate.
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References
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1. Krumsdorf U, Ostermayer S, Billinger K, et al. Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients J Am Coll Cardiol 2004;43:302-309.[Abstract/Free Full Text]
2. Anzai H, Child J, Natterson B, et al. Incidence of thrombus formation on the CardioSEAL and the Amplatzer interatrial closure devices Am J Cardiol 2004;93:426-431.[CrossRef][Medline]
3. Zapol WM. Heparin–protamine lung vasoconstriction at heart surgery. Crisp U.S. Data Base National Institutes of Health, 1992: 94/HL42397–03..
4. Anderson JM, Johnson TA. Hypertension associated with protamine sulfate administration Am J Hosp Pharm 1981;38 ISS:701-703.
5. Kimmel SE, Sekeres MA, Berlin JA, et al. Risk factors for clinically important adverse events after protamine administration following cardiopulmonary bypass J Am Coll Cardiol 1998;32:1916-1922.[Abstract/Free Full Text]
6. Just-Viera JO, Fischer CR, Gago O, Morris JD. Acute reaction to protamineIts importance to surgeons. Am Surg 1984;50:52-60.[Medline]
7. Carruthers SG, Hoffman BB, Melmon KL, Nierenberg DW. Melmon and Morelli's Clinical Pharmacology: Basic Principles in Therapeutics4th ed. New York, NY: McGraw-Hill Medical Publishing; 2000777–8.
8. Royal Pharmaceutical Society of Great Britain The Complete Drug Reference3rd ed. London, UK: Pharmaceutical Press; 20021020–1.
9. Eyer KM. Complications of transfemoral coronary arteriography and their prevention using heparin Am Heart J 1973;86:P428.[CrossRef]
10. Dotter CT, Keller FS, Rosch J, et al. Value of protamine following heparin-covered angiography: double blind placebo controlled study Radiology 1980;135 ISS:229-230.
11. Pan M, Suarez de Lezo J, Medina A, et al. In-laboratory removal of femoral sheath following protamine administration in patients having intracoronary stent implantation Am J Cardiol 1997;80:1336-1338.[CrossRef][Medline]
12. Ducas J, Chan MC, Miller A, et al. Immediate protamine administration and sheath removal following percutaneous coronary intervention: a prospective study of 429 patients Catheter Cardiovasc Interv 2002;56:196-199.[CrossRef][Medline]
13. Briguori C, Di Mario C, De Gregorio J, et al. Administration of protamine after coronary stent deployment Am Heart J 1999;138:64-68.[CrossRef][Medline]
14. Kuiper KK, Nordrehaug JE. Early mobilization after protamine reversal of heparin following implantation of phosphorylcholine-coated stents in totally occluded coronary arteries Am J Cardiol 2000;85:698-702.[CrossRef][Medline]
15. Chessa M, Carminati M, Butera G, et al. Transcatheter occlusion of secundum atrial septal defect J Am Coll Cardiol 2002;39:1061-1065.[Abstract/Free Full Text]
16. Braun MU, Fassbender D, Schoen SP, et al. Transcatheter closure of patent foramen ovale in patients with cerebral ischemia J Am Coll Cardiol 2002;39:2019-2025.[Abstract/Free Full Text]
17. Braun M, Gliech V, Boscheri A, et al. Transcatheter closure of patent foramen ovale (PFO) in patients with pardoxical embolism. Periprocedural safety and mid-term results of three different device occluder systems Eur Heart J 2004;25:424-430.[Abstract/Free Full Text]
18. Gaul C, Heckmann JG, Bremer J, et al. Thrombus attached to a Sideris septal occluder system 6 years later Dtsch Med Wochenschr 2004;128:87-90.[CrossRef]
19. Moore JW, Levi DS. Transcatheter closure of atrial shuntsFocus on a lingering issue. J Am Coll Cardiol 2004;43:310-312.[Free Full Text]
Related Article
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Risk of thrombus formation on devices used to close transcatheter atrial septal defect and patent foramen ovale
- Chessa Massimo, Butera Gianfranco, and Carminati Mario
J. Am. Coll. Cardiol. 2004 44: 1712.
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