So Far, So Good …

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So Far, So Good . . .

JOHN K. TRIEDMAN, M.D.

From the Department of Cardiology, Children’s Hospital, Boston, Massachusetts, USA

Editorial Comment

A common problem encountered in retrospective clinicalstudies is the attribution of the effects of random or uncon-trolled influences to a therapeutic intervention. In an idealworld, every clinical problem worthy of study would presentitself frequently, with a large number of clinically specificendpoints that could be easily and cost effectively evaluatedby prospective randomized study. In reality, many clinicalproblems occur at low frequency and/or in small patient pop-ulations. Thus, the careful interpretation of retrospective dataremains an important foundation of clinical practice.

Thromboembolism is a rare but feared complication ofcatheter ablation. Early studies, including a survey of ablationpractice in adults,1 an ablation registry for children,2 and anindustry-sponsored regulatory study,3 demonstrated an em-bolic risk between 0.6% and 0.8%. Left-sided procedures hada higher risk, ranging from 1.8% to 2%.3,4 An understandingof thromboembolism and its prophylaxis during ablation hasbecome even more important, as practitioners target a widerrange of left atrial mechanisms for ablation. Procedures totreat atrial fibrillation and macroreentrant left atrial tachy-cardias, performed in patients already at high risk for throm-boembolism, involve placing more catheters in the left atriumfor a longer duration, in order to make more lesions. Concernsthat increased rates of thromboembolism might complicatethese types of procedures appear justified, with reported ratesin small series ranging from 2.5% to 5%.5,6

In this issue of the Journal, Cauchemez et al.7 examinethe effect of sheath irrigation and other aspects of sheathmanagement on the incidence of thromboembolism in pa-tients undergoing left atrial ablation. Their clinical protocolentails careful attention to anticoagulation and serial neu-rologic evaluations performed before and after the proce-dure. Initially, they irrigated the transseptal sheaths used forleft atrial access at a low rate (3 mL/hour). Midway throughtheir reported experience, several serious neurologic eventswere observed. This prompted the change highlighted in thisreport—substitution of high-flow (180 mL/hour) for low-flowirrigation of the transseptal sheath—as well as other, lesswell-quantified modifications of sheath management. Thesechanges were followed by an apparent elimination of theconsiderable risk of cerebrovascular event that they experi-enced in their initial patients. Multivariate statistical analysissuggested that the principal variable associated with this de-creased risk was, in fact, the change made to irrigation flowrate. Is this a controlled trial? How should this potentiallyimportant and valuable observation be interpreted?

J Cardiovasc Electrophysiol, Vol. 15, pp. 284-285, March 2004.

Address for correspondence: John K. Triedman, M.D., Department of Car-diology, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115.Fax: 617-566-5671; E-mail: john.triedman@cardio.chboston.org

doi: 10.1046/j.1540-8167.2004.03589.x

At least three plausible contributors to embolic risk havebeen postulated: (1) patient factors predisposing to throm-boembolism and unrelated to ablation; (2) a thrombogeniceffect of thermal injury on the endocardial surface; and(3) activation of the clotting system and/or release of em-bolic fragments from the catheters and sheaths themselves.In clinical studies, the relative rarity of embolic events hasmade it difficult to isolate risk factors for thromboembolismbeyond the obvious predilection for ablations performed onthe left side of the heart. Epstein et al.3 noted that almostall patients experiencing thromboembolic events had predis-posing risk factors for embolic events, whereas duration ofablation, number of lesions, anticoagulation, and impedancerises did not correlate with thromboembolism. Thakur et al.4

found no association of intraprocedural or postprocedural an-ticoagulation to the incidence of this complication.

Studies also have been performed to explore the relation-ship of catheterization and ablation to more subtle mark-ers of thrombogenicity. A controlled study of postablationD-dimer levels showed evidence of reactive fibrinolysis inthe first postablation day, an effect partially suppressed bypretreatment with antiplatelet agents.8 Anfinsen et al.9 ob-served that fibrinolytic activity increased with placement ofsheaths and diagnostic catheter before ablation, that earlyadministration of heparin prevented activation of thrombo-genesis, and that saline irrigation of sheaths had no effectin patients not given early heparin.10 Rapid appearance ofthrombus on sheaths inserted in the left atrium also has beenobserved by echocardiographic study.11 Together, these stud-ies indicate a significant thrombogenic effect of catheteriza-tion procedures. This effect is independent of preexisting riskfor thromboembolism, but also of uncertain relation to clini-cal thromboembolic events.

The extensive analysis of their patient group byCauchemez et al. leads the authors to conclude that high-flowsheath irrigation was associated with a large reduction in therisk of thromboembolism. One possible explanation for thisis that irrigation inhibits thrombus formation by eliminatingregions of blood stasis at the luminal surfaces and tip of thesheath. Unfortunately, the strength of this potentially impor-tant conclusion is weakened by the retrospective design of thestudy. This design may allow for biased patient selection and,therefore, an erroneous estimate of initial risk, as well as theinclusion of unknown covarying factors that may be tightlycoupled to the intervention to which risk has been attributed.In this particular group of patients, an elevated risk of throm-boembolism manifested itself as a cluster of bad outcomes,which prompted the investigators to suspend their work andconsider possible solutions to this problem. Although thispause allowed the adoption of several sensible changes inthe clinical protocol, it also caused the initial “sick” group ofpatients to be selected as the “control group.” Because thosechanges in practice were made, well...so far, so good!!

What can be concluded from these data is that they tendto confirm the importance of the mechanical presence of the

Triedman Editorial Comment 285

catheters themselves in the arterial circulation as a risk factorfor thromboembolism—one clearly not entirely obviated byadministration of heparin alone. The data also suggest that,in addition to the provision of anticoagulation, meticulousmanagement of the devices used in ablation may substan-tially ameliorate that residual risk. If a simple interventionsuch as increasing the rate of sheath irrigation decreases therisk of thromboembolic event during ablation, it should bepromptly adopted as a standard clinical practice. The po-tential presence of confounding factors in this retrospectiveanalysis does not invalidate these useful observations madeby the authors but highlights the importance of testing themin a properly controlled study. Hopefully, further structured,prospective investigation of the safety and efficacy of thisintervention will be forthcoming.

References

1. Hindricks G: The Multicentre European Radiofrequency Survey(MERFS): Complications of radiofrequency catheter ablation ofarrhythmias. The Multicentre European Radiofrequency Survey(MERFS) investigators of the Working Group on Arrhythmias of theEuropean Society of Cardiology. Eur Heart J 1993;14:1644-1653.

2. Kugler JD, Danford DA, Deal BJ, Gillette PC, Perry JC, Silka MJ, VanHare GF, Walsh EP: Radiofrequency catheter ablation for tachyarrhyth-mias in children and adolescents. N Engl J Med 1994;330:1481-1487.

3. Epstein MR, Knapp LD, Martindill M, Lulu JA, Triedman JK, CalkinsH, Huang SK, Walsh EP, Saul JP: Embolic complications associated

with radiofrequency catheter ablation. Atakr Investigator Group. Am JCardiol 1996;77:655-658.

4. Thakur RK, Klein GJ, Yee R, Zardini M: Embolic complications afterradiofrequency catheter ablation. Am J Cardiol 1994;74:278-279.

5. Haissaguerre M, Jais P, Shah DC, Garrigue S, Takahashi A, Lavergne T,Hocini M, Peng JT, Roudaut R, Clementy J: Electrophysiological endpoint for catheter ablation of atrial fibrillation initiated from multiplepulmonary venous foci. Circulation 2000;101:1409-1417.

6. Kok LC, Mangrum JM, Haines DE, Mounsey JP: Cerebrovascular com-plication associated with pulmonary vein ablation. J Cardiovasc Elec-trophysiol 2002;13:764-767.

7. Cauchemez B, Extramiana F, Cauchemez S, Cosson S, Zouzou H,Meddane M, d’Allonnes LR, Lavergne T, Leenhardt A, Coumel P,Houdart E: High flow perfusion of sheaths for prevention of throm-boembolic complications during complex catheter ablation in the leftatrium. J Cardiovasc Electrophysiol 2004;15:276-283.

8. Manolis AS, Vassilikos V, Maounis TN, Psarros L, Melita-ManolisH, Papatheou D, Haliassos A, Christopoulou-Cokkinou V, CokkinosDV: Pretreatment with aspirin and ticlopidine confers lower throm-bogenic potential of radiofrequency catheter ablation. Am J Cardiol1997;79:494-497.

9. Anfinsen OG, Gjesdal K, Brosstad F, Orning OM, Aass H, KongsgaardE, Amlie JP: The activation of platelet function, coagulation, and fibri-nolysis during radiofrequency catheter ablation in heparinized patients.J Cardiovasc Electrophysiol 1999;10:503-512.

10. Anfinsen OG, Gjesdal K, Aass H, Brosstad F, Orning OM, Amlie JP:When should heparin preferably be administered during radiofrequencycatheter ablation? Pacing Clin Electrophysiol 2001;24:5-12.

11. Maleki K, Mohammidi R, Steinberg JS: Thrombus on transseptal sheath:detection by continuous intracardiac ultrasound and successful treat-ment by aspiration. (Abstract) Pacing Clin Electrophysiol 2003;26:987.