Debate: Asymptomatic Patients with Ventricular Preexcitation Require EP Testing for Risk Stratification. Carlo Pappone, MD, PhD, FACC

Transcription

1 Debate: Asymptomatic Patients with Ventricular Preexcitation Require EP Testing for Risk Stratification Carlo Pappone, MD, PhD, FACC

2 The Wolff-Parkinson-White Syndrome Demographics Δ waves detectable on an ECG have been reported to be present in 0.15 to 0.25% of the general population.1,2 1. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of electrocardiographic preexcitation in men. The Manitoba Follow-up Study. Ann Intern Med 1992;116: Sorbo MD, Buja GF, Miorelli M, et al. The prevalence of the Wolff-Parkinson-White syndrome in a population of 116,542 young males. G Ital Cardiol 1995;25: A higher prevalence of 0.55% has been reported in first-degree relatives of patients with accessory pathways.3 3. Vidaillet HJ Jr, Pressley JC, Henke E, Harrell FE Jr, German LD. Familial occurrence of accessory atrioventricular pathways (preexcitation syndrome). N Engl J Med 1987;317:65-9.

3 Gollob, M. H. et al. N Engl J Med 2001;344: Regulation and Function of AMP-Activated Protein Kinase

4 The Wolff-Parkinson-White Syndrome Pathophysiology According to current guidelines, the diagnosis of WPW syndrome is reserved for patients who have both pre-excitation and tachyarrhythmias.

5 The Wolff-Parkinson-White Syndrome ECG features WPW Normal ECG QRS QRS Δ wave T T P Short PR P Normal PR

6 The Wolff-Parkinson-White Syndrome Atrio-Ventricular Reciprocating Tachycardia

7 Atrial fibrillation and the risk of sudden cardiac death

8 Preexcited Sustained Atrial Fibrillation

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10 Therapeutic approach according to current guidelines Symptomatic WPW Asymptomatic WPW Class I indication Class I indication Transcatheter radiofrequency ablation of the accessory pathway NONE

11 Main indication to AP Ablation At HSR Silent Lifethreatening arrhyhtmias 4% Prophylactic 12% High-risk occupations 9% Palpitations due to AVRT 75%

12 SINDROME DI WOLFFPARKINSON-WHITE

13 RF Ablation

14 AP Localization Antero-Septal Anterior Antero-lateral Antero-lateral AORTA Lateral HIS Lateral MITRAL VALVE TRICUSPID VALVE CORONARY SINUS Postero-lateral DISTRIBUTION OF ACCESSORY PATHWAY Postero-lateral 24% Postero-Septal 42% 6% 9% 2% 1% 2% 23% AS LFW PS+RFW PS RFW LFW+RFW LFW+PS

15 Case Volume From 1989 to Center: HSR Milan Brescia Palermo Catania 2500 No./year Year AFlutter AFib AVNRT Asymptomatic AP Concealed AP Manifest AP 2003

16 Cumulative Success Rates (n=18600 pts) Mean F/U 359 ± 35 Mo. AVRT-free 99.8% Multiple AP 98.8%* Single AP 99.9%*

17 Safety (N=18600) Death 0 (0%) Pericardial effusion 15 (0.1%) Anesthesia-related 24 (1.6%)* Complete AV block 4 (0.02%)** Bundle branch block 24 (0.16%) Femoral venous hematoma 36 (0.24%) *relative to the pediatric population, N=1467 **in two patients a dual-chamber PKR was implanted

18 Therapeutic approach according to current guidelines Symptomatic WPW Asymptomatic WPW Class I indication Class I indication Transcatheter radiofrequency ablation of the accessory pathway NONE?

19 Sudden Death in WPW Syndrome and Risk Stratification The incidence of sudden cardiac death in patients with WPW syndrome has been estimated to range from 0.15 to 0.39% over 3- to 10-year follow-up. It is unusual for cardiac arrest to be the first symptomatic manifestation of WPW syndrome. Conversely, in about half of the cardiac arrest cases in WPW patients, it is the first manifestation of WPW syndrome. Given the potential for AF among patients with WPW syndrome and the concern about sudden cardiac death resulting from rapid pre-excited AF, even the low annual incidence of sudden death among patients with WPW syndrome is of note and supports the concept of liberal indications for catheter ablation.

20 Atrial fibrillation and the risk of sudden cardiac death

21 Preexcited Sustained Atrial Fibrillation

22 Preexcited Sustained Atrial Fibrillation degenerating into VF

23

24 Inducible patients were younger and with a shorter APERP

25 Patients who became symptomatic were younger and with a shorter APERP

26 By putting all clinical and electrophysiological variables, we found only a younger age and inducibility as predictors of future arrhythmias APERP had no significant impact on arrhythmic risk and cannot be used in a schema for stratify risk

27 KM analysis of the cumulative risk of arrhythmic events

28 The first 3 VF cases we had young, multiple AP inducibility

29 Should the current guidelines be changed? It is difficult to make a strong recommendation for a strategy that, in the final analysis, will arguably result in comparable morbidity and mortality to the problem addressed. If an EP study is performed for risk stratification, the combination of inducible AVRT and a SPRR interval in AF of <250 ms provide the most compelling indications for ablation.

30 Despite the JACC study... Management of Patients With Asymptomatic WPW The role of electrophysiological testing and catheter ablation in asymptomatic patients with pre-excitation is controversial. The decision to ablate pathways in individuals with high-risk occupations, such as school bus drivers, pilots, and scuba divers, is made on the basis of individual clinical considerations.

31 On the Background of the JACC paper... That YOUNG AGE AND INDUCIBILITY identify asymptomatic patients with a Wolff Parkinson White pattern on the ECG as being at HIGH RISK for arrhythmic events. We tested the hypothesis that PROPHYLACTIC CATHETER ABLATION of accessory pathways would provide meaningful and durable benefits as compared with no treatment.

32 From the Department of Cardiology, Electrophysiology and Cardiac Pacing Unit, San Raffaele University Hospital, Milan N Engl J Med 2003;349:

33 Study Protocol Among 224 eligible asymptomatic WPW patients, patients at high risk for arrhythmias were randomly assigned to catheter ablation (37 patients) or no treatment (35 patients). The end point was the occurrence of arrhythmic events over a fiveyear follow-up period.

34 High-Risk WPW The fourth VF case All patients continued to exhibit ventricular preexcitation 60 percent had arrhythmic events. The arrhythmic event was SVT in 15 patients, AF in 5 patients and VF as the presenting symptom in a 22-year-old man.

35 Low-Risk WPW Symptoms of supraventricular tachycardia developed in six patients. All but 1 of the 148 had single accessory pathways. Twenty patients stopped having ventricular preexcitation during follow-up.

36 Results Two patients in the ablation group (5 percent, AV nodal tachycardia) and 21 in the control group (60 percent) had arrhythmic events. One control patient had ventricular fibrillation as the presenting arrhythmia. The 5-year Kaplan Meier estimates of the incidence of arrhythmic events were 7 percent among ablated patients and 77 percent among the controls (P<0.001 by the log-rank test). The risk reduction with ablation was 92 percent (relative risk, 0.08; 95 percent confidence interval, 0.02 to 0.33;P<0.001).

37 High-Risk WPW

38 High-Risk WPW

39 Conclusions Prophylactic ablation markedly reduces the frequency of arrhythmic events in asymptomatic WPW patients who are at high risk.

40 Conclusions Thus, we suggest expanding recommendations for invasive evaluation of asymptomatic WPW patients. Patients without inducible arrhythmias do not require prophylactic ablation. Young patients with inducible arrhythmias may be divided into two subgroups. In those with inducible AVRT, whether or not it triggers sustained AF, ablation is mandatory. On the other hand, in patients with inducible, nonsustained AF, ablation may be deferred.

41 Whether prophylactic ablation for the prevention of symptomatic episodes will gain wide acceptance remains to be seen. What is certain is that these new data will animate debate on a critical question that was thought to have been put to rest.

42 From the Department of Cardiology, Electrophysiology and Cardiac Pacing Unit, San Raffaele University Hospital, Milan N Engl J Med 2004;351:23-31.

43 172 Children recruited 7 Excluded 165 Eligible 105 Low-risk 60 High-risk FOLLOW-UP RANDOMIZATION 3 Dropouts 10 Dropouts 20 Children who underwent ablation 27 Control children 7.6% AVRT/AF 44% AVRT/AF 2 VF, 1 SCD 5% AVRT All patients underwent an EPT to asses inducibility Patients in whom AVRT or AF was reproducibly induced were considered to be at high risk and were randomly assigned to either RF ablation of AP (the ablation group) or no ablation (the control group). Patients in whom arrhythmias were not induced were considered to be at low risk.

44 Low-Risk WPW Symptoms of SVT developed in 8/105 children. All but 7 /105 had single accessory pathways. No subjects stopped having ventricular preexcitation during f/u.

45 High-Risk WPW All patients continued to exhibit ventricular preexcitation 12 out 27 untreated high-rigk children developed arrhythmias 7 had SVT leading to syncope or presyncope. 5 developed asymptomatic or minimally symptomatic life-threatening arrhythmias including 1 SD 2 VF The last 3 VF cases

46 The number of high-risk patients needed to treat to prevent arrhythmic events in one of these patients was 2.0 (95%CI, 1.4 to 3.1). For all the high-risk patients, the independent predictors of arrhythmic events were the absence of prophylactic ablation (HR, 69.4; 95%CI, 5.1 to 950.0; P=0.001) and

47 and multiple accessory pathways (HR, 12.1; 95%CI, 1.7 to 88.2; P=0.01). Indeed, patients in the control group who had single APs were more likely to be free of arrhythmias than those with multiple APs.

48 Conclusions Prophylactic ablation markedly reduces the frequency of arrhythmic events EVEN in asymptomatic WPW patients who are at high risk.

49 Conclusions Thus, we suggest expanding recommendations for invasive evaluation of asymptomatic WPW children. Children without inducible arrhythmias do not require prophylactic ablation. Children with inducible arrhythmias may be divided into two subgroups. In those with multiple AP ablation is mandatory. On the other hand, in children with a single AP, ablation may be deferred.

50 This study is important because it indicates that a WPW ECG in an asymptomatic child is not necessarily a benign finding and that a procedure can be performed to prevent an adverse outcome. But the identification and treatment of high-risk children would require the availability of centers with sufficient experience to perform intracardiac studies and ablative procedures in children with minimal risk and no long-term adverse effects.

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52 The Natural History of WPW Syndrome Because previous longitudinal natural history studies enrolled mostly older subjects, it is not surprising that they reported a much lower incidence of life-threatening events, probably missing the peak of events that usually occur in younger patients. To define the true natural history of the disease, larger numbers of asymptomatic subjects, particularly children, are required.

53 Study Design Submitted to Lancet

54 Study Patients Variable Arrhythmic events All patients (n = 477) Yes (n = 80) No (n = 397) < < <0.001 Location of accessory pathways (%) Left free wall Right free wall Posteroseptal Anteroseptal <0.001 Left free wall and posteroseptal Left free wall and right free wall Right free wall and posteroseptal <0.001 Length of AVRT cycle (msec) Median Interquartile range SPRR interval during sustained AF (msec) Median Interquartile range Age (yr) Median Interquartile range Male sex (%) Associated disease (%) Anterograde APERP (msec) Median Interquartile range Multiple accessory pathways (%) Arrhythmia induction (%) Ns-AF AVRT AVRT triggering s- AF P Value APERP: accessory pathway effective refractory period; Ns-AF: non sustained atrial fibrillation; s-af: sustained atrial fibrillation; AVRT: atrioventricular reentrant tachycardia. Submitted to Lancet

55 Age Distribution among 477 Asymptomatic WPW 25 % Age (years) Submitted to Lancet

56 A Remaining Asymptomatic (%) Remaining Asymptomatic (% B Age class 0.2 > Age (years) Age (years) Submitted to Lancet

57 Sex-related Effects Submitted to Lancet

58 AP-related Effects Submitted to Lancet

59 Inducibility-related Effects Submitted to Lancet

60 Predictors of Outcome A. Overall Arrhythmic Events Variable Estimated Coefficient P value Hazard Ratio 95% Confidence Interval Lower Upper Age* Age >5 15 (years) < Age >15 25 (years) < Age >25 35 (years) Multiple AP Inducibility on EP Testing < AP Effective Period P value Hazard Ratio Refractory B. Life-Threatening Arrhythmic Events Variable Estimated Coefficient 95% Confidence Interval Lower Upper Age** Multiple AP Inducibility on EP Testing AP Effective Period Sex Refractory P values by Multivariate Cox regression analysis; a backward conditional stepwise method for variable selection was applied, including age, sex, the presence of associated structural heart disease, inducibility on EP testing, Multiple AP, and baseline anterograde refractory period of the accessory pathways. *Subjects >35 years were regarded as reference category with an attributable hazard ratio of 1. WPW: Wolff-Parkinson-White; AP: accessory pathways; EP: electrophysiological testing **As continuous variable Submitted to Lancet

61 The Natural History of WPW Syndrome VF free- Survival probability Log Rank p = A total of 7 cases of VF were observed among high-risk untreated subjects as compared with none among subjects traeted prophylactically. high risk ablated high risk non-ablated Time (years) 3 4 Submitted to Lancet

62 The Natural History of WPW Syndrome Baseline characteristics of the eight asymptomatic subjects with the Wolff-Parkinson-White syndrome experiencing ventricular fibrillation. Variable Patient #1* Patient #2 Patient #3 Patient #4 Patient #5* Patient #6 Patient #7 Age (yr) Male sex M F M M M M M Structural heart disease no no no no No no no Anterograde refractory period of accessory pathways (msec) Anterograde refractory period of accessory pathways after isoproterenol (msec) Multiple accessory pathways yes yes yes Yes Yes yes yes LFW+RFW LFW+PS LFW+PS LFW+PS LFW+PS LFW+PS Inducibility yes yes yes Yes Yes yes yes AVRT triggering AF yes yes yes Yes Yes yes yes Length of atrioventricular reciprocating tachycardia cycle (msec) Shortest preexcited RR interval during sustained atrial fibrillation (msec) Location of multiple accessory pathways LS+RS Submitted to Lancet

63 Conclusions We prospectively collected data on 477 asymptomatic untreated WPW subjects of all ages. In a total observation time of 2070 patientyears, 16.8% became symptomatic, and 26 of them had life-threatening arrhythmias, including VF, from which 5 subjects were resuscitated and 2 subjects died. Younger age, inducibility, and multiple pathways independently predicted arrhythmic events along with AP AERP

64 A P<0.001 Submitted to Lancet

65 B High-Risk (>50%) Age 25, Inducible, Multiple AP (87%) Age >25, Inducible, Multiple AP (60%) Age 25, Inducible, Single AP (59%) Intermediate-Risk (20% to 50%) Age >25, Inducible, Single AP (32%) Age 25, Not-Inducible, Multiple AP (25%) Low-Risk (<20%) Age 25, Not-Inducible, Single AP (7%) Age >25, Not-Inducible, Single AP (2%) Age >25, Not-Inducible, Multiple AP (0%) Submitted to Lancet

66 Conclusions Careful risk stratification should be employed for clinical decision making in asymptomatic ventricular preexcitation. It is reasonable to limit prophylactic RF catheter ablation to the asymptomatic subjects who have the highest risk.

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68 Ramaining Asymptomatic (%) P< With catheter ablation the risk of arrhythmic events is lowered to that of low-risk subjects in whom prophylactic ablation is not recommended. 0.2 High-Risk Ablated Subjects High-Risk Non-Ablated Subjects Low-Risk Subjects Follow-up (months) 36 48

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70 Number needed to treat to harm Absolute difference in survival Number needed to treat to benefit Time since randomization (years) The number of high-risk patients needed to treat to prevent arrhythmic events in one of these patients was 2.0 with an increased benefit as time since randomization increase. Of note at no follow-up point ablation was harm

71 Conclusions Although we agree with Wellens conclusions that noninvasive studies may be the first step to identify the low-risk patient, our data provide sufficient evidence that it will be beneficial to address the role of invasive testing in future guidelines to identify high-risk subjects for prophylactic catheter ablation.