The Benefit of Pacemaker Therapy in Patients with ... - CiteSeerX

DOI: 10.1161/CIRCEP.113.001103

1

The Benefit of Pacemaker Therapy in Patients with Presumed Neurally-Mediated Syncope and Documented Asystole is Greater when Tilt Test is Negative. An Analysis from the Third International Study on Syncope of

Uncertain Etiology (ISSUE-3)

Running title: Brignole et al.; Pacemaker efficacy and tilt test responses

Michele Brignole, MD1; Paolo Donateo, MD1; Marco Tomaino, MD2; Riccardo Massa, MD3;

Matteo Iori, MD4; Xulio Beiras, MD5; Angel Moya, MD6; Teresa Kus, MD, PhD7; Jean Claude

Deharo, MD8; Silvia Giuli, MSc9; Alessandra Gentili, MSc9; Richard Sutton, DSc10 on behalf of

the International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators

Department of Cardiology, 1Ospedali del Tigullio, Lavagna; 2Ospedale di Bolzano, Bolzano;3Ospedale SS. Antonio e Biagio e Cesare Arrigo, Alessandria; 4Arcispedale S. Maria Nuova, Reggio

Emilia, Italy; 5Hospital Xeral de Vigo, Vigo; 6Hospital Universitario Vall d’Hebron, Barcelona, Spain; 7Hopital du Sacre-Coeur de Montreal, Montreal; Canada; 8Hopital La Timone Adultes ,

Marseille, France; 9EMEA Regional Clinical Center, Medtronic Clinical Research Institute, Italy;10St.Mary’s Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom

Investigators in the ISSUE-3 study are listed in the Data Supplement.

Correspondence:

Michele Brignole, MD

Arrhythmologic Centre, Department of Cardiology

Ospedali del Tigullio

16033 Lavagna

Italy

Tel: +39 0185 329569

Fax: +39 0185 306506

E-mail: [email protected]

Journal Subject Codes: [33] Other diagnostic testing, [106] Electrophysiology, [120] Pacemaker, [5] Arrhythmias, clinical electrophysiology, drugs

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DOI: 10.1161/CIRCEP.113.001103

2

Abstract:

Background - In the Third International Study on Syncope of Uncertain Etiology (ISSUE-3)

cardiac pacing was effective in reducing recurrence of syncope in patients with presumed

neurally-mediated syncope (NMS) and documented asystole but syncope still recurred in 25% of

them at 2 years. We have investigated the role of tilt testing (TT) in predicting recurrences.

Methods and Results - In 136 patients enrolled in the ISSUE-3, TT was positive in 76 and

negative in 60. An asystolic response predicted a similar asystolic form during implantable loop

recorder monitoring, with a positive predictive value of 86%. The corresponding values were

48% in patients with non-asystolic TT and 58% in patients with negative TT (p=0.001 vs

asystolic TT). Fifty-two patients (26 TT+ and 26 TT–) with asystolic NMS received a

pacemaker. Syncope recurred in 8 TT+ and in 1 TT – patients. At 21 months, the estimated

product-limit syncope recurrence rates were 55% and 5%, respectively (p=0.004). The TT+

recurrence rate was similar to that seen in 45 untreated patients (control group), which was 64%

(p=0.75). The recurrence rate was similar between 14 patients with asystolic and 12 with non-

asystolic responses during tilt testing (p=0.53).

Conclusions - Cardiac pacing was very effective in NMS patients with documented asystolic

episodes in whom TT was negative; conversely, there was insufficient evidence of efficacy from

this dataset in patients with a positive TT even when spontaneous asystole was documented.

Present observations are unexpected and need to be confirmed by other studies

Clinical Trial Registration - clinicaltrials.gov; Identifier: NCT01463358.

Key words: arrhythmia, syncope, reflexes, cardiovascular, nervous system, autonomic, pacemaker, implantable loop recorder, tilt table test

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DOI: 10.1161/CIRCEP.113.001103

3

The randomized, double-blind, Third International Study on Syncope of Uncertain Etiology

(ISSUE-3) showed that dual-chamber permanent pacing was effective in reducing the recurrence

neurally-mediated syncope (NMS)

documented by implantable loop recorder (ILR) 1. Nevertheless, patients who had received

pacing therapy had an estimated syncopal recurrence rate of 25% at 2 years. Previous

randomized controlled trials 2,3,4,5,6 enrolled patients with a positive (TT). In ISSUE-3 only about

a half the patients had a positive test. Owing to its sequential design, the study lacked the power

to make any subgroup analysis. The aim of this study was to investigate the role of TT response

in predicting syncopal recurrence in the whole ISSUE-3 population

Methods

Patient selection

The multicenter, prospective ISSUE-3 study included patients s old who

syncopal episodes with a clinically assessed neurally-mediated mechanism (presumed) in the

previous 2 years. NMS was defined as reflex syncope, with the exception of carotid sinus

syndrome, with a sufficiently severe clinical presentation to warrant specific treatment. These

individuals received an ILR and were followed up. In accordance with the guidelines of the

European Society of Cardiology 7, NMS was diagnosed when the clinical history was consistent

with NMS and competing diagnoses had been excluded. Detailed inclusion criteria and study

protocol has been previously published 1,8.

TT was recommended, but its result was not taken into account in the subsequent

management. The Italian protocol 9 was recommended, which consists of 60°-70º passive tilting

for 20 minutes or until syncope occurs. If the passive tilt phase did not induce syncope, 0.4 mg

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DOI: 10.1161/CIRCEP.113.001103

4

sublingual nitroglycerine spray was administered to the patient while the table was maintained in

the same position; the test was continued for 15 minutes after pharmacological challenge. TT

was considered positive if syncope occurred in presence of hypotension with or without

bradycardia; positive responses were classified according to the New VASIS classification 10 as

an asystolic or VASIS 2B form ( ) or mixed or vasodepressor forms

(all the other forms without asystole). TT was considered negative if syncope did not occur.

Study protocol

After ILR implantation, all patients were followed up quarterly until the first documented

syncopal recurrence, occurrence of a diagnostic arrhythmic event or the end of the study. Events

were classified according to the ISSUE classification 11 as: type 1 (asystole >3 s), type 2

(bradycardia), type 3 (slight or no rhythm variations) and type 4 (tachycardia).

For the purpose of this study, the selected group consisted of those patients who had

performed a TT and had a diagnosis established by means of ILR documentation. Those with

asystolic episodes received a DDD pacemaker which was programmed in rate drop response

pacing mode (lower rate of 40/min, drop size of 20 beats with a drop rate of 50/min within a

detection window of 1 minute) and were followed up quarterly for 24 months or up to the first

episode of recurrence of syncope. The control group consisted of those patients who, despite an

established diagnosis, did not receive active treatment; there were 31 asystolic NMS patient (29

of whom assigned to inactive pacemaker arm of the randomized trial) and 14 not asystolic NMS.

The protocol was approved by a research ethics board at each center and each patient

provided signed informed consent.

Statistical Analysis

Continuous data are shown as averages±SDs or medians (25th–75th percentile), as appropriate,

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DOI: 10.1161/CIRCEP.113.001103

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while absolute and relative frequencies were used to describe categorical data. The Shapiro-Wilk

test was performed to check the skewness of distributions. Continuous variables were compared

by unpaired Student’s t test or e non-parametric Mann-Whitney test, depending on data

distribution. Fisher’s exact test was used to compare proportions. Differences with a p value

<0.05 were indicated. The time to the first recurrence of syncope was analyzed by means of

Kaplan – Meier survival curves, which were compared by using the log-rank test. Analyses were

carried out by means of SAS 9.3.

Results

Study participants were enrolled from July 2006 to November 2010 and follow-up was

concluded in November 2012. During the observation period, 162 of 504 patients had a

presumed diagnosis of NMS documented by ILR, which showed an ECG pattern consistent with

a reflex mechanism (i.e., types 1, 2 and 3 of the ISSUE classification 11). In another 25 patients,

the ILR documented an event that was inconsistent with the diagnosis of NMS (e.g., persistent

AV block, brady-tachy syndrome, atrial or ventricular tachyarrhythmias); these patients were

therefore excluded from the analysis.

Among the 162 patients with presumed NMS, TT was positive in 76 (during the passive

phase in 22 and during drug challenge in 54) and negative in 60 (not performed in 26). Their

clinical characteristics are listed in Table 1. Patients with positive and negative TT had very

similar characteristics; apart from TT response, the two groups were indistinguishable. An

asystolic response (type 2B of the VASIS classification) predicted a similar asystolic form

during ILR monitoring (type 1 of the ISSUE classification), with a positive predictive value of

86% (95% CI: 70%-95%) (Figure 1). The corresponding values were 48% in patients with non-

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DOI: 10.1161/CIRCEP.113.001103

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asystolic TT (p=0.001 vs asystolic TT) and 58% in patients with negative TT (p=0.001 vs

asystolic TT).

Fifty-two patients (26 TT+ and 26 TT –) with asystole documented by ILR received a

pacemaker (Figure 2). Apart from TT response, the two groups had similar clinical

characteristics (Table 2). Syncope recurred in 8 (31%) TT+ and in 1 (4%) TT– patients: it

occurred in standing or sitting positions in all and was preceded by a prodrome in 8. At

multivariable analysis, TT+ and total number of events were the only independent predictor of

syncope recurrence (see supplementary web file table W1). At the 21st month, the estimated

product-limit syncope recurrence rates were 55% (95%CI 29-85) and 5% (95%CI 1-32),

respectively (p=0.004). The recurrence rate in TT+ patients was similar to that seen in 45

untreated controls (table 2 and supplementary web figure W1), which was 64% (95%CI 48-80),

p=0.75. The 14 TT+ patients with an asystolic Vasis 2B response had a recurrence rate of 35%

(95%CI 13-75) at 12 months and of 57% (95%CI 24-93) at 21 months; these rates were similar

to those observed in 12 non-asystolic TT+ patients, p=0.53. There was a trend toward a longer

median time to first syncope recurrence in the 4 asystolic TT+ patients who suffered syncopal

recurrence than in the 4 non-asystolic TT+ patients who suffered syncopal recurrence: 8 (4-15)

and 2 (0-4) months, p=0.1 (Figure 3). Finally, 10 patients who had not performed TT had

asystole documented by ILR and received a pacemaker: 1 had syncopal recurrence (estimated

product-limit syncope recurrence rate at 21 months of 14% [95%CI 2-67]).

Discussion

The study was able to provide some insight into pacing failure observed in a quarter of patients

in the double-blind, randomized, ISSUE-3 trial. Indeed, we found that the benefit of pacemaker

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DOI: 10.1161/CIRCEP.113.001103

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therapy in patients with presumed NMS and documented asystole was not substantial in those

with a positive TT. Syncope recurrence was independent from the type of response during TT.

Although an asystolic response during TT predicted spontaneous asystole, we were unable to

show a benefit greater than in patients with non-asystolic responses. Therefore, we speculate

that pacing failure was due to hypotensive syncope (either vasodepressor NMS or orthostatic

hypotension), which is disclosed by TT susceptibility and which cannot be prevented by cardiac

pacing. It is commonly accepted that hypotension plays a major role in all forms of TT-induced

NMS and that it precedes (and perhaps triggers) bradycardia and syncope in the vast majority of

patients even in those with cardioinhibitory syncope according to the modified VASIS

classification 12, 13.

TT+ and TT– patients had similar clinical characteristics, similar outcomes and similar

ECG patterns when an episode was documented by ILR (Table 1). These findings had already

emerged from the ISSUE 1 and ISSUE 2 studies 14,15 and other studies in the literature 16,17,18,19.

Even though the two groups were indistinguishable in terms of clinical characteristics, the

different effect of pacing prompts us to infer that the underlying mechanism of syncope is

different, i.e. that a vasodepressive mechanism is dominant in TT+ patients while a

cardioinhibitory mechanism is dominant in TT– patients. Thus, the utility of TT shifts from that

of a tool for clinical diagnosis to a tool for pathophysiological classification, with obvious

therapeutic implications. Before the ISSUE-3 trial, cardiac pacing for NMS had only been

evaluated in randomized trials which enrolled patients with TT+ 2,3,4,5,6, TT being considered the

standard means of diagnosing NMS; no indication for pacing in TT– NMS patients existed.

ISSUE-2 enrolled both TT+ and TT- patients but the outcome was not considered separately 15.

ISSUE-3 included both TT+ and TT– patients, and clinical history and initial evaluation were

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DOI: 10.1161/CIRCEP.113.001103

8

regarded as the standard for diagnosis. By showing that TT– NMS patients are those who

benefit most from cardiac pacing, the present study inverts previous knowledge on indications

for pacing.

In this subanalysis of ISSUE-3 study, pacemaker therapy in TT+ patients showed no

benefit, despite the documentation of a long asystole at the time of a spontaneous event; the

syncopal recurrence rate was also similar to the 37% and 57% rates observed at 1 and 2 years in

the pacemaker-off arm of ISSUE-3. This result was largely unexpected as previous five major

multicenter, randomized, controlled trials 2,3,4,5,6 performed on TT+ showed some efficacy of

pacing even in the absence of documentation of spontaneous asystole. When pooled together, the

five trials evaluated 318 patients; syncope recurred in 21% of the paced patients and in 44% of

unpaced patients (P <0.001). A meta-analysis suggested a non-significant 17% reduction in

syncope in the double-blind studies and a 84% reduction in the studies in which the control

group did not receive a pacemaker 20. Our study group was small and the confidence interval of

the probability of recurrence of syncope at 21st month ranged from 29% to 85%. We cannot

therefore exclude a type II error; some benefit of pacing may still be possible, especially in

patients with an asystolic TT+ response. What we have observed here in NMS patients is similar

to what was observed in patients paced for carotid sinus syndrome. In Gaggioli et al’s study 21

patients with carotid sinus syndrome and TT+ had a 2.7-fold increased risk of syncopal

recurrence compared with carotid sinus syndrome and TT- : at a mean follow-up of 33 months,

syncope recurred in 21% of 70 patients versus 9% of 99 patients (p=0.02); positive TT was the

only independent predictor of syncopal recurrence. Solari et al, 22, in 141 patients affected by

carotid sinus syndrome, found a mixed or vasodepressor response to TT was the only

independent predictor of syncopal recurrence (HR=1.8; p=0.01). In conclusion, in the light of the

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DOI: 10.1161/CIRCEP.113.001103

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present study and of the above literature, it is clear that cardiac pacing is very effective when TT

is negative while syncope can frequently recur when TT is positive.

Limitations

As discussed above, the study group was small with a large confidence interval of the probability

of recurrence of syncope. Some benefit of pacing may still be possible in patients with positive

TT response. For example, we observed a 4-fold longer median time to syncope recurrence (8

versus 2 months) in asystolic than in non-asystolic TT+ patients on pacemaker treatment. The

same finding was observed in the SYNPACE trial 6, in which the time to the first syncope

recurrence was longer on pacemaker therapy than on placebo in patients who had shown an

asystolic (ventricular pause of 13±8 s) response during tilt table testing: 97 versus 11 days,

p=0.06. We did not evaluate the effect of cardiac pacing in asystolic TT+ patients who did not

achieve the end-point of an ILR event documentation; theoretically, these patients could have a

better outcome with a pacemaker.

It is not completely clear that all of patients had NMS. It is important to acknowledge that

the ISSUE-3 population is by no means the typical NMS type of patients. Many ISSUE-3

patients were old and had atypical presentation with no or subtle prodrome and lack of

recognizable triggers. NMS could not be confirmed by TT which was negative in half patients. It

is possible that these patients simply had an intermittent form of extreme bradycardia (i.e.,

asystole) different from NMS. A great overlap between extrinsic sinus node dysfunction and

dysautonomic conditions exists 23,24. Idiopathic paroxysmal AV block has been recently

described as a different cause of unexplained syncope in patients without structural heart disease

25.

Compared with TT-, TT+ patients treated with a pacemaker had a longer history of more

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DOI: 10.1161/CIRCEP.113.001103

10

syncopal episodes during life (but not in the last 2 years) and fewer were males. Albeit marginal,

these differences, could indicate a different susceptibility to NMS and partly influence pacing

results.

Finally, this study suggests a strategy of pacing indication largely based on the result of

TT despite TT being regarded as having questionable diagnostic accuracy and reproducibility

17,19.

For all the above reasons, the findings of the present study cannot be taken as conclusive;

the largely unexpected prompt future studies which may show similar results to ours.

Conclusions

In the present study, cardiac pacing was very effective in NMS patients with documented

asystolic episodes in whom TT was negative; conversely, there was insufficient evidence of

efficacy from this dataset in patients with a positive TT even when spontaneous asystole was

documented. Present observations are unexpected and need to be confirmed by other studies

Conflict of Interest Disclosures: M. Brignole reports receiving modest consultancy fees from

Medtronic and being a direct shareholder of F2 solutions; R. Sutton is a consultant to Medtronic,

receiving modest fees, and is a paid lecturer for St Jude Medical; A. Moya reports receiving

modest consultancy fees from Medtronic; Dr Deharo reports receiving limited consultant fees

from Medtronic; Beiras reports receiving limited consultant fees from Medtronic and St Jude

Medical; S. Giuli and A. Gentili are employees of Medtronic; the other authors have no financial

disclosures.

References:

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results to ours.

n

e

p o

o

ed Present obser ations are ne pected and need to be confirmed b other st die

ns

entntntnt study, carddiaac pappacingngngg wass veeeryy efffeeectiivee innnn NNNMSMMM pppaaatienntss wwwiw ttht doocoo umumu eenteeeddd

pisodododdesees iiiinn whhhhom TTTTTTT was nenenenegativeeee;;;; cooonverselyy, thththt ererereree wawawaas inii sufficieieieiennnnt eviiidddence o

om hthhiiis dddatasetetett iin papp iitients with hhh a popp isiitive TTTT TTT even whehheh nnn n sppponononntaneous asysysysystototot lelll w

ded PPr tt bob tatiio ttedd dd ded tt bbe fifi ded bb tothhe tst ddiie



DOI: 10.1161/CIRCEP.113.001103

11

mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation. 2012;125:2566-2571.

2. Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope : pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000;102:294-299.

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WWWWililililkokokokoffffffff BBBBL,L,L,L, MMMMooororilililillolloloCCCCh recururrerentnttt sseveverere eMA 2020202003030303;2;2;2;289898989:2:22222222222444 2

A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R, Brignole M. Ts

1

eA, Hohnloser S, Janousek J, Kapoor W, Kenny RA, Kulakowski P, Masotti G, MA S tton R Theodorakis G Ungar A Wieling W Priori SG Garcia MA B da

AAAA, GGiGG ada F,FFF MMMeneee ozozozzizizi CCCC, SpSpSppececece a G,G,G, OOOrararaziz SS, Gaaaspsppspararararini i ii G,G,G,G SSSutututttott n R,R,R,R BBBBrirr gngngnolololo ee e M.MMM Tsyyyynnncn ope and ppacinng trialalal (Synpn aaacee). A AA randndommmizizizedededed plaaaccceboo-cconnntrtrolleeeed dd sttuddy ofofof papapacicicing forrr tttreattmeeennt of f f reeecurrrrrrrenennt vasososovagagal sysyssynnncopopopo e. EEEur HeHearrrrt J.JJJ 20000000 4:225:11177741

e M,M AAAlblblbonii i PPP, BBBBendididitt DDD, BBBeB rgggfffeldldldt LLL,L BBBBlllanc JJ,JJ TTTThohh mssen PPPE,EEE GGGGert t van DiDiDiDijkjkjkjk J, A, Hohnlnlnlosososo ererere SSSS,,,, JaJaJaJanonononoususususekeekek JJJJ,,, , KaKaKaKapopopopoorororr WWWW,,, KeKeKeKennnnny y y y RARARARA,,, KuuKuKulalalaakokokokowswswswskikikiki PPPP, ,, MaMaMaMasotti G, MAA SS tttt RR ThTh ddo kiki GG UU AA WiWi leliin WW PP iri ii SGSG GGa iia MMAA BB dda



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13. Verheyden B, Liu J, van Dijk N, Westerhof BE, Reybrouck T, Aubert AE, Wieling W. Steep fall in cardiac output is main determinant of hypotension during drug-free and nitroglycerine-induced orthostatic vasovagal syncope. Heart Rhythm. 2008;5:1695–1701.

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15. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, Andresen D, Benditt DG, Vardas P. Early application of an Implantable Loop Recorder allows a mechanism-based effective therapy in patients with recurrent suspected neurally-mediated syncope. Eur Heart J. 2006;27:1085–1092.

16. Grimm W, Degenhardt M, Hoffman J, Menz V, Wirths A, Maisch B. Syncope recurrence can better be predicted by history than by head-up tilt testing in untreated patients with suspected neurally mediated syncope. Eur Heart J. 1997;18:1465–1469.

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21. Gaggioli G, Brignole M, Menozzi C, Devoto G, Oddone D, Gianfranchi L, Gostoli E, Lolli G. Positive response to head-up tilt testing predicts syncopal recurrence in carotid sinus syndrome patients with permanent pacemakers. Am J Cardiol. 1995;76:720–722.

22. Solari D, Maggi R, Oddone D, Solano A, Croci F, Donateo P, Brignole M. Clinical context and outcome of carotid sinus syndrome diagnosed by means of the “method of symptoms”. Europace. 2013: Sep 20. [Epub ahead of print]

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eling WWWW AAAAndndndndrerereresesesesennnn DDDG, Vardas P. Early application of an Implantable Loop Recorder allows a mechanc0

m W, Degenhardt M, Hoffman J, Menz V, Wirths A, Maisch B. Syncope recurrenr ee

n R Rose S Koshman ML Comparison of patients ith s ncope of nkno n ca

G, VaVaVaVardrdrdrdasasss PPP. EaEaEaarlrr y application of an Implplplplanana table Loop RRRecororororder allows a mechanctttiviviviveeee therappppy y y ininnin patatatieieientntntts sss wiwiiwithththh rrecececuruu reeentntnt sussppectttedededed nnnneueurrrralllllll yyy-m-mm-medee iaateteteted d d d sysysyyncncncopopopopeee. EuEE006060606;27:1085–110092.

m W, DDDDegggegenhardddttt M,M,M HHHHoffmfmfmfmaanan J, MeMeMeMenznznz VVVV, WiWiWiW rtttthshshshs AAAA, MaMaMaMaisisisi chhh BBBB. SySySyyncncncncoppe recurrenredicccctetetet d d d d bybybyb hhhhisisisi tototot ryryryy ttthahahahan nnn bybybyby hhheaaaaddd---upupupup tttiilt teteteesttinininng g g g inininin uuuntntntntrererereatatata ededed ppppatatatatieieieientntnts ss s wiwiwithththth ssssusususpepepep cteediatedd d syyyncopopoppe. EuEE r HHHeart J. 111999999777;1118:1114646465–555 14141446969696 .

RR RR SS KK hhm MMLL CC iri fof tatiie tnt iithth ff kkn



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DOI: 10.1161/CIRCEP.113.001103

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Table 1. Baseline characteristics and ILR findings

Characteristics Tilt, alln=136

Tilt +n=76

Tilt –n=60

Tilt not performedn=26

Age, mean (SD), y 64±13 64±13 64±14 64±15Men, No. (%) 60 (44) 29 (38) 31 (52) 14 (54)Syncope events:

- Total events, median (IQR) 8 (5-14) 10 (5-15) 6 (5-11) 6 (5-10) - No. (%) 74 (54) 46 (61) 28 (47) 9 (35)- Events in the last 2 years, median (IQR) 4 (3-7) 4 (3-7) 4 (3-7) 4 (3-5) - No. (%) 90 (66) 48 (63) 42 (70) 17 (65)- Events in the last 2 years without prodromes, median (IQR) 2 (0-4) 2 (0-4) 2 (0-4) 2 (0-4)- Age at first syncope, mean (SD), y 46±23 43±24 51±21 55±17- Interval between first and last episode, median (IQR), y 9 (3-25) 10 (4-35) 9 (3-20) 4 (1-16)- History of presyncope, No (%) 75 (55) 44 (58) 31 (52) 14 (54)- Hospitalization for syncope, No (%) 54 (40) (a) 29 (38) 15 (25) 14 (54)(a)- Injuries related to fainting, No (%)

- Major injuries (fractures, brain concussion) 13 (10) 10 (13) 3 (5) 3 (12)- Minor injuries (bruises, contusion, hematoma) 64 (47) 39 (51) 25 (42) 11 (42)

- Typical vasovagal presentation, No (%) 71 (52) 43 (57) 28 (47) 9 (35)- Typical situational presentation, No (%) 27 (20) (a) 17 (22) 10 (17) 1 (4) (a)- Without prodromes 73 (54) 39 (51) 34 (57) 14 (54)

Medical history, No (%)- Structural cardiac abnormalities 15 (11) 5 (7) 10 (17) 4(15)- Atrial tachyarrhythmias 6 (4) 4 (5) 2 (3) 2 (8)- Hypertension 63 (46) 34 (45) 29 (48) 13 (50)- Diabetes 13 (7) 6 (8) 7 (12) 3 (12)-Neurological/psychiatric disturbances 7 (5) 2 (3) 5 (8) 0 (0)

Concomitant medications, No. (%)- Anti-hypertensive 65 (48) 32 (42) 33 (55) 12 (46)- Psychiatric 19 (14) 12 (16) 7 (12) 4 (15)- Any other drugs 35 (26) 16 (21) 19 (32) 9 (35)-Mean number of drugs per patient, No (SD) 1.2±1.3 1.1±1.3 1.4±1.3 1.4±1.4

Baseline mean heart rate (SD), bpm 69±9 68±9 69±9 71±9Supine arterial blood pressure (SD), mmHg 130±18 131±20 129±15 134±16Standing arterial blood pressure 119±20 (b) 118±22 121±17 128±17 (b)Echocardiogram:

-Left ventricular ejection fraction (SD), % 62±6 62±8 62±6 61±8-Left ventricular diastolic diameter (SD), mmHg 49±7 48±6 51±8 49±3

-Left ventricular systolic diameter (SD), mmHg 33±7 32±7 34±6 28±5-Any abnormality, No. (%) 9 (7) 3 (4) 6 (10) 4 (15)

Tilt testing: positive, No. (%) 76 (56) - - --Asystolic response (VASIS 2B form), No. (%) 28 (21) 28 (37) - - -Asystole duration in VASIS 2B form (IQR), s 14 (8-24) 14 (8-24) - --Non-asystolic response 48 (79) 48 (63) - -

ILR findings:-Time to diagnosis median (IQR), months 6 (2-12) 6 (2-14) 5 (1-11) 6 (1-11)

-ISSUE classification, No (%)-type 1 (asystole) 82 (60) 47 (62) 35 (58) 17 (65)-type 2 (bradycardia) 16 (12) 12 (16) 4 (7) 4 (15)-type 3 (no/slight rhythm variations) 38 (28) 17 (22) 21 (35) 5 (19)

-Asystole duration (IQR), s 10 (6-18) 10 (6-17) 8 (6-19) 7 (4-13)

a: p=0.05; b: p=0.06

3333)))) 3333 (5(5(5(5))) 33331) 25252525 ((((42424242)))) 111111117) 2828282 ((((47)) 9

0

p , ( ) ( ) ( ) ( ) ( ) (4

rl 4

c 23

ime 2

p , ( ) ( ) ( ) ( ) ( ) (prododododrorororomes 73 (54) 39 (((51515151) 34 (57) 14

ry,y,y, NNNoN (%)l carrrdiac abnormallitiies 1515155 (((111111) 5 (77) 10 (11711 ))) 4

chyyyyarrrrhr ythmiass 6 66 6 (4) 4 (55) 2 (333) 2sion 63636363 ((((4646464 )))) 34343434 (((454545)))) 29292929 ((((4848484 ) 13111

133 ((((7)7)7) 6 6 6 6 (8(8(8))) 7 (1(1(1( 2)2)22 3 ical/ppppsysyychchchiaiaiatrtrtriccc dddisisistututuurbrbrbbananancececesss 7 77 (5(5(5( ))) 22 2 (3(3(3))) 555 (8(8(8( ))) 0mememedidicacacatitionononsss, NoNo. (%(%))ertensive 65555 ((((48484848)))) 3232322 (((42424242)))) 3333333 (((55555555))) 12



DOI: 10.1161/CIRCEP.113.001103

15

Table 2. Baseline characteristics of the 52 patients with asystole documented by ILR who received an active pacemaker and of 45 control patients who did not

Characteristics PM, all n=52

PM, TT+n=26

PM, TT-n=26

Control n=45

Age, mean (SD), y 62 (13) 63 (13) 61 (13) 65 (13)Male gender, No. (%) 27 (50) 10 (38) 17 (65) 15 (33)Syncope events:

- Total events, median (IQR) 7 (4-12) 10 (5-14) 6 (4-10) 8 (5-10) - No. (%) 25 (48) 17 (65)(a) 8 (31) (a) 24 (53)- Events in the last 2 years, median (IQR) 4 (3-5) 4 (3-6) 4 (3-5) 4 (3-6) - No. (%) 33 (63) 16 (62) 17 (65) 30 (67)- Events in the last 2 years without prodromes, median (IQR) 3 (1-4) 2 (0-4) 3 (1-4) 2 (0-4)- Age at first syncope, mean (SD), y 45 (24) 42 (24) 48 (24) 47 (23)- Interval between first and last episode, median (IQR), y 8 (3-31) 13 (3-38) 6 (2-17) 10 (3-30)- History of presyncope, n (%) 29 (56) 15 (58) 14 (54) 25 (56)- Hospitalization for syncope, n (%) 36 (69) 18 (69) 18 (69) 28 (62)- Injuries related to fainting, n (%) - Major injuries (fractures, brain concussion) 4 (8) 2 (8) 2 (8) 9 (20) - Minor injuries (bruises, contusion, hematoma) 22 (42) 11 (42) 11 (42) 21 (47)- Typical vasovagal presentation, n (%) 26 (50) 11 (42) 15 (58) 25 (56)- Typical situational presentation, n (%) 10 (19) 6 (23) 4 (15) 13 (29)- Without prodromes 27 (52) 11 (42) 16 (62) 29 (64)

Medical history, n (%)- Structural cardiac abnormalities 6 (12) 1 (4) 5 (19) 4 (9)- Atrial tachyarrhythmias 4 (8) 2 (8) 2 (8) 2 (4)- Hypertension 20 (38) 9 (35) 11 (42) 23 (51)- Diabetes 5 (10) 1 (4) 4 (15) 5 (11)-Neurological/psychiatric disturbances 3 (6) 0 (0) 3 (12) 0 (0)

Concomitant medications, No. (%)- Anti-hypertensive 22 (42) 9 (35) 13 (50) 11 (24)- Psychiatric 8 (15) 5 (19) 3 (12) 10 (22)- Any otherdrugs 12 (23) 5 (19) 7 (27) 4 (9)-Mean number of drugs per patient (SD) 1.3 (1.4) 1.1 (1.3) 1.5 (1.5) 1.0 (1.1)

Baseline mean heart rate (SD), bpm 67 (10) 67 (10) 67 (10) 71 (9)Supine arterial blood pressure (SD), mmHg 131 (18) 131 (21) 131 (15) 133 (18)Standing arterial blood pressure 120 (21) 118 (23) 122 (20) 123 (20)Echocardiogram:

-Left ventricle ejection fraction (SD), % 62 (5) 60 (3) 63 (6) 60 (6)-Left ventricle diastolic diameter (SD), mmHg 50 (8) 52 (5) 49 (10) 50 (6)

-Left ventricle systolic diameter (SD), mmHg 33 (6) 34 (7) 33 (6) 31 (5)-Any abnormality, % 4 (8) 2 (8) 2 (8) 3 (7)

Tilt testing: performed, No (%) 52 (100) - - 37 (82)- Positive of those performed, No. (%) 26(50) - - 24 (65)

-Asystolic response (VASIS 2B form), No. (%) 14 (27) 14 (54) - 9 (24) -Asystole duration in VASIS 2B form (IQR), s 17 (12-26) 17 (12-26) - 15 (10-15)

-Non-asystolic response 12 (23) 12 (23) - 15(41)ILR findings:

-ISSUE classification, No (%)-type 1A (asystole due to sinus arrest) 31 (60)(b) 13 (50) 18 (69) 16 (36)(b)-type 1B (asystole due to sinus brady + AV block) 9 (17) 5 (19) 4 (15) 7 (16)-type 1C (asystole due to AV block) 7 (13) 4 (15) 3 (12) 7 (16)-type 1, undefined asystole 5 (10) 4 (15) 1 (4) 1(2)

-no type 1 (no asystole) 0 (0) (c) 0 (0) 0 (0) 14 (31) (c)-Asystole duration (IQR), s 8 (6-13) 10 (6-18) 8 (6-14) 10 (6-20)

a: p=0.02; b: p=0.05; c: p=0.001

2222 (8(8(8(8)))) 9 999 (2(2(2(20)0)0)0)) 11111111 ((((42424242)))) 21212121 ((((444747) 151515 ((((58585858)))) 25252525 ((56

ituational presentation, n (%) 10 (19) 6 (23) 4 (15) 13 (29p 4y

cs

1c

me 4c 8 (15) 5 (19) 3 (12) 10 (22

ituational prpp esentation, n (%) 10 (19) 6 (23)))) 4 (15) 13 (29prododdodroooommmmes 27 (52) 11 (4242422)))) 16 (62) 29 (64y, nn ((((%%%%)cccardddid ac abnormalitiiess 6 (1(11122)2 1 (4) 5 (19)999 444 4 ((99)

chyhyhyhyarrrrhrr ythmias 4 (8(88(8))) 222 (8) 2 (8)))) 222 (444)sion 202020 (((3838388))) 9 9 9 9 (3(3(335)5)) 11111 (((442424 ) 232232 (((55

5 (1( 0))) 1 (44(44))) 4 (1(( 5)5)55 5 (11cal/psysysychchcchiaiaiatrtricicic dddisistututurbrbrbrbananncecees 3 3 3 3 (6(6(6(6))) 0 0 0 (0(0(0)) 3333 (1(1(1( 2)2)2 0 000 (0)

medications,,, No. (%%(%)))ertensive 22222 (((4242422))) 9 9 9 9 (3(3(335)5)5)5) 1311313 (((50505050)))) 11 (24c 88 (1(15)5) 55 (1(19)9) 33 (1(12)2) 1010 ((2222



DOI: 10.1161/CIRCEP.113.001103

16

Figure Legends:

Figure 1. Correlation between tilt test responses and the mechanism of syncope, as documented

by ILR

Figure 2. Kaplan-Meier freedom from syncope recurrence after pacemaker therapy in tilt-

negative asystolic NMS and in tilt-positive asystolic NMS patients. The curve of a control group

of untreated patients is also superimposed

Figure 3. Kaplan-Meier freedom from syncope recurrence after pacemaker therapy in patients

who had had an asystolic response during TT (VASIS 2B) and in those who had not.

K e

a

Kaplplplananana -MeMeMeMeieii r frfrfrf eedom from syncope recccuuru rrence after pappp cemammm ker therapy in patie

addd d aaana asystolicc rrespopponsee e ddudd riiingn TTTTT (VVAAASISIS 2B)B)B)B aaaandnndn innn thossee whwhwhw o haaad ddd nonon t..



Moya, Teresa Kus, Jean Claude Deharo, Silvia Giuli, Alessandra Gentili and Richard SuttonMichele Brignole, Paolo Donateo, Marco Tomaino, Riccardo Massa, Matteo Iori, Xulio Beiras, Angel

International Study on Syncope of Uncertain Etiology (ISSUE-3)Documented Asystole is Greater when Tilt Test is Negative. An Analysis from the Third

The Benefit of Pacemaker Therapy in Patients with Presumed Neurally-Mediated Syncope and

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2013 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

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1

Supplemental material

Appendix Steering committee: Michele Brignole (Chairman), Dietrich Andresen, David Benditt, Jean Jacques Blanc, Roberto Garcia‐Civera, Andrew Krahn, Carlo Menozzi, Angel Moya, Richard Sutton, Panos Vardas, Wouter Wieling. End‐point committee: Michele Brignole, Richard Sutton, Andrea Ungar, Angel Moya. The following centers and investigators participated in this ISSUE‐3 substudy: Italy: Ospedali del Tigullio, Lavagna ‐ P.Donateo and D. Oddone; Ospedale di Bolzano, Bolzano ‐ M. Tomaino, C. Romeo, P. Sgobino and F. Pescoller; Ospedale SS. Antonio e Biagio e Cesare Arrigo, Alessandria – E. Vitale and R. Massa; Arcispedale S.Maria Nuova, Reggio Emilia ‐ C. Menozzi, F. Quartieri, M. Iori and G. Lolli; Ospedale Santa Croce, Moncalieri ‐ F. Rabjoli and C. Cecchinato; Ospedale di Manduria, Taranto ‐ V. Russo, Dr. F. Pierri and M.G. Matino; Ospedale S.Giovanni Battista Le Molinette, Torino ‐ M. Iorfida and P. Golzio; Ospedale S. Pietro Igneo, Fucecchio ‐ A. Del Rosso and V. Guernaccia; Azienda Ospedaliera Villa Scassi, Genova ‐ G. Gaggioli and M. Laffi; AO di Rilievo Nazionale e di Alta Specializzazione Garibaldi, Catania ‐ M. Gulizia and M. Francese; Ospedale di Venere, Bari ‐ M. Palella and C.D'Agostino; Ospedale Santa Croce e Carle, Cuneo ‐ A. Vado and A. Menardi; Ospedale S. Gerardo ‐ Monza, A. Vincenti and S. De Ceglia; Ospedale San Giovanni di Dio, Firenze ‐ A. Bartoletti and Domenico Rossi; Spain: Complejo Hospitalario Universitario de Vigo, Vigo ‐ X. Beiras Torrado and E.G. Campo; Hospital Universitario Vall d’Hebron, Barcelona ‐ Á. Moya, I. Roca, N. Rivas, J. Perez, G. Senador and C. Alonso; Consorcio Hospitalario Provincial de Castellón, Castellón ‐ L. Fácila Rubio, F. Perez Alcalá, V. Montagud Balaguer, A. Peset and T. Mut; Hospital Universitario Puerta de Hierro, Madrid ‐ J.Toquero Ramos, I. F. Lozano and V. Castro; Complejo Hospitalario Universitario de Albacete, Albacete ‐ J.F. García Sacristán, R. Ceres and J. Enero; Hospital General de Granollers, Granollers ‐ E. Chueca and J. Mercader; Hospital Clínico Universitario de Valencia, Valencia ‐ R. Garcia Civera, R. Ruiz Granell and S. Morell Cabedo. Germany: Vivantes Klinikum Am Urban, Berlin ‐ D. Andresen, G. Wedegärtner and I. Atmowihardjo; Kardiologiske Gemeinschaftspraxis, Riesa – H.H. Ebert and G. Stenzel; Vivantes Humboldt, Berlin – U. Bach and J. Ohler; Charité ‐ Campus Benjamin Franklin, Berlin – S. Spencker and A. Schirdewahn; Klinikum der Universität München ‐ Großhadern und Innenstadt, München – S. Kääb and M.F. Sinner; Kreiskrankenhaus Hameln, Hameln‐Pyrmont – H. Topp. United Kingdom: St Mary's Hospital, London ‐ R. Sutton and D. Francis; William Harvey Hospital, Kent ‐ K. Kamalvand and M. Asgari. Canada: Hôpital du Sacré‐Coeur de Montreal , Montreal – T. Kus and M. Strurmer; The Netherland: Academisch Medisch Centrum, Amsterdam ‐ W. Wieling and R.E. Knops; Atrium Medisch Centrum, Heerlen ‐ A.J.J. Aerst; Catharina Ziekenhuis, Eindhoven ‐ L.R.C Dekker and P.H. van der Voort; Medisch Centrum Alkmaar, Alkmaar ‐ J.H. Ruiter and J.J.C.M. Romme. France: Hôpital de la Timone, Marseille ‐ J.C. Deharo and E. Peyrouse; Switzerland: Centre Hôpitalier Universitaire Vaudois – Lausanne – E. Pruvot and D. Graf. Austria: A.ö. Bezirkskrankenhaus Hall, Hall in Tirol – W. Grander and P. Eller.

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Supplemental Table W1. Factors predicting recurrence of syncope after pacemaker

therapy in patients with neurally-mediated syncope and documented asystole.

Characteristics Recurrence

n=9

No recurrence

n=43

Age, mean (SD), y 62 (13) 63 (13)

Male gender, No. (%) 4 (44) 23 (53)

Syncope events:

- Total events, median (IQR) 10 (10-18) (a) 6 (4-10)(

a)

-≥8 episodes, No. (%) 9 (100) 16 (37)

- Events in the last 2 years, median (IQR) 4 (4-6) 4 (3-5)

-≥4 episodes, No. (%) 8 (89) 25 (58)

- Events in the last 2 years without prodromes, median

(IQR) 2 (0-6) 3 (1-4)

- Age at first syncope, mean (SD), y 36 (27) 47 (24)

- Interval between first and last episode, median (IQR), y 23 (9-31) 6 (2-27)

- History of presyncope, n (%) 6 (67) 23 (53)

- Hospitalization for syncope, n (%) 7 (78) 29 (67)

- Injuries related to fainting, n (%)

- Major injuries (fractures, brain concussion) 1 (11) 3 (7)

- Minor injuries (bruises, contusion, hematoma) 5 (56) 17 (40)

- Typical vasovagal presentation, n (%) 6 (67) 20 (47)

- Typical situational presentation, n (%) 2 (22) 8 (19)

- Without prodromes 3 (33) 24 (56)

Medical history, n (%)

- Structural cardiac abnormalities 1 (11) 7 (16)

- Atrial tachyarrhythmias 1 (11) 3 (7)

- Hypertension 5 (56) 15 (35)

- Diabetes 0 (0) 5 (12)

-Neurological/psychiatric disturbances 1 (11) 2 (5)

Concomitant medications, No. (%)

- Anti-hypertensive 5 (44) 17 (40)

- Psychiatric 2 (22) 6 (14)

- Any otherdrugs 1 (11) 11 (26)

-Mean number of drugs per patient (SD) 1.1 (1.4) 1.3 (1.4)

Baseline mean heart rate (SD), bpm 73 (10) 66 (10)

Supine arterial blood pressure (SD), mmHg 135 (25) 130 (17)

Standing arterial blood pressure 127 (20) 118 (21)

Echocardiogram:

-Left ventricle ejection fraction (SD), % 60 (4) 62 (6)

-Left ventricle diastolic diameter (SD), mmHg 52 (6) 50 (9)

-Left ventricle systolic diameter (SD), mmHg 35 (3) 33 (7)

-Any abnormality, % 2 (22) 2 (5)

Tilt testing: performed, No (%) 9 (100) 43 (100)

- Positive of those performed, No. (%) 8 (89)(b) 18 (42) (

b)

-Asystolic response. No. (%) 4 (44) 10 (23)

-Asystole duration (IQR), s 20 (11-35) 17 (12-24)

-Non-asystolic response 4 (44) 8 (19)

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ILR findings:

Asystole duration (IQR), s 9 (5-19) 8 (6-14)

-ISSUE classification, No (%)

-type 1A (asystole due to sinus arrest) 4 (44) 27 (63)

-type 1B (asystole due to sinus brady + AV block) 3 (33) 6 (14)

-type 1C (asystole due to AV block) 2 (22) 5 (12)

-type 1, undefined asystole 0 (0) 5 (12)

a: p=0.018; b: p=0.022

Multivarible analysis of factor predicting syncopal recurrence. Once tested the proportional hazard

assumption, univariate Cox regression models have been fitted to estimate hazard ratios among the clinical

variables listed in the supplementary web file table 1; then independent predictors of syncope recurrence

have been found using a multivariable model with stepwise automatic variables selection method,

considering p=0.1 as entry criterion and p=0.05 as significance level for exit from the model. Positive tilt

testing and total number of events were identified as independent predictors of syncopal recurrence,

respectively with an hazard ratio of 12.8 (p-value 0.02) and 1.03 (p-value 0.02); the other variables were

not included in the model.

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Supplemental table W2. Kaplan-Meier 3-monthly freedom from syncope recurrence (average and 95%

confidence interval) after pacemaker therapy in tilt-negative asystolic NMS and tilt-positive asystolic NMS

patients and in controls untreated patients.

PM TT+ 3 6 9 12 15 18 21 months

# pts at risk 14 10 9 8 6 4 3

Failure estimate % (95% CI)

21 (8-47) 33 (16-60) 33 (16-60) 40(21-67) 40(21-67) 40(21-67) 55(29-85)

PM TT- 3 6 9 12 15 18 21 months

# pts at risk 19 19 15 11 10 9 9


--- --- 5 (1-32) 5 (1-32) 5 (1-32) 5 (1-32) 5 (1-32)

NO THERAPY 3 6 9 12 15 18 21 months

# pts at risk 35 31 22 22 18 14 9


18 (10-33) 28 (17-44) 40 (27-56) 40 (27-56) 43 (29-59) 49 (35-66) 64 (47-80)

5

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Fre

ed

om

fro

m s

yn

cop

al re

curr

ence

31 22 18 16 16 13 10 6Asystole

14 13 13 6 6 5 4 3No Asystole

Number at risk

0 3 6 9 12 15 18 21Months

log rank: p=0.68

No PM, no asystole

No PM, asystole

Figure W1. Kaplan-Meier freedom from syncope recurrence was similar in the 31 patients with asystolic

NMS (type 1 of ISSUE classification) and in the 14 non-asystolic NMS (no type 1) who constituted the

control unpaced group reported in the Figure 1 of the text.

Supplemental table W3. Kaplan-Meier 3-monthly freedom from syncope recurrence (average and 95%

confidence interval) in the 31 patients with asystolic NMS (type 1 of ISSUE classification) and in the 14 non-

asystolic NMS (no type 1) who constituted the control unpaced group reported in the Figure 1 of the text.

No PM, asystole

3 6 9 12 15 18 21 months

# pts at risk 13 13 6 6 5 4 3 Failure estimate % (95% CI)

--- --- 41(20-73) 41(20-73) 51(27-81) 51(27-81) 63(36-90)

No PM, No asystole

3 6 9 12 15 18 21 months

# pts at risk 22 18 16 16 13 10 6 Failure estimate % (95% CI)

26 (14-45) 39 (25-59) 39 (25-59) 39 (25-59) 39 (25-59) 49 (32-69) 64 (45-83)

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