Adenosine testing in syncope Dr Steve W Parry Falls and Syncope Service Royal Victoria Infirmary and Institute for Ageing and Health, Newcastle University.

Adenosine testing in syncope

Dr Steve W Parry

Falls and Syncope Service

Royal Victoria Infirmary and Institute for Ageing and Health,

Newcastle University

OutlineOutline

What is it? What does an adenosine test diagnose? What do the guidelines tell us about adenosine

testing? How do you do it? Where are we now?

Adenosine triphosphate (ATP)

Ubiquitous purinergic amine Rapid catabolism to adenosine

(ATP: some vagal effects) Profound negatively chronotropic and

dromotropic effects on AV node High degree AV block, asystole

ATP and syncope investigation

Confusion re diagnostic criteria and underlying pathophysiology– VVS

– Sinus node disease

– High degree AV block

– “Adenosine-sensitive syncope”

– “Brady-pacing indications”

ATP and vasovagal syncope

Supine ATP in Dx of neurally mediated syncope and SND (Brignole PACE 1994)

– 20mg iv ATP, 79 older patients (71 years) v 31 controls (62 years)

– Similar ATP test positivity in both groups, all diagnoses

– More recent results in 175 patients• “ATP no substitute for HUT” (Brignole et al Heart 2000)

Adenosine and vasovagal Adenosine and vasovagal syncopesyncope

ATP and syncope investigation:Vasovagal syncope

“Fainting rats” (Waxman et al Circulation 1998)

– VVS rats: isoproterenol and IVC clamp

– Dipyridamole (adenosine inhibitor) caused paradoxic bradycardia at lower iso doses

– ? Adenosine augments sympathoinhibition during vasovagal response

Humans: higher plasma adenosine levels during positive HUT in patients with VVS

(Saadjian, Circulation 2002)

ATP and vasovagal syncope

Adenosine IV as provocateur during head up tilt table test– Adenosine tilt less

sensitive than isoproterenol tilt(Shen et al JACC 1996, Perez-Paredes et al Rev Espanol Cardiol 1998)

ATP and vasovagal syncope

Flammang et al (Circulation 1997) ATP 20mg– 10 sec duration of AVB for diagnosis

– Initial studies “cardio-inhibitory VVS”• No proof, diagnostic criteria

– 316 patients with VVS, 51 younger controls

– 130 (41%) patients pauses >10 sec (84% AVB) v only 3 controls

– Increasing positivity with advancing age– Further studies establishing reproducibility (J Cardiovasc

Elect 1998) and response to pacing (Circulation 1999)

– Account for around half of all patients reported

The Flammang experience.....

Flammang et al (Heart Rhythm, 2006 abstr)

– Multicentre “placebo-controlled” RCT• DDD v AAI @ 30bpm

– Patients with SUO, “mostly vasovagal”• No HUT, no data on why VVS

– 77 patients age 78 years

Rhythm 2006Europace 1999Circulation 1997

Retrospective study (n=316)

Prospective study (n=20)

Multicenter study (n=77)

The Flammang experience.....

Adenosine and sinus node Adenosine and sinus node dysfunctiondysfunction

ATP and sinus node dysfunction

Brignole et al 1994: ATP unhelpful in SND diagnosis, though SND needed for ATP-related sinus arrest

Burnett et al Am Heart J 1999– 10 patients with SND v 67 age matched controls

– 80% sensitivity, 97% specificity Fragakis et al Europace 2007

– Similar results• Editorials: “promising but more work needed”

Adenosine and atrioventricular Adenosine and atrioventricular blockblock

ATP and high degree AVB

Brignole et al (Circulation 1997)

– 60 patients (57+/-19 y) v 90 controls

– 15 with AVB and 9 with sinus arrest

– Upper 95th percentile in controls 6000ms

– ATP >6 sec in 53% AVB patients, none of SA

– ? Higher susceptibility of pts with AVB to ATP

Newcastle pilot study (Parry et al QJM 2009)

Adenosine 20mg iv bolus (Negative HUT, CSM, EP diagnosis excluding

alternative diagnoses) Paced groups

– CSS

– SND

– AVB VVS “Clean” EP controls

ATP and “brady-pacing indications”

Diagnosis N= Mean age (sd) Adenosine positive

(>6 sec asystole)

Sensitivity

(%)

SSS

AVB

CSS

VVS

EPC

5 (4 F)

7 (1F)

7 (4F)

10(8F)

8 (7F)

77 (5.7)

69 (15.0)

75 (4.9)

57 (19.0)

37 (14.6)

5

7

6

5

1

100

100

85.7

50

163 screened, 37 enrolled (!):

50% unsuitable (contraindications, AF)

40% refusal of CSM, 10% refusal of adenosine

ATP and ILRs

ATP and ILRs

Donateo et al (JACC 2003)

– 36 ATP positive patients with ILR, 69 yr

– 22 had syncope• 11 (69%) had bradycardia• 50% had long ventricular pause

Deharo et al (JACC 2006)

– 25 patients with tilt +ve VVS, 8 CI, mean 60 yr, all ILR

– No relation between adenosine and CI response during tilt

ATP and ILRs

ISSUE 2 Brignole et al Eur Heart J 2006

– 392 patients, 343 tilted, 164 (48%) +ve

– 180 ATP, 53 (29%) positive

– Syncope with ILR in 106 (26%) at 3/12

– No relationship between ATP positivity and HUT results

What do the guidelines say?

ACC/AHA/HRS and ESC pacing guidelines– Adenosine testing not mentioned

ESC syncope guidelines 2009– “Cannot be recommended”; Class III

If you must.....

• Usual cautions/contraindications

• Counsel your patient....

• Continuous ECG/BP monitoring

• 20 mg IV adenosine with rapid flush

• > 6 sec asystole or > 10 sec high degree AVB abnormal

• No adverse events to date in >1500 patients and control subjects

Where are we with ATP?

Contradictory evidence base– Some indications of unmasking of conducting

tissue disease

– Predominantly older patients in non-VVS literature

– Increasing positivity with advancing age

– ILR studies show little or no correlation between ATP positivity and real-time ECG/tilt diagnosis

• Difficult patient groups – confusion re underlying diagnoses, many with VVS

– Good evidence from pacing intervention studies of efficacy in ATP positive patients

Where are we with ATP?

ATP or Adenosine, – Contradictory evidence

– Both used in the literature

– ATP metabolism to adenosine very fast

– Pelleg, Flammang “vagal effect vital”• Dog studies, not replicated in guinea pig or cat

6 sec or 10 sec asystole– 6 sec based on Brignole’s work, 95th centile in 175

controls

– 10 sec based on Flammang’s work, ditto!