Fibrillazione atriale : causa diretta marker di rischio di eventi cerebrovascolari non solo embolici?

Size: px

Start display at page:

Download "Fibrillazione atriale : causa diretta marker di rischio di eventi cerebrovascolari non solo embolici?"

Deirdre Briggs
6 years ago
Views:

1 Fibrillazione atriale : causa diretta marker di rischio di eventi cerebrovascolari non solo embolici? Fabrizio Ammirati Dipartimento Medicina UOC Cardiologia Ospedale GB Grassi ASL Roma 3 Sept 2013

2 Patients with AF are at increased risk of stroke and related complications if not appropriately anticoagulated 2x in mortality in patients with AF vs those without 2 Every 5 strokes 1 happens in patient with AF Without anticoagulation treatment ~ 5% of patients with AF will have a stroke every year 1 in disability including aphasia, severe limb weakness and diminished alertness in AF- vs non-af-related stroke 3,4 1. Atrial Fibrillation Investigators. Arch Intern Med 1994; 2. Benjamin EJ et al. Circulation 1998; 3. Lin HJ et al. Stroke 1996; 4. Dulli DA et al. Neuroepidemiology 2003 Sept 2013

3 Insula injury and risk of cardiac arrhythmias and death in acute stroke Pts. with vascular hystory Pts. without vascular hystory Ins - Ins + Ins - Ins + Ins - : no insula lesion Ins + : insula lesion The cortex of the Insula is known to activate the central autonomic network and may trigger arrythymias Abboud H et al., Ann Neurol 2006;59:691-99

5 Chicken-Egg dilemma

6 Stroke risk persists even in symptomatic/ paroxysmal AF The risk of stroke with asymptomatic or paroxysmal AF is comparable to that with permanent AF 1,2 Annual risk of stroke (%) Observed rate of ischaemic stroke 1 Intermittent AF Sustained AF Low Moderate High Stroke risk category 1. Hart RG et al. J Am Coll Cardiol 2000;35:183 7; 2. Flaker GC et al. Am Heart J 2005;149: Dec 2011

Relation between AF and Stroke Background Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke;

In 18 patients (35%), SCAF was detected before stroke or systemic embolism.

7 Relation between AF and Stroke Background Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. Conclusions Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event. M. Brambatti, Circulation 2014

Temporal Relationship of Atrial Fibrillation & Thromboembolism Although AT burden was associated with thromboembolism, there was no temporal relationship

8 Temporal Relationship of Atrial Fibrillation & Thromboembolism Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. 29 pts with TE event and AF AF Burden (0 to 100%, log scale) Months from TE

9 Temporal Relationship of Atrial Fibrillation & Thromboembolism AF Burden (0 to 100%, log scale) Months from TE

10 Temporal Proximity of Silent AF Episodes to Thromboembolic Event Trial AF prior to stroke (at any time) AF prior to stroke (<30 days) New AF after stroke TRENDS (Daoud EG, et al Heart Rhythm 2011;8: ) ASSERT (Brambatti M et al Circulation 2014 Mar 14) IMPACT (all) Martin DT, ACC Session, 2014, March 29 20/40 (50%) 9/40 (22%) 6/40 (15%) 18/51 (35%) 4/51 (8%) 8/51 (16%) 20/69 (29%) n.a. 9/69 (13%)

11 Silent or Asymptomatic AF Cardiovascular Health Study (1) 30% of patients SPAF trial 45% Metrix Investigators study 20% of the episodes were symptomatic Olmsted County Minnesota Silent in 29% of patients, atypical in 38%, symptomatic in 18% 1. Furberg AJC Blackshear MCP Timmermans JACC 2000

Detecting and monitoring AF Main challenges: Poor correlation between symptoms and AF episodes AF episodes may be asymptomatic Symptoms may not relate to AF episodes Intermittent

12 Detecting and monitoring AF Main challenges: Poor correlation between symptoms and AF episodes AF episodes may be asymptomatic Symptoms may not relate to AF episodes Intermittent monitoring leads to AF undersensing Likelihood of inappropriate decisions concerning anticoagulation and AA drugs therapy Likelihood of inappropriate evaluation of therapy outcome

13 Longterm Continuous Monitoring vs. Standard Methods Comparison of monitoring strategies for AF detection: Extended monitoring results in more AF detection Adapted from A. Arya. PACE 2007; 30: G. Boriani et al. Cardiostim 2008, abstract Ziegler P, et al. Heart Rhythm 2006; 3: Botto GL, et al. J Cardiovasc Electrophysiol 2009; 20: Continuous AF monitoring is currently only possible in ICD/PM patients

Atrial fibrillation management Clinical Evidence Many cardiac device patients without history of atrial fibrillation show new or yet undiagnosed AF after implantation >13% of all ICD and pacemaker

14 Atrial fibrillation management Clinical Evidence Many cardiac device patients without history of atrial fibrillation show new or yet undiagnosed AF after implantation >13% of all ICD and pacemaker patients have previously unknown AF * ~23% On 2438 paz. implanted with CRT 23% show AF episodes. * Ricci, RP. et al., Remote control of implanted devices through Home Monitoring technology improves detection and clinical management of atrial fibrillation. Europace ** Camm, AJ. et al., Guidelines for the management of AF: the Task Force for the Management of AF of the European Society of Cardiology (ESC). Europace

15 Israel MD, et al. JACC 2004; Frequency of Asymptomatic AF 110 pacemaker patients with paroxysmal or persistent AF More than one third (38%) of AF episodes were asymptomatic Difficult to know if patients are remaining in sinus rhythm Number of Patients Device Documented AF >48 Hours (19 month follow up) Asymptomatic 30 Symptomatic

16 Clinical implications of AF The presence of atrial high rate events in the pacemakers diagnostics is an independent predictor of total mortality, stroke and chronic atrial fibrillation in patients with sinus node dysfunction. Kaplan-Meier plot of death or non-fatal stroke after 1 year of ancillary study follow-up in patients with AHREs vs those without AHREs; P= MOST indicates Mode Selection Trial; AHRE, atrial high rate episodes. Glotzer T.V. et al. Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke - Report of the atrial diagnostics ancillary study of the Mode selection Trial (MOST).Circulation 2003;107:1614-9

17 AT/AF episodes longer than 24 h were associated with a threefold increased stroke rate. While these data relate to pacemaker recipients, the evidence in ICD recipients is unclear

TRENDS: Glotzer Circ A&EP 2009 The relationship between AT/AF and stroke in device patients Purpose: To assess the association between device detected AT/AF and thromboembolic event (TE) among

18 TRENDS: Glotzer Circ A&EP 2009 The relationship between AT/AF and stroke in device patients Purpose: To assess the association between device detected AT/AF and thromboembolic event (TE) among patients with stroke risk factors. Methods: De novo IPG/ICD/CRT, >1 stroke risk factors, w/o persistent AT/AF Observational Results: 2486 pts with mean CHADS 2 score of followed for 1.4 Yrs Device detected AT/AF (>175 bpm for >20 sec) occurred in 24% of pts Annualized TE event rate was 1.2% (40 pts) High AT/AF burden (>5.5 hr) within 30 days was associated with higher TE rate (2.4) and increased risk of TE event (HR 2.2 [0.96, 5.05]; p=0.06) TE Rates for the Overall Study Group (Unadjusted) Hazard Ratios for Thromboembolic Events Associated With AT/AF Burden Adjusted for Stroke Risk Factors and Antithrombotic Therapy High and low burden are separated by the median value of 30 day windows having nonzero AT/AF burden; that is, high corresponds to a burden of >5.5 hours, low corresponds to a burden of 20 seconds to <5.5 hours. *Estimates based on Cox model with time varying AT/AF burden and antithrombotic therapy. Implications: TE risk is low in these device patients despite a moderately high CHADS 2 risk score. Suggestive of a temporal relationship in that high AT/AF burden (>5.5 hrs) on any day in the most recent 30 days doubles the risk for TE Glotzer TV, et al. (TRENDS) Circ A&EP 2009;2:

19 Ischemic Stroke in ASSERT 2580 pacemaker and ICD patients with hypertension and no history of AF 10% experienced asymptomatic AF (episodes of atrial rate >190 beats per minute for more than 6 minutes) within 3 months. Asymptomatic AF was associated with a 2.5 fold increase in the risk for ischemic stroke and systemic embolism (P=0.007). Events (% per year) Risk of Ischemic Stroke or Systemic Embolism, by CHADS2 Score and Presence of Subclinical AF within first 3 months Healey JS, et al. NEJM 2012; 366: AF Present AF Absent 1 2 >2 CHADS2 Score 19

20 ASSERT: Healey NEJM 2012 The relationship between AT/AF and stroke in device patients Purpose: To assess the association between device detected AT/AF and stroke. Methods: De novo IPG/ICD <8 wks, hypertension, w/o AT/AF and anticoagulation Observational Results: 2580 pts with mean CHADS 2 score of 2.29 followed for 2.5 Yrs % pts with >1 Subclinical AF episode (>190 bpm for >6 min) within first 3 months Associated with increased risk of Clinical AF (HR 5.56 [ ]; p<0.001) Associated with increased risk of Ischemic Stroke or Systemic Embolism (HR 2.49 [ ]; p=0.007) Among pts with AT/AF episodes >17.72 hrs, annual rate of stroke or systemic embolism was 4.89 (95% CI, 1.96 to 10.07). Implications: Suggests that the presence of Subclinical AF in the first 3 months increases the risk of stroke or peripheral emboli and also increases the risk of clinically evident AT/AF Cumulative Hazard Cumulative Hazard Risk of Clinical AF Risk of Ischemic Stroke or Systemic Embolism Healey JS, et al. (ASSERT) NEJM 2012;366:120 9.

The presence and duration of AF are a determinant TE risk factor Risk of thromboembolic events in patients with pacemakers and history of AF depends on the presence and duration of AF and

21 The presence and duration of AF are a determinant TE risk factor Risk of thromboembolic events in patients with pacemakers and history of AF depends on the presence and duration of AF and CHADS2 score. Considering the combination of these parameters is possible to divide the population into two subgroups with a significant difference of thromboembolic risk (0.8% vs 5.0%, p = 0.035)

PURPOSE: To assess the association between maximum daily AT/AF burden and risk of stroke The analysis cohort was comprised of 3 clinical databases: TRENDS, PANORAMA and the Italian ClinicalService

22 PURPOSE: To assess the association between maximum daily AT/AF burden and risk of stroke The analysis cohort was comprised of 3 clinical databases: TRENDS, PANORAMA and the Italian ClinicalService Project (total of 10,016 eligible patients, with a median follow up time of 24 months) Several cut off points for the maximum Daily AT/AF Burden from Cardiac Compass were used to dichomotize the patients, to enable comparison of the risk for stroke < 5 min vs > 5 min < 1 hr vs > 1 hr < 6 hr vs > 6 hr < 12 hr vs > 12 hr < 23 hr vs > 23 hr the results were adjusted for factors which are known to influence stroke risk, i.e. CHADS2 classification and use of OAC (at baseline)

23 AF Burden and Risk of Stroke AF Burden value Hazard Ratio 95% Confidence Interval P value < 5 vs. > 5 min p=0.041 < 1 vs. > 1 hr to 3.64 p=0.008 < 6 vs. > 6 hr to 3.41 p=0.067 < 12 vs. > 12 hr to 3.22 p=0.090 < 23 vs. > 23 hr to 3.01 p=0.332

24 AF Burden and Risk of Stroke and TIA AF Burden value Hazard Ratio 95% Confidence Interval P value < 5 vs. > 5 min to 3.09 p<0.001 < 1 vs. > 1 hr to 2.90 p=0.003 < 6 vs. > 6 hr to 2.41 p=0.065 < 12 vs. > 12 hr to 2.44 p=0.092 < 23 vs. > 23 hr to 2.56 p=0.1317

25 Daily Maximum Increase in AF Burden For every additional hour increase in the daily maximum of AF burden, the relative risk for stroke increases by about 3% 6 hour increase AF burden implies an increase in risk of stroke of 17% 12 hour increase AF burden implies a 37% increase in risk

26 Intervention Studies for SCAF 1. IMPACT Intensive remote monitoring + SCAF-OAC algorithm vs. usual care 2. ARTESiA Apixaban vs. ASA 3. NOAH Edoxaban vs. Placebo

Patients with: SCAF 6 min to 24 hrs Risk factors for stroke (age 75, previous stroke/ TIA/ SE or multiple risk factors)* No clinical AF/not on OAC, no contraindication *New amendment Doubleblind,

27 Patients with: SCAF 6 min to 24 hrs Risk factors for stroke (age 75, previous stroke/ TIA/ SE or multiple risk factors)* No clinical AF/not on OAC, no contraindication *New amendment Doubleblind, doubledummy design Apixaban Arm: 5mg or 2.5mg bid (+ placebo aspirin) CONSENT and RANDOMIZE Aspirin Arm: 81 mg OD (+ placebo apixaban) 4000 patients from ~150 hospitals in Canada, USA and Europe Target is 1 4 patients per month at each site Follow up Visits: 1 month and every 6 months ( avg 3 yrs follow up) 1 Efficacy Outcomes: Stroke (including TIA with imaging), Systemic Embolism 1 Safety Outcome: Major Bleed

28 Primary Efficacy: Stroke (including TIA with DWI) (rapid onset of neuro symptoms with no other readily identifiable cause, confirmation of diagnosis e.g., specialist consult or imaging) Systemic Arterial Embolism (clinical signs and symptoms plus at least one objective measure) Primary Safety: ISTH Major Bleeding (fatal, symptomatic in critical area or organ, Hg drop 2 g/dl or transfusion 2 units blood) Central Adjudication by Neurologist Central Adjudication by Neurologist, Cardiologist or Thrombosis specialist Central Adjudication by Neurologist, Cardiologist or Thrombosis specialist

29 Remote control of implanted devices through Home Monitoring technology improves detection and clinical management of AF Ricci et al., Europace 2009;11:54-61 HM & AF Study: pilot italian single center study 166 pt. (121 PM, 22 ICD, 23 CRT-D). Mean FU 488±203 days 42 (26%) pt. with AF ALERT - 33/42 (78%) pt. unscheduled FU (HM detection) - 22/33 (67%) No AF history - 24/33 (73%) asymptomatic - 16/33 (48%) began antiarrhythmics treatment Actionability : 88% - 17/33 (51%) began anticoagulants treatment! Early Detection: 148 days (5 months earlier) before scheduled FU*! Early detection Asymptomatic AF *(every 6 months for ICDs e 12 months for PMs) Follow-Up Mean 148 days gained through HM Next follow-up

30 COMPAS TRIAL Home Monitoring reduces the rate of hospitalizations for atrial arrhythmias and related stroke Population: 538 PPM patients Incidence of hospitalizations for atrial arrhythmias and related stroke n=18 Control group (n=246) p=0.02 n=6 Home Monitoring group (n=248) COMPAS showed a 66% reduction in hospitalizations for atrial arrhythmia and related stroke* *despite the fact that the study was not powered to this assumption 18 events in Control group consisted of 10 atrial arrhythmias and 8 strokes 6 events in HM group consisted of 4 atrial arrhythmias and 2 strokes Mabo P et al. Eur Heart J 2011; doi: /eurheartj/ehr419

31 Atrial Fibrillation in CIEDs and Stroke Relative risk for ischemic stroke appears increased for all types of AF and SCAF Appears to be a stepwise increase in ABSOLUTE risk with greater AF burden There is lack of Temporal Relationship of AF & Thromboembolism Large clinical trials will define the role of OAC in SCAF

33 Open issues: 1. Not clear criteria to start anticoagulation - at which AF episode duration? - at which Burden? 2. Not clear criteria when to start or to discontinue OAT - No temporalized correlation AF and TE events clinical risk factors should play a first-line role in making decision!

Subclinical AF: Implications of device based episodes

Subclinical AF: Implications of device based episodes Michael R Gold, MD, PhD Medical University of South Carolina Charleston, SC Disclosures: Clinical Trials and Consulting: Medtronic, Boston Scientific