Contemporary Surgical
Therapy for Atrial Fibrillation
John F. Grehan, M.D., Ph.D.
AllinaHealth
United Heart and Vascular Clinic
Minneapolis Heart Institute
Grand Rounds
April 1, 2013
Objectives
 Provide a understanding of AF pathophysiology and
clinical impact on the surgical population
 Understand the rationale for the Maze IV lesion set
 Review preoperative considerations and proper
classification of AF patients
 Understand how to safely and efficiently complete
each step of the concomitant Maze IV procedure
 Discuss postoperative and post discharge
considerations
Overview
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•
•
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Pathophysiology of Atrial Fibrillaiton
Rationale for Concomitant Treatment
Challenges to the Adoption of Treatment
Rationale for the Cox Maze IV lesion set
ABLATE Study
Patient Selection Criteria
Post ABLATE Trial
Summary
Conclusions
AF Pathophysiology & Patient
Impacts
Rev A
Pathogenesis of AF
• Multiple-wavelet
hypothesis1
• Focal mechanism
with fibrillatory
conduction2
• “Autonomic”
hypothesis3
Taken from 2007 HRS Guidelines
1. Moe GK, Abildskov JA. Am Heart J. 1959;58(1):59-70.
2. Konings KT, et al. Circulation. 1994;89(4):1665-1680.
3. Task Force of the European Society of Cardiology and the North American Society of Pacing
and Electrophysiology. Circulation. 1996;93(5):1043-1065.
Focal Origin of AF
RA
•
LA
94% of atrial triggers in
PVs (45 pts)
• The pulmonary veins are
an important source of
ectopic beats, initiating
frequent paroxysms of AF
• These foci respond to
treatment with RF ablation
Hassaiguerre M, NEJM, 1998.
17
SVC
FO
Pulmonary Veins
6
IVC
CS
31
11
Pulmonary Veins
• Myocardium extends 1–4cm
into vein
• Complex fiber orientation
• Site of embryological
pacemaker tissue
• Exhibits automaticity and
triggered activity
• Lower refractory periods
Myocardium extends from the
atrium along the pulmonary vein
Macro-Reentrant Circuits
Substrate modification
occurs due to near
continuous firing in
the cells and some
cells with the atria
begin to fire without
being (externally)
activated creating
additional triggers
The Rationale for the Maze IV Lesion Set
Risks of Untreated AF – Target Population
• Structural heart disease requiring:
– Mitral valve surgery
– Aortic valve surgery
– Coronary artery bypass
• Mayo Clinic/Cleveland Clinic Investigations:
– Compared subjects with Preoperative AF vs. no AF
– No AF Ablation surgery performed
– Statistical matching
Indication
Citation
Number of
Patients
CABG
Quader et al
Annals of Thor Surgery 2004
46984
Aortic Valve
Ngaage et al
Annals of Thor Surgery 2006
1487
Mitral Valve
Ngaage et al
Annals of Thor Surgery, 2007
2821
Risks of Untreated AF in Cardiac Surgery
Patients
CABG
• > 20% increase in mortality by 10 yrs
• Increased post op morbidity (2 X stroke)
Aortic Valve
• Worse late survival (RR = 1.5)
• More post op stroke (16% vs. 5%) and CHF
(25% vs. 10%)
Mitral Valve
• 18% difference in survival by 10 yrs
• Increase in late cardiac events/stroke (32%
difference)
Midterm survival in patients treated for atrial
fibrillation: A propensity-matched comparison to
patients without a history of atrial fibrillation
3262 consecutive patients
813 with AF and 2449 w/out
AF undergoing cardiac surgery
April 2004 to April 2009.
The American Association for Thoracic Surgery
doi:10.1016/j.jtcvs.2012.02.006
Improved Patient Survival With Concomitant
MAZE Procedure Compared With Heart Surgery
Alone
Conclusions. The restoration of sinus rhythm by a Maze procedure combined
with heart surgery markedly improved long-term survival in this series.
Ann Thorac Surg 2009;87:440-7
Conclusions. AF associated with
mitral valve disease should be treated,
because restoration of the sinus
rhythm might lead to a lower
incidence of thrombo-embolism and
valve-related complications in the
later period.
Challenges to Adoption
Concomitant AF Treatment
25 Years of Surgical AF Treatment
2012
2002
1987
1st Cut and Sew Maze
Dr. Cox reports high
success rates with
“Cut and Sew” Maze
procedure.
Cox Maze IV Using RF
Clamp
Period of significant trial
and error in energy
sources and lesion sets to
increase adoption and
reproducibility.
FDA Approval of
AtriCure Synergy
clamp for AF
Treatment (NPAF)
Opportunity to
standardize procedure
through rigorous training.
Do Societies Recognize Surgical AF Treatment
Or Is This Still Considered “Investigational?”
“It is advisable that all patients with documented
AF referred for other cardiac surgeries undergo a
left or biatrial procedure for AF at an experienced
center, unless it… will add significant risk…
Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac
Arrhythmia Society, in collaboration with the American College of Cardiology,
American Heart Association, and Society of Thoracic Surgeons.
Consensus Statement on CA and Surgical AF 2012
The ISMICS Consensus
Recommendations
Concomitant surgical ablation is recommended to
increase the incidence of sinus rhythm both at shortand long-term follow-up (class 1, level A) to improve
ejection fraction and exercise tolerance (class 2a, level A)
and to reduce the risk of stroke and thromboembolic
events, to improve long-term survival (class 2a, level A).
Under-Treatment by Procedure
MV/Aortic Valve Procedures
with AF Diagnosis
Coronary Artery Bypass
with AF Diagnosis
27,000
61%
55,000
93%
4,000 7%
17,000
39%
Concomitant AF
Concomitant AF
No Concomitant
AF
No Concomitant AF
(ICD-9 427.31)
Source: Agency for Health Care Quality and Research (AHRQ)
Cost and Utilization Project Nationwide Inpatient Sample 2009
Structural Heart Disease Procedures with PreExisting AF Diagnosis
50,000US Concomitant AF Treatment Rates – STS Database
Untreated
Treated
Number of Patients
40,000
33%
30,000
20,000
24%
67%
10,000
0
28%
52%
48%
Mitral Valve
76%
62%
(1)
Aortic Valve
(1)
Isolated CABG
Total
(Mitral + Aortic +
Isolated CABG)
Source: Gammie, Annals 2008;85:909-15
Surgeon Survey, “Why Don’t You Routinely Perform Maze
Procedure on Surgical Patients with Pre-Op AF?
35%
30%
Highest Scoring Reasons
25%
20%
15%
10%
5%
0%
Adds complexity to
primary procedure
Added “on pump”
time
Results may not be
reproducible
Added patient risks Lack of consensus on
to primary
what works
procedure
Adds costs
Refering physician
Do we increase the operative risk by adding the
Cox Maze III procedure to aortic valve
replacement and coronary artery bypass surgery?
Ad et al.
J Thorac Cardiovasc Surg Jan 2012
Keys to Maze IV Adoption
• Standardization on concomitant procedure
• Focus on safety and efficacy
• Provide reference materials and support
throughout the learning curve
• Build a substantial body of evidence on
durability of outcomes
Rationale for the Maze IV
Lesion Set
Surgical Treatment of Atrial Fibrillation:
The Cox Maze Procedure
• Are all the left atrial lesions necessary?
• There have been virtually no randomized
trials, but there are observational data.
Surgical Treatment of Atrial Fibrillation :
How about pulmonary vein isolation alone ?
PULMONARY VEIN ISOLATION ALONE IS NOT
EFFECTIVE IN PATIENTS WITH PERMANENT AF AND
VALVULAR HEART DISEASE
• 105 patients with AF undergoing valve surgery were
randomly assigned to three groups: “U” or “7” linear
cryoablation of left atrium or PV isolation
• Mean ablation time: 18 ± 3, 15 ± 4, 14 ± 4 minutes
for U, 7, and PVI respectively.
Gaita et al. Circulation 2005;111:136-142
• Mean follow-up: 41 ± 17 months
• Successful lesion creation by EAM:
0%
65%
71%
(0/17)
(11/17)
(12/17)
U lesions
7 lesions
PVI
• NSR at last follow-up:
76%
76%
29%
(13/17)
(13/17)
(5/17)
Gaita et al. Circulation 2005;111:136-142
U lesions
7 lesions
PVI
PULMONARY VEIN CRYOABLATION FOR
CHRONIC AF
• 101 pts having concomitant cardiac surgery
underwent PVI with spherical cryoprobe
• Mean age: 63 ± 12 years
• Mean AF duration 3.4 ± 3.3 years
• NSR at discharge: 75%
• NSR at last follow up: 53%
• NSR without AA drugs at last followup: 25%
Isobe et al.Circ J 2005;69:446-455
Left Atrial Lesions of the Cox-Maze IV
Right atrial lesion set of the Cox Maze IV
CM-IV: Predictors of Late Recurrence
Multivariate Analysis (n=282)
Months to f/u
1.
2.
3
6
12
% Freedom from Afib
89%
93%
89%
% Freedom Afib/Off AADs
63%
79%
78%
Recurrence Variables
OR, CI
p- value
Box lesion set
0.38 [0.167-0.871]
0.022
LA diameter
Early ATAs
1.42 [1.04-1.94]
3.05 [1.299-7.17]
0.027
0.010
94% had 24 hr Holter (3,6,12 months)
Compliant to HRS Guidelines for definition of success (no AF, AT, Flutter off of AADs)
Damiano et al. J Thorac Cardiovasc Surg 2011
The Cox Maze IV for Lone AF: A single center
experience in 100 consecutive patients
Freedom from ATAs at 12 Months
Isthmus lesion
Weimar T et al
J Interv Card Electrophysiol; 2011
Are the Right Atrial Lesions of the
Cox-Maze IV Necessary?
Left Atrial Ablation Versus Biatrial Ablation
in the Surgical Treatment of Atrial Fibrillation
Breda et al
Comparison of Bilateral and Unilateral RF
Ablation In RF: Early Results
Bi-Atrial VS. Left Atrial
Barnett SD, Ad N. J Thorac Cardiovasc Surg: 2006;131:1029-30
Surgical Treatment of Atrial
Fibrillation in Mitral Valve Disease:
Left Atrial Ablation
• Meta-analyses have shown significant differences
(87 vs 73%, p=.05) between bi-atrial and left lesion set
Ad et al. J Thorac Cardiovasc Surg 2006;131:1029
• Results have been very variable with left atrial ablation
(range 21-95%) and are dependant on the technology used,
the lesion set, and the patient population.
• A well designed randomized trial showed only a 44%
success rate at 1 year for LA ablation !
Doukas et al. JAMA 2005;294:2323
What are the important lesions of the
Cox Maze procedure?
Conclusions
• All of the left atrial lesions are needed to ensure a
success rate of over 80% and to prevent late left
atrial flutter.
• The right atrial lesion set adds to the overall
success rate but may not be necessary in all
patients. However, in patients undergoing valve
surgery, it takes only 10-15 minutes to perform
and adds little morbidity.
ABLATE Primary Endpoints
• Primary Safety Endpoint
– Composite of Death, Stroke, TIA, MI and
Excessive Bleeding within 30 days or prior to
hospital discharge
• Primary Efficacy Endpoint
– AF Free (24 hr Holter) and off Class I and III
antiarrhythmic drugs at 6 months
Left Atrial Lesion Set Checklist








Left Atrium
Right Antral Pulmonary Vein isolation
Left Antral Pulmonary Vein isolation
Left Atrial Appendage otomy or excision
Left Atrial Appendage to PVI
LA roof connecting lesion
LA floor connecting lesion
Mitral Valve Isthmus lesion
Coronary Sinus/MV annulus lesion
(epi / endo)
Electrical Isolation Testing (Pacing or Sensing)
KEY:
Blue lines represent typical clamp lesions.
Orange line represents typical cryo lesions.
Purple line represents surgical incisions.


Right Pulmonary Veins
Confirmation of Right Antral PVI P / S
Confirmation of Left Antral PVI P /S
Right Atrial Lesion Set Checklist
Connecting lesion along medial
walls of RAA toward TV annulus
Left Pulmonary Veins
KEY:
Blue lines represent typical clamp lesions.
Orange lines represent typical cryo lesions.
Purple oval represents RAA otomy.






Right Atrium
Right Atrial Appendage Oblique
Vertical right atriotomy
Connecting lesion from the RAA Oblique to the
MEDIAL Tricuspid annulus (10 o’clock position)
Connecting lesion from vertical atriotomy to the SVC
Connecting lesion from vertical atriotomy to the IVC
Connecting lesion from the vertical atriotomy to the
MEDIAL Tricuspid annulus (2 o’clock position)
ABLATE: Enrolled Patient
Disposition
55 Patients Enrolled
n=2 Patients expired
53 Patients
@ 30 day follow up
n=2 Patients expired,
n=1 withdrawal
50 Patients
@ 6 Months
n=2 Patients expired
48 Patients
Long-term
Median= 21.6 Months
ABLATE: Demographics
ABLATE
(N=55)
Age (years)
Mean +/-SD
Median (Min, Max)
Gender
Male
Ethnic Group
Caucasian
Black
Asian
Hispanic
70.5 +/- 9.3
72.0 (45.0, 88.0)
%
n
58.2
32
90.9
3.6
1.8
3.6
50
2
1
2
ABLATE: Demographics
ABLATE
(N=55)
EF (%)
Mean +/-SD
Median (Min, Max)
LA Size (cm)
Mean +/-SD
Median (Min, Max)
NYHA Classification
I
II
III
IV
50.0 +/- 10.3
50.0 (20.0, 70.0)
5.9 +/- 1.0
6.0 (3.9, 7.7)
%
n
16.4
41.8
40.0
1.8
9
23
22
1
ABLATE: Baseline AF Status
ABLATE
(N=55)
Form of AF
Paroxysmal
Persistent
Long-standing persistent
%
n
7.3
40.0
52.7
4*
22
29
Duration (months) of AF prior to enrollment
Mean +/-SD
61.2 +/- 49.5
Median (Min, Max)
48.6 (1.78, 188.39)
Current / Prior failed
anti-arrhythmic drugs
Paroxysmal Subjects:* LA Size > 5 cm: (3/4); Hx of AF > 12 mos (4/4)
25.5
14
ABLATE Primary Surgical
Procedure
ABLATE
(N=55)
Surgery
CABG
%
18.2
n
10
Mitral Valve
18.2
10
Aortic Valve
21.8
12
Double Valve
16.4
9
CABG & Valve
16.4
9
CABG & Double Valve
9.1
5
ABLATE Primary Safety Endpoint- Results
Primary Safety Endpoint
Details of Primary Safety Endpoint
Operative Mortality (Death)
Stroke
TIA
MI
Excessive Bleeding
(>2 units with reop)
%
9.1
n
5
3.6
1.8
0.0
0.0
2
1
0
0
3.6
2
Primary Safety Endpoint – Major Adverse
Event Rate: Non-paroxysmal Population
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
9.8%
7.8%
0.0%
N= (5/51)
ABLATE
ABLATE AF
N= (5/64)
Combined
Six Month Efficacy: Non-paroxysmal
Population
Success
Rate
AF Free off AADs
AF Free
(Primary Endpoint)
(Secondary Endpoint)
100.0%
91%
83%
80.0%
84%
82%
75%
74%
60.0%
40.0%
20.0%
N= (34/46)
N= (38/46)
N= (9/11)
N= (10/11)
N= (43/57)
N= (48/57)
0.0%
ABLATE
Data on File
ABLATE AF
Combined
Patient Selection & Patient
Considerations
2007 HRS Consensus StatementConcomitant Indications
• Symptomatic AF patients undergoing other cardiac surgery
• Selected asymptomatic AF patients undergoing cardiac surgery
in whom the ablation can be performed with minimal risk
Reviewing Relevant Patient History
• Factors That Influence Decision To Treat
and Potential Outcomes of Concomitant
Treatment:
– Patient Age
– Left Atrial Size
– Preoperative Duration of AF
– Unrelated Co-morbidities
– Number of Concomitant Procedures Related to
the Patient
Cox - Regression Freedom from Late AF
Recurrence Stratified by Duration of Preop AF
Freedom from Recurrence (%)
100
80
60
1 yr.
5 yrs.
10 yrs.
15 yrs.
20 yrs.
40
20
0
1
2
3
4
p=<0.001
5
6
Time from Surgery (years)
7
8
9
10
Gaynor SL, Damiano RJ; J Thorac
Cardiovasc Surg 2005;129:104-11
Post Operative and Post Discharge
Patient and Rhythm Management
2007 HRS Guidelines for AF Reporting
Outcomes
Blanking period
• A blanking period of three months should be employed after ablation when
reporting outcomes.
Definition of success
• Freedom from AF/flutter/tachycardia off antiarrhythmic therapy is the
primary endpoint of AF ablation.
• Freedom from AF at various points following ablation may be a better marker
of true benefit and should be considered as a secondary endpoint of ablation.
• An episode of AF/flutter/tachycardia detected by monitoring should be
considered a recurrence if it has a duration of 30 seconds or more.
Postoperative Considerations and
Expectations
Junctional rhythm occurs quite
frequently in post-ablation patients
and may be due to some degree of
sinus node dysfunction. Pacemaker
insertion should not be considered too
hastily, and without clear indications.
Heart rates in post operative full Maze
patient are often in the low 50-60 BPM
range. Some patients may be sent
home in junctional rhythm.
Continued
• Patients with junctional rhythm often have
extend hospitalization ranging from 7–10
days on average which allows for
stabilization of their cardiac rhythm.
• Cardioversion may be considered during the
early postoperative period if the patient is
cardiovascularly unstable or prior to
discharge from hospital.
Clinical management after surgery for atrial
fibrillation focuses on four areas:
1) Fluid retention occur in 12-30% of patients. This may be considered as:
– Early 24-36 hrs: Pulmonary congestion
– Late: Pleural effusion and weight gain
Managed as per standard ICU protocol.
2) Atrial tachyarrhythmias (ATA)– Over 40% of patients experience ATA
(AF, Aflutter, AT, SVT) post operatively.
– Intraoperative antiarrhythmics/Amiodarone may be administered as per
hospital protocol. This may be continued into the postoperative period except
for patients with bradycardia or junctional rhythm. Cardioversion may also be
considered for these patients as outlined in the previous slide at physician’s
discretion.
Clinical considerations after surgery :
continued
3) Anticoagulation—(At Physician’s Discretion)
– Aspirin is usually resumed on POD-1 unless contraindicated.
– Coumadin is usually started/restarted on postoperative day (POD)-2.
Coumadin should be delayed if the patient experiences a bradycardic
rhythm requiring a pace maker.
– An INR range of 2.0-2.5 is the recommended level to maintain for patients.
– The duration of Coumadin is dependent on physician discretion and may
be based upon several factors including, (i) Patient remaining in sinus
rhythm (ii) Concomitant procedure performed ie. mechanical valve
replacement, and (iii) CHADS2 score.
4) Perioperative sinus/AV dysfunction— (At Physician’s Discretion)
– The need for a permanent pacemaker (PPM) is more common in patients
with preoperative SA node dysfunction. If the patient develops
postoperative bradycardia and/or junctional rhythm, all antiarrhythmics
should be discontinued. The patient may be treated conservatively for 7-10
days before a PPM is implanted. Bradycardic rhythms can often resolve
within this time period.
ABLATE
Post Approval Study
• Atricure Synergy Ablation Lesions for NonParoxysmal Forms of Atrial Fibrillation
Treatment During Concomitant On-Pump
Endo/Epicardial Cardiac Surgery
Trial Design
• Site Selection:
– 50 US centers
– Up to 10 OUS centers
• 3 categories:
– ABLATE AF Registry subjects (will be transferred into
the ABLATE PAS study); need to be re-consented to
participate in PAS
– Existing Users – uses Synergy Ablation System, but not
part of clinical trial(s)
– New Users – new users to the Synergy Ablation System
• Certification:
– All participating surgeons will have successfully
completed the Certification process
Trial Design
• Enrollment procedures:
– All non-paroxysmal subjects presenting with AF
and scheduled to undergo a primary open cardiac
surgery requiring bypass including valve and/or
CABG are eligible
– Patients are PRE-SCREENED for eligibility and
offered the opportunity to participate
Eligibility Criteria
Inclusion Criteria
• Subject ≥18
• Subject has a history of a non-paroxysmal form of AF as defined by the
HRS/EHRA/ECAS Consensus Statement
• Persistent AF
• Longstanding Persistent AF
• Subject agrees to participate in this study by signing the IRB approved
informed consent form.
• Willing and able to return for scheduled follow-up visits
Eligibility Criteria
Exclusion Criteria
• Stand alone AF without indication(s) for concomitant cardiac
surgery.
• Need for emergent cardiac surgery
(i.e. cardiogenic shock)
• Preoperative need for an intra-aortic balloon pump or intravenous
ionotropes
• Pregnancy or desire to get pregnant for the duration of the study
• Enrolled in another clinical trial that could confound the results of
this study.
Study Outcomes
Primary Safety Outcome
•
Proportion of subjects with any serious adverse events within 30 days
post procedure or hospital discharge (whichever is later) considered to
be:
– device-related or ablation procedure-related
– Excluding pacemaker implantation (reviewed
separately)
• Adjudicated by clinical events committee
Study Outcomes
Secondary Safety Outcome
•
Composite major adverse event:
– Serious adverse events occurring within 30 days postprocedure or hospital discharge (whichever is later)
including:
– Death (includes deaths after 30 days or hospital
discharge if death is procedure related).
– Stroke (resulting in significant permanent disability)
– TIA
– Myocardial infarction, and
– Excessive bleeding (requiring >2 units of blood
replacement and surgical intervention).
Study Outcomes
Primary Efficacy Outcome
• The proportion of subjects free from AF while off Class I and III
AADs
– determined by 48 hour Holter recording at a minimum of 12, 24 and
36 months post operatively
• Zio™ Patch or Permanent Pacemaker interrogation can be performed in lieu of 48
hour Holter
– Success = AF Free while off of Class I and III AADs
• i.e. no episodes lasting >30 continuous seconds of atrial fibrillation, atrial flutter
or atrial tachycardia
Study Outcomes
Secondary Efficacy Outcome
• Proportion of patients free from AF, regardless of AAD usage
– determined by 48 hour Holter recording at a minimum of 12, 24
and 36 months post operatively
• Zio™ Patch or Permanent Pacemaker interrogation can be performed in lieu of
48 hour Holter
– Secondary Success = AF Free (regardless of AAD usage) i.e. no
episodes lasting >30 continuous seconds of atrial fibrillation, atrial
flutter or atrial tachycardia
Study Follow-up
• 36 month follow-up period
• Post-procedure follow up visits at:
–
–
–
–
–
30 days
4 months
12 months
24 months
36 months
Follow-up Assessments
30 day follow-up
• Window: +7 days
–
–
–
–
–
–
–
Physical assessment
Medications
NYHA Classification
12 Lead ECG
AE assessment
INR – if anticoagulated
Cardioversion if subject is in AF
Follow-up Assessments
4 month follow-up
• Window: +/- 30 days
–
–
–
–
–
–
–
Physical assessment
NYHA Classification
12 Lead ECG
AE assessment
Review of medications
INR – if anticoagulated
Cardioversion if subject is in AF
Follow-up Assessments
12 month follow-up
• Window: +/- 60 days
–
–
–
–
–
–
Physical assessment
AE assessment
Review of medications
INR – if anticoagulated
Cardioversion if subject is in AF
Primary endpoint evaluation: 48 hour Holter
monitor assessment (Zio™ Patch or Pacemaker
Interrogation acceptable)
Follow-up Assessments
24 month follow-up
• Window: +/- 60 days
–
–
–
–
–
–
Physical assessment
AE assessment
Review of medications
INR – if anticoagulated
Cardioversion if subject is in AF
48 hour Holter monitor assessment (Zio™ Patch or
Pacemaker Interrogation acceptable)
Follow-up Assessments
36 month follow-up
• Window: +/- 60 days
–
–
–
–
–
–
Physical assessment
AE assessment
Review of medications
INR – if anticoagulated
Cardioversion if subject is in AF
48 hour Holter monitor assessment (Zio™ Patch or
Pacemaker Interrogation acceptable)
Summary
Pathogenesis of AF multifactorial
PV responsible in majority
LA Substrate modification contributes
Maze IV lesion set address multiple mechanisms
At least all left atrial lesions
RA lesions add to efficacy-minimal cost
AF portends to worse long-term outcomes in surgical patients
CABG, AVR, MVR
Efficacy Rates of near 80% off AAD can be achieved
Little extra time and minimal increase in risk
NSR improves outcomes in all cardiac surgery patient groups
studied
Conclusions
All patients with atrial fibrillation undergoing
cardiac surgery should be considered for
concomitant maze procedure utilizing the
Cox maze IV lesion set.