EVAC-HF is a Prospective, Multi-center, Randomized Study to Compare the Effects on LV Systolic Function Following Radiofrequency Catheter Ablation of Frequent Premature Ventricular Contraction With Optimized Medical Therapy Alone.
Phase: NA
Conditions: Premature Ventricular Contractions, Congestive Heart Failure
Sponsor: University of Maryland, Baltimore

Elimination of Premature Ventricular Contractions in 
Heart Failure (EVAC-HF) 
 
 
 
NCT 01757067 
 
 
9-17-2011 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Elimination of Premature Ventricular Contractions in 
Heart Failure (EVAC-HF) 
 
Premature ventricular contractions (PVC) are the most common arrhythmia to be 
observed in the absence of structural heart disease, and ‘frequent’ PVCs are 
estimated to occur in 1–4% of the general population.1 Idiopathic PVCs are 
usually associated with a benign course from the standpoint of arrhythmic death, 
but may result in a cardiomyopathy that is reversible with suppression of the 
PVCs.2 
 
The concept that frequent PVCs might be responsible for the development of a 
cardiomyopathy was originally suggested following the observation that 
pharmacological suppression of frequent PVCs (>20,000/24 hour holter 
recording) in patients with dilated cardiomyopathy led to dramatic improvements 
in left ventricular (LV) systolic function and dimensions.3 Since that time, a 
number of additional reports documented a reversal of LV dilatation and 
impairment by both chemical and radiofrequency ablation (RFA), supporting the 
hypothesis that frequent PVCs (as few as 5,000 ectopic beats) might have a 
causative role in the genesis of LV dysfunction.4-8 A recent analysis of 174 
patients found that a PVC burden of 24% best separated patients with >50% EF 
from <50% EF.9 
 
It is well documented that RFA is a safe and effective procedure in patients with 
symptomatic frequent ventricular ectopic beats and PVC-induced 
cardiomyopathy. Successful PVC suppression ≥80% of RV and LV PVCs has 
been reported to be as high as ~80% using an ablation approach.9 
Studies found improvements in LV dysfunction following ablation, and, notably, 
demonstrated a significant inverse correlation between EF and PVC burden 
before ablation, and a significant post procedural improvement in EF in 82% of 
patients who had abnormal systolic function before ablation.8 Improvement of the 
overall LV EF ranged from 13%-23% after PVC ablation.5,8,10 While the 
mechanism of PVC-induced cardiomyopathy is not clear, possible etiologies 
include asynchronous ventricular contraction generated by the PVCs, impaired 
calcium handling, or a decrease in calcium transient.10  
 
Previous studies have been limited to case reports and non-randomized, 
observational studies with variable, non-consistent adjunctive heart failure 
treatment.  As such, the efficacy of RFA ablation above optimized medical and 
possible device therapy for heart failure with reduced LV function and frequent 
PVCs is still uncertain.   
 
Justification: 
Frequent PVCs can be associated with cardiomyopathies and may be a target for 
therapy.  To date, there have been no randomized, prospective trials to evaluate 
the efficacy of PVC suppression using RFA±antiarrhythmic therapy in improving 
left ventricular systolic function compared to optimal medical therapy. 

Consequently no unified treatment approach for these patients exist. While some 
physicians prefer aggressive PVC suppression using ablation procedures, other 
opt for intensive pharmacological heart failure treatment first. If the treatment 
effects observed in the observational studies of improvement of EF of ~15% 
could be verified in a randomized trial this would open a uniquely effective, new 
treatment strategy in this patient population. 
 
Study Objective: 
EVAC-HF will be a prospective, multi-center, randomized study to assess if in 
patients with frequent PVCs (>20%) and non-ischemic cardiomyopathy 
(EF≤45%) PVC suppression of >80% using RFA and antiarrhythmic therapy 
results in an improvement of EF after 6 months compared to optimized medical 
therapy (OMT) alone. Patients and/or their physicians will be contacted for follow-
up to assess symptoms, any hospitalizations, and obtain any study related 
procedure(s) documentation that may have occurred at 1 year and 2 years post 
enrollment.  
 
Recruited patients will be randomized in a 1:1 fashion between continuation of 
stable optimal medical therapy alone (i.e. ACE-inhibitors/ARBS, beta-blockers, 
aldosterone antagonists, diuretics, and digoxin as indicated) and RFA 
ablation±antiarrhythmics plus OMT.   
 
 
Study Population 
Inclusion Criteria: 
1. Patients with reduced ejection fraction (EF ≤45%) demonstrated by 
transthoracic echocardiogram and deemed to be non-ischemic by nuclear 
stress test or cardiac catheterization. 
2. Patients with >20% PVCs on 24 hour holter-recording  
3. Patient is 18 years of age or older 
4. Optimized medical therapy on stable therapy for minimum 3 months with 
no changes in beta-blocker, ACE-I/ARB, digoxin doses (varying diuretic 
doses permitted). 
 
Exclusion Criteria: 
1. Patients who are under the age of 18 years of age 
2. Patients with >2 dominant PVC morphologies 
3. Patients with cardiac surgery in previous 3 months or scheduled for 
following 6 months 
4. Patients who were implanted with a biventricular device during the last 
three months or single/dual chamber device (with ventricular pacing 
>10%) during the last three months  
5. Significant symptoms associated with PVCs that would make favor 
immediate ablation 
6. Intracardiac mural thrombus or  myxoma 

7. Pregnancy 
 
 
Procedures 
Enrollment 
Patients will be recruited from cardiology or medicine clinics, inpatient services, 
cardiology consult service or referrals. Prior to enrollment patients should have 
been kept on stable doses of beta-blocker, afterload reducing agents and 
aldosterone antagonist for three months, while diuretics doses can have been 
adjusted. Beta blockers should be advanced to the highest tolerated dose with a 
target average heart rate of <70bpm. Patients on stable antiarrhythmic therapy 
but a residual PVC burden of ≥20% are eligible for the study. At chart review the 
results of a clinically performed TTE and Holter acquired after at least three 
months of stable therapy will be screened. If the PVC burden is ≥20% and the 
EF≤45% a copy of the anonymized TTE and Holter report will be send to the 
echo core lab/coordinating center at UMD. If both criteria are confirmed the 
patient will undergo the following research procedures: 
- Randomization (1:1) to standard of care OMT or clinically indicated PVC 
ablation±antiarrhythmic therapy plus OMT.  Assignment of randomization 
will be provided by the coordinating center; University of Maryland Medical 
Center. 
- Blood draws at enrollment for  biomarker studies performed at the UMD 
core lab.  
- If available, a copy of the anonymized cardiac MRI, which is part of the 
standard clinical work-up of these patients in many centers, will be send to 
the radiological core lab at UMD.  
- A copy of the anonymized clinical TTE and Holter studies obtained 
during screening/enrollment, will be send to the core lab at UMD 
- The patient will undergo a 6 minute walk test at baseline. 
- The patient will answer heart failure questionnaires (Kansas City 
cardiomyopathy as well as the Minnesota Living with Heart Failure 
Questionnaire and optionally SF12/36) at baseline. 
 
 
All patients will remain on their stable, optimized heart failure regiment during the 
6 month’s study duration. A cross-over is planned after 6 months. If during these 
6 months of standard clinical follow-up a clinical deterioration would lead to a 
documented decrease in the EF in an OMT patient a crossover to the PVC 
ablation group will be allowed prior to the 6 months follow-up.   
 
Standard of Care Endocardial/Epicardial Ablation 
Patients randomized to PVC suppression will undergo a clinically indicated, 
standard of care PVC ablation. The electrophysiology procedures will be 
performed according to the clinical standard of care in the respective institutions. 

The following description is meant as a guideline, but will be modified according 
to the local expertise, best clinical care and outcome.  
The ablation will be performed in the fasting state after informed consent is 
obtained.  The PVC mapping will be performed using an endocardial and 
possibly epicardial ablation approach. Placement of the endocardial RV mapping 
catheters will be performed via femoral venous access. Mapping of the LV will be 
performed either via femoral arterial sheath and retrograde aortic access or via 
transseptal puncture. Epicardial access, if required, will be performed via a 
substernal, percutaneous puncture or a limited, surgically created epicardial 
access. Systemic heparinization to achieve an activated clotting time of 300s is 
performed for left- sided procedures. In the presence of frequent spontaneous 
ectopy, activation mapping might be performed with an open-irrigated catheter 
using a clinical three-dimensional mapping system. If the ectopy is infrequent, 
isoproterenol is administered. If PVCs remain infrequent, pace mapping can be 
performed at a pacing cycle length that matches the coupling interval of the 
spontaneous ventricular ectopy. RFA is performed at the site of earliest 
endocardial activation or best pace map. The energy is titrated to achieve an 
impedance drop of 10 ohms. The applications are continued for at least 30 s if 
adequate heating at the electrode-tissue interface is achieved. If the PVCs are 
abolished within 30 seconds, the energy application is continued for 60 secs and 
followed by another 60 sec application. If PVCs are still present after 30 secs, the 
energy application is terminated and mapping is continued after ablation of the 
PVCs, isoproterenol is administered at 2–10 mg/min as needed to shorten the 
sinus cycle length to 400 –500 ms to conﬁrm that PVCs are not inducible by 
adrenergic stimulation. An effective procedure is deﬁned as a reduction in PVC 
burden of 80%.  In the event of pleomorphic PVCs, the dominant PVC 
morphologies will be targeted. VT induction is strongly encouraged (but not 
mandatory) during the PVC ablation. If patients with prosthetic valves are 
included the ablation approach will take this into account to minimize any 
possible negative effect on the valve function as determined by the local PI. 
Procedure success will be confirmed with a 24 hour Holter monitor during the first 
seven days after ablation therapy, which is standard of care after PVC ablations. 
If the goal of PVC reduction of ≥80% cannot be achieved with the initial 
procedure, then PVC suppression using either a repeat ablation procedure within 
6 weeks of the initial procedure or  a pharmacological approach with 
antiarrhythmics such as amiodarone, sotalol, dofetilide or dronedarone will be 
chosen for the duration of 6 months. If a PVC reduction of ≥80% cannot be 
achieved with a second ablation antiarrhythmic therapy will be chosen for the 
study duration of 6 months. Patients that had < 3 continuous sinus beats prior to 
the PVC-suppressive therapy will undergo a clinically indicated TTE after PVC 
suppression to obtain accurate echocardiographic measurements.  
 
Follow-up 
 
During regular clinic visits patients will be assessed for NYHA class and 
compliance with medications. Approximately six months after enrollment or the 

last RF ablation a clinically indicated TTE and 24h Holter monitor will be 
performed. 
All patients will undergo the following research interventions at the 6 months 
follow up: 
- A copy of anonymized clinical TTEs and Holter recordings will be sent 
to the UMD echo core lab and UMD coordinating center. 
- A second blood draw will be performed and sent to the UMD core lab. 
- A second 6 MWT will be performed. 
- The patient will answer heart failure questionnaires (Kansas City 
cardiomyopathy as well as the Minnesota Living with Heart Failure 
Questionnaire and optionally SF12/36) after 6 months. 
- If any additional clinical cardiac MRI has been performed an anonymized 
copy will be send to the radiological core center at UMD 
- Patients and/or treating physicians may be contacted for clinical follow-up 
at 1 year and 2 years post enrollment to assess for symptoms, 
hospitalizations and clinical events.  It will be attempted to obtain any 
records from medical procedures that were conducted during that time 
such as but not limited to echocardiograms, Holter monitors, CT, MRI or 
cardiac catheterizations. 
 
 
Risks: 
 
Ventricular tachycardia ablation procedures have a definite morbidity and 
mortality, with a major complication rate ranging from 2.5 to 6 %. This is to due to 
both patient-related and procedure-related factors. Patients typically suffer from 
congestive heart failure and other comorbidities and the procedures are long, 
requiring the patient to lie flat for up to eight hours at times. 
 
In addition to the risks of sedation, standard risks of an endocardial procedure 
include bleeding and other vascular access complications, stroke, myocardial 
infarction and rarely myocardial rupture and pericardial tamponade, aortic valve 
avulsion, and entanglement of the catheter in the mitral valve apparatus requiring 
surgical intervention, and death. The safety data of PVC ablations is not as well 
established as for VT ablations. In general, significantly less ablation lesions 
have to be applied frequently reducing the procedure time and volume 
administered. Additionally, many PVC ablations can be performed from the RV 
resulting in less risk of thromboembolic events or groin complications than for 
left-sided ventricular tachycardia ablations.  
Epicardial ablations will have to be performed in a subgroup of patients. This 
approach has been associated with complications such as RV perforation, 
coronary artery or phrenic nerve injury or abdominal bleeding. 
 
There are no known significant risks associated with echocardiograms or Holter 
monitors. There is a slight possibility of skin redness or irritation due to the 

placement of the ECG electrodes, which should disappear within several hours of 
removing the electrodes.  
 
Blood drawing can cause pain, bruising, lightheadedness and, on rare occasion, 
infection. 
 There are risks of loss of confidentiality to patients that participate in this trial; 
however all necessary precautions will be taken to assure the patient’s 
confidentiality is maintained. The information will be kept in secure locations.  In 
any publication or presentation of research results, patient’s identity will not be 
disclosed. 
 
Pregnant females are excluded from participation in this trial because they are 
not eligible for catheter ablation due to radiation risks to the developing fetus.  All 
females with child bearing potential that want to participate will need to do a 
pregnancy test the morning of the ablation procedure, and the test must be 
negative to have an ablation.  
 
 
 
 
Specific data to be collected: 
1- Patient demographics (not identified) 
2- Peripheral blood samples will be collected and stored from the time of 
randomization and at 6 months.  These samples will be send to core 
laboratory and assayed for relevant biomarkers including BNP, galectin-3, 
soluble ST2. 
3- Blood samples will be collected at initial visit for genome analysis 
4- Echocardiographic and electrocardiographic data 
5- 24 hour Holter recordings with available HRV data 
6- Procedural data such as 3-dimensional left ventricular mapping data 
including number and origin of PVCs and the successful ablation sites  
7- Peri-procedural data collection including mode of sedation, inducibility, 
dose of sympathomimetic drugs, procedure duration and fluoroscopy time 
8- The complications, if any, of the procedure 
9- The acute and intermediate-term success rate of the procedure. 
10- Procedure, medication and outpatient visit costs 
11- 6 MWT at baseline and 6 months 
12- Heart Failure Questionnaire at baseline and 6 months 
13- Clinically performed high-resolution CMRI studies performed prior to the 
enrollment, during randomizatoin duration and after 6 months will be 
collected to assess anatomic, perfusion and delayed enhancement 
myocardial fibrosis. 
14- Tissue samples that may become available during the study duration from 
clinically indicated procedures such as biopsy, LVAD placement or heart 
transplantation will be stored for further tissue analysis 

15- Clinical data such as past medical history, medications, NYHA class, 
physical exam findings, hospitalizations will be assessed during the 2-
years follow-up 
 
 
 
 
 
References 
 
1. Ezzat VA, Liew R, Ward DE: Catheter ablation of premature ventricular 
contraction-induced cardiomyopathy. Nat Clin Pract Cardiovas Med 2008, 5:289–
293.  
 
 
2. Gaita F, Giustetto C, Di Donna P, et al. Long-term follow-up of right ventricular 
monomorphic extrasystoles. J Am Coll Cardiol 2001, 38:364–70.  
 
3. Duffee DF, Shen WK, Smith HC. Suppression of frequent premature 
ventricular contractions and improvement of left ventricular function in patients 
with presumed idiopathic dilated cardiomyopathy. Mayo Clin Proc 1998;73:430 – 
3.  
 
4. Chugh SS. First Evidence of Premature Ventricular Complex-Induced 
Cardiomyopathy: A Potentially Reversible Cause of Heart Failure  J Cardiovasc 
Electrophysiol 2000, 66:328-329 
 
5. Yarlagadda RK, Iwai S, Stein KM, et al.: Reversal of cardiomyopathy in 
patients with repetitive monomorphic ventricular ectopy originating from the right 
ventricular outflow tract. Circulation 2005, 112:1092–1097    
 
6. Takemoto M, Yoshimura H, Ohba Y, Matsumoto Y, Yamamoto U, Mohri M,  
Yamamoto H, Origuchi H. Radiofrequency catheter ablation of premature 
ventricular complexes from right ventricular outﬂow tract improves left ventricular 
dilation and clinical status in patients without structural heart disease. J Am Coll 
Cardiol 2005, 45:1259–1265 
 
7. Efremidis M, Letsas KP, Sideris A, Kardaras F: Reversal of premature 
ventricular complex-induced cardiomyopathy following successful radiofrequency 
catheter ablation.  
Europace 2008, 10:769–770  
 
8. Bogun F, Crawford T, Reich S, et al.: Radiofrequency ablation of frequent, 
idiopathic premature ventricular complexes: comparison with a control group 
without intervention. Heart Rhythm 2007, 4:863–867. 
 

9. Baman RS, Lange D, Ilg KJ, et al: Relationship between burden of premature 
complexes and left ventricular function. Heart Rhythm 2010;7:865-69. 
 
10. Sarrazin JF, Labounty T, Kuhne M et al. Impact of radiofrequency ablation of 
frequent post-infarction PVC on left ventricular ejection fraction. Heart Rhythm 
2009;6:1543-9.