Systematic Review & Meta Analysis-Final Proof Reading-Final Checked-Improved

Is Cryoablation Safer And Effective Than Radiofrequency Ablation In The Treatment Of Paroxysmal
Atrial Fibrillation?
Is Cryoablation Safer And Effective Than

Radiofrequency Ablation
In The Treatment Of Paroxysmal Atrial
Fibrillation?
A Systematic Review & Meta-Analysis
Date: August 29th, 2016
Lecturer:
Presented by: Farrukh Hameed Khan
Student ID:
Table of Contents
Abstract...........................................................................................................3
Objective.......................................................................................................3
Design...........................................................................................................3
Data sources.................................................................................................3
Eligibility criteria for selecting studies..........................................................3
Results..........................................................................................................3
Conclusions...................................................................................................3
Introduction:....................................................................................................4
Methods:..........................................................................................................5
Identification & Selection of Studies:............................................................5
Data extraction and data items....................................................................6
Risk of bias in individual studies...................................................................7
Statistical analysis........................................................................................7
Summary Measures:.....................................................................................8
Synthesis of Results & Additional Analysis:...................................................9
Results:............................................................................................................9
Study Selection:............................................................................................9
Risk of bias in individual studies.................................................................11
Risk of bias across studies..........................................................................12
Meta-analysis Results:................................................................................13
Table 5: Fixed and Random Effect Models...................................................15
Limitations..................................................................................................16
Discussion:.....................................................................................................17
Statement of principal findings...................................................................17
Strengths and weaknesses of the study.....................................................19
Strengths and weaknesses in relation to other studies..............................19
Meaning of the study: possible explanations and implications for clinicians
and policymakers........................................................................................19
2
Un-answered questions and future research..............................................20

Conclusion:....................................................................................................20
References.....................................................................................................21
Abstract
Objective: Between the two different used systems of pulmonary vein
isolation via catheter ablation of paroxysmal atrial fibrillation, radiofrequency
is traditionally the preferred source of applied energy over cryoablation.
The study would aim to evaluate the differences between the two systems
and to acquire adequate evidence of the superiority or inferiority of one
system over another.
Design: By undertaking a systematic review and meta-analysis of the

available data from published randomised controlled trials (RCTs), we seek to
gain an in depth understanding and compare the two systems in terms of
efficacy and safety. The studies will also be individually assessed for the risk
of biases such as selection, performance, detection, attrition, reporting and
industry sponsorship.
Data sources: A detailed search of relevant trials, published in English,

was undertaken by an intensive search on PubMed and CENTRAL databases
indexed up to June 2016. Four eligible RCTs were selected with a total of 637
patients randomised to radiofrequency arm and 633 patients randomised to
cryoablation arm.
Eligibility criteria for selecting studies: The studies were (only)

considered for inclusion if they were randomised trials of drug refractory
patients, with no particular age or gender specifications, with paroxysmal
atrial fibrillation having a head to head comparison of radiofrequency
Ablation with cryoablation.
Results: The overall analyses showed that the patients randomised to

cryoablation had no significant difference between radiofrequency ablation
and cryoablation during Redo Ablation (Odds ratio;95% CI; P: 1.06; 0.65
-1.73; 0.308), during Arrhythmia recurrence in cryoablation was better (Odds
ratio; 95% CI; P: 0.89;0.56-1.42; 0.055), non-arrhythmic complications were
slightly more in cryoablation (Odds ratio;95%CI;P: 1.20;0.58-2.52;0.121).
3
Conclusions: Our findings report clearly a non-inferiority of cryoablation

over radiofrequency ablation in the treatment of paroxysmal atrial fibrillation.
Introduction:
According to the European Society of Cardiology (2012), the current
popularity of atrial fibrillation worldwide is within the range of 1.5% to 2%
among general population, with age of patients averaging within range of 75
to 85 years.
AF is related with higher risks of strokes and congestive heart failure likewise higher mortality, as arrhythmia is considered a cardiovascular challenge
even in modern society as arrhythmias medical, social and economic
aspects are getting worse.
There are three types of atrial fibrillation: paroxysmal, persistent and
permanent. Paroxysmal atrial fibrillation (self-limiting Episodes lasting <7
days) are considered comparatively more amenable to successful treatment.
The treatments include medical management and pulmonary vein isolation
via catheter ablation. In drug refractory cases of paroxysmal atrial fibrillation,
pulmonal vein isolation (PVI) remains the mainstay of treatment.
According to ESC-Guidelines (2012), patients with recurrent paroxysmal AF
catheter ablation is an alternative to antiarrhythmic drug therapy although
only an experienced operator (Class I A Recommendation) should perform it.
The pulmonal vein isolation is achieved through catheter ablation via two
different types of systems namely radiofrequency (RF) and cryoablation (CB).
The two systems differs in the energy source and the mode of application.
The most common/older method is radiofrequency current application on
point by point mode using irrigated radiofrequency energy emitting
catheters, which leads to cellular necrosis by tissue heating; the newer
method is cryogenic where energy applied with a balloon in a single step
mode leading to necrosis by freezing.
The advantages of radiofrequency ablation include limited use of fluoroscopy
since the catheter guidance to the pulmonary veinostia is achieved via an
electroanatomical mapping system.
However, the approach mandates extensive training which is time

consuming. thus limiting this therapy to fewer centres.
In comparison, the cryoablation requires a more extensive fluoroscopic time
for the appropriate positioning of the balloon around the pulmonary vein
ostia. However, it has shorter procedure duration and comparatively less
demanding learning curve.
Quite a few studies have been published comparing the advantages of
cryoballoon ablation over radiofrequency ablation. Therefore for the purpose
we will be undertaking a systematic review and meta-analysis of randomised
controlled trials which will compare the efficacy and safety features of RF
against CB.
The following question which is the focus of our investigation was
formulated:
Is the novel Cryoballoon ablation technique safer or more
efficacious than traditional Radiofrequency pulmonary vein isolation
for paroxysmal atrial fibrillation?
Methods:
Identification & Selection of Studies:
After the question was formulated intensive research was undertaken across
PubMed and CENTRAL databases up to June 2016. The key terms in our
search strategy included atrial fibrillation, cryoablation, cryothermal,
cryoablation, cryotherapy, cryoballoon. The search was limited to studies
published in English language. An example of the adopted search strategy
for PubMed is illustrated below:
Figure 1: Search Preview
The researches were filtered which fulfils the following requirements:

5
a) Drug refractory patients with only paroxysmal atrial fibrillation,

b) Randomised trial with a head to head comparisons between
radiofrequency ablation and cryoablation,
c) Outcomes of interest were fluoroscopic time, ablation time, peri procedural
complications, and rates of recurrence of atrial fibrillation.
All the potentially relevant titles and abstracts were initially screened
independently by two of the authors. After removal of duplicates, the full
texts of the screened articles were examined. The articles with differing
opinions were reviewed by the third author and were either selected or
discarded by consensus. There were neither age nor gender specifications.
Studies of alternate designs as well as those including both paroxysmal and
persistent forms of atrial fibrillation were excluded, if separate data for each
were not available. The average length of follow up was around 12 months.
Data extraction and data items:

From the selected studies, two authors independently extracted the data and
entered them into a standard Excel template.
The baseline characteristics of patients and the settings are given below:
Year
Author
Study
Name
Paroxysm
al only?
2016
2015
Kuck et al
Hunter et
al
Luik et al
Perez et al
FIRE and ICE

Cryo versus
RF
Freeze AF
COR
2015
2013
Total
No.
YES
YES
Cryoablati
on versus
RF
YES
YES
YES
YES
YES
YES
315
50
762
157
From studies the data taken included name of the first author, year of
publication, name of the study, total number of participants, follow up
duration, characteristics of patients such as age, body mass index,
percentage of males, left atrial diameter, percentages of hypertension,
diabetes, coronary artery disease, stroke, heart failure between the two arms
etc.
6
The continuous outcomes extracted were fluoroscopy time, total procedure

time, ablation time, complications and repeat Ablations. Complications were
grouped together and included cardiac tamponade, pleural effusions, phrenic
nerve palsies, hematomas, pulmonary vein stenosis, femoral
pseudoaneurysm, hemoptysis etc.
Table 4: Intervention Characteristics
Risk of bias in individual studies:

Each study was individually assessed for risk-of-bias using the Cochrane
Collaboration risk-of-bias tool. The trials were assessed for the following
threats to validity such as:
a) Selection
b) Performance
c) Blinding
d) Attrition
e) Selective reporting of Outcomes
f) Industry sponsorship bias.
7
Statistical analysis
The Categorical variables used are stated as means with their respective
Standard Deviation or Standard Error and to statistically analyze the results
we will be studying the quantitative outcomes where weighted mean
difference between cryoballoon and radiofrequency ablation procedures will
be compared at 95 percent confidence interval as well as the p-values of the
respective results will be analyzed to evaluate the level of significance.
We will also be studying the primary end points estimates of the respective
treatments by using logistic regression whose result will be presented as
odds ratios or Outcome as 95 percent confidence interval.
Further we will also be evaluating the standard error as well as study weight
and study effect which mainly depicts as how much effect the study have on
the combined research respectively.
The above will be done as a part of sensitivity analysis respectively.
We will be studying the end points as liberty from the AF/AT although after 3
months the use of antiarrhythmic drugs is generally considered a failure as
the primary endpoint would be the success rate at first year which will be
followed by a single procedure completely without any antiarrhythmic drugs
intake while the secondary endpoints will be estimated by the complication
rates, procedure times and fluoroscopy times along with their respective pvalues.
Since the outcomes of interest were Fluoroscopy time, procedure duration,
ablation time (continuous) we will be also assessing the weighted average
proportion of the anti-arrhythmic drug use, periprocedural complication rate
and AF free survival at 12 months & 6 months along with the level of
significance.
Summary Measures:
From the below table we can observe that the mean of outcomes is all most
the same except the Perez et al. while the mean of standard deviation or
8
standard error is also quite low other than Perez et al. suggesting the results
from the study should be used with caution respectively.
Study
Events
Sample
Size
Kuck et al
(n=762)RD
Kuck et al
(n=762)Cryo
Hunter et al (n=
157RD
Hunter et al (n=
157Cryo
Luik et al
(nRD
376
762
374
762
77
157
78
157
159
315
Luik et al
156
315
25
50
25
50
(nCryo
Perez et al (n=
50)RD
Perez et al (n=
50)Cryo
Summary
Outcome
Odd
Ratio
SE
0.4934
0.4680
0.0254
0.4908
0.4654
0.0254
0.4904
0.4346
0.0559
0.4968
0.4406
0.0563
0.5048
0.4647
0.0400
0.4952
0.4556
0.0397
0.5000
0.4000
0.1000
0.5000
0.4000
0.496439
0.1000
0.0047
While the combined odd ratio is as follows:

Study
Kuck et al
(n=762)RD
Hunter et al (n=
157RD
Luik et al
(nRD
Perez et al (n=
50)RD
Combined
Odd Ratio
0.933
0.875
0.920
0.800
Synthesis of Results & Additional Analysis:

Sensitivity analysis will also be performed as well as the meta-regression will
be analyzed to evaluate the degree of variability between variables at the
respective trials which may be due to heterogeneitys effect in the estimates
of cryoballoon and radiofrequency ablation procedures.
9
Furthermore we will measures the respective heterogeneity with in the

respective studies selected using the sum of weighted effect size sum and
the difference between the effect due to individual study and the combined
effect of studies.
Here heterogeneity Cochran's Q value would be calculated although it should
be noted that the Q will have low value as compared to the comprehensive
test of heterogeneity when there are only few number of studies involved as
in our case.
We will be mainly using the Q to evaluate the heterogeneity as part of our
meta-analysis as well as because it will also help us to identity the random
effects with respect to the pooling method although heterogeneity results
should always be used with our measures.
We will also study the I statistic depicting the degree of variation within the
studies selected for the purpose of evaluation which measures the degree of
inconsistencies present within the results of the studies. We will also be using
the I statistic to evaluate whether we should use fixed effect model or
random effect would be more appropriate as if the I statistic is low fixed
effects would be a better choice suggesting the lack of heterogeneity and
vice versa.
Results:
Study Selection:
We identified 706 relevant articles on PubMed and CENTRAL databases upto
June 2016; 44 articles were assessed for eligibility. After further exclusion, it
was narrowed down to 4 relevant RCTs. The exclusion of the 40 articles were
due to,
a) Non randomisation,
b) Studies involving both forms of atrial fibrillation,
c) Only one ablation system,
d) Repeat ablation, and
e) Other comparator etc.
10
There were a total of 637 patients randomised to radiofrequency arm and

633 patients randomised to cryoablation arm from the RCTs. A flow diagram
illustrating the process of exclusion of articles with reasons is shown below.
Study Characteristics
The baseline characteristics of patients and the settings are given below
while the methodological characteristics can be observed from table 2
showing that the follow-up period was 3months, 6months and 12months:
Year
Author
Study
Name
Paroxysm
al only?
Cryoablati
on versus
RF
Total
No.
YES
YES
YES
YES
YES
YES
YES
YES
762
157
315
50
FIRE and ICE

2016 Kuck et al
2015 Hunter et al Cryo versus RF
Freeze AF
2015 Luik et al
Perez
et
al
COR
2013
Table 2: Methodological characteristics
Mean FU-Duration (months)

6m
12m
Study Tota 3m
11
Kuck et al
Hunter et al
Luik et al
Perez et al
l
12
12
12
12
YES
YES
NO
NO
YES
YES
YES
NO
YES
YES
YES
YES
Risk of bias in individual studies:

The below table 5 depicts most of the biases present in the respective
studies,
Table 5: Risk of biases
Bias domain
Luik et al
Perez et al
1:1
Hunter et
al
Yes
1:1
1:1(Permuted block)
Allocation
concealment
Unclear
No
Unclear
No
Blinding of
Participants and
personnel
No
No Blinding
of patients or
physicians
Unclear
No
Detection
Blinding of Outcome
Yes
Unclear
Unclear
No
Attrition
Incomplete Outcome
data
Selective reporting
No
No
No
No
No
No
No
No
Industry
Yes
(Medtronic)
Yes
(Medtronic)
Yes
(investigato
Selection
Performance
Reporting
Sponsorship
Source of bias
Kuck et al
Random sequence
generation
Private
Private
Private
Yes
(National Institute of
Health Carlos III, Madrid,
Spain & the Spanish
Society of Cardiology)
Medical Society
Yes
Yes
Investor
No
Profit
Making
Profit Making
Profit
Making
Non-Profit
Supervision by
other Agencies
Yes
Yes
No
Yes
Centre/Multice
ntre
Multicentre
Single
Single
Single
r-initiated)
Sponsors Type
Company
Sponsor Class
12
As can be observed from the above table Kuck et al. (2016) and Hunter el at.
(2015) are sponsored as well as both gave similar results other than
complication rate which will be analyzed latter in the report although there
seems to be no evidence of high correlation or strong biases.
In the case of Kuck et al.(2016) the initial trial was funded by Medtronic
although oversight was done by FGK Representative Service as legal sponsor
but the Institute for Clinical Cardiovascular Research, Munich, Germany
gathered and maintained the respective data which suggest that the bias
risk is low.
While regarding the Hunter et al.(2015) it is funded by Medtronic but Barts
Health NHS Trust Cardiology Department collected and analyzed all data as
well as wrote the manuscript without any feedbacks or suggestions by
Medtronic which also suggest that the bias risk would be low.
Further regarding the Perez et al.(2015), we can observe that it is funded by
National Institute of Health Carlos III, Madrid, Spain & the Spanish Society of
Cardiology which is a nonprofit organization as well as it is also supervised
accordingly by other agencies which depicts that this is the least risky with
respect to any potential presence of biases in all the respective studies
selected.
Hence since in the case of Kuck there are several agencies involved and its
a multicenter, there are quite less risk of bias involved. However in the case
of Luik et al. (2015) there is an extremely high chances of biases since its a
single center as well as funded by provate investors who gave EUR 20,000
for the research and equipment were bought from Medtronics.
Further there were no supervisory agencies involved and the investors
identity is also unknown like-wise the motives, thus it suggest that the
research conducted by Luik should be used with high caution as there are
high risk of biases respectively.
Risk of bias across studies:

We decided to choose randomised controlled trials since it is generally
considered as the gold standard for evaluating intervention effects. The
random allocation increases the likelihood that the difference between the
intervention group and the control group is the intervention itself. Still the
flaws in the design, conduct, analysis and reporting of randomised controlled
13
trials generally lead to bias. We did not want to include other designs which
hinted at the possibility of cherry picking patients for the intervention vs
control thereby leading to a bias.
Although the risk of bias across studies would be least because the
researchers conducted their own trial as well as we restrained ourselves to
utilize or reference data from other studies.
However in the selection phase we came across several studies and we do
have to study several articles and journals but in the report neither of those
studies were used nor the data is biased since this research is conducted
solely using the data and values from the four selected researches
respectively.
Hence the risk of bias across studies would be extremely low.
Meta-analysis Results:
The patients demographics can be observed from Table 1
Table 1: Patient Demographics
Kuck et al (n=762)
RF
Number
Cryo
Hunter et al (n=
157)
RF
Cryo
Luik et al
(n=315)
RF
Cryo
Perez et al (n= 50)

RF
Cryo
376
374
77
78
159
156
25
25
60.1+/9.2
236
59.9+/9.8
221
61+/12
47
56+/11
56
60.3+/9.6
91
60.3+/8.8
100
52.3+/15.5
22
55+/-12.5
Hypertension
221
215
23
27
103
96
LA diameter
(mm)
CAD
40.6+/5.8
32
40.8+/6.5
31
43+/0.5
6
42+/0.4
6
n.a
n.a
20
19
41.6+/5.18
n.a
42.6+/5.92
n.a.
Diabetes Type 2
22
37
17
14
Previous
Stroke/TIA
Heart failure
14
16
12
12
n.a
n.a.
98
111
n.a
n.a
unclear
unclear
106
115
n.a
n.a
n.a
n.a
n.a
n.a.
Mean age +SD

Males
Hyperlipidemia
17
LV-Hypertrophy
n.a
n.a
n.a
n.a
unclear
unclear
Valve-Diseases
n.a
n.a
n.a
n.a
159
154
n.a
n.a.
Table 3 would be utilized to study the end points as freedom from AF/AT
which lasts for30 sec after which three month blanking period in the case of
Kuck et al. (2016) can be considered a success, although after 3 months the
14
use of antiarrhythmic drugs is generally considered a failure as the primary

end point would be the success rate at first year which will be followed by a
single procedure completely without any antiarrhythmic drugs intake while
the secondary endpoints will be estimated by the complication rates,
procedure times and fluoroscopy times, although complication rates may not
be evident in all the respective studies or the sample size does not
incorporate the data from that dimension.
Table 3: Secondary End Points & Procedural Data
Hence the outcomes of interest will be the fluoroscopy time, procedure
duration, ablation time (continuous), peri-procedural complication rate, antiarrhythmic drug use, peri-procedural complication rate and AF free survival
at 1 year.
Figure 2: Complication Rate & Freedom from AF-12 months
80.00%
100.00%
200.00%
300.00%
400.00%
600.00%
700.00%
61.10%
60.00%
40.00%35.90%
60.30%
48.00%
47.00%
50.00%
800.00%
68.00%
67.00%
70.00%
500.00%
34.60%
30.00%
20.00%
12%
10.00%
2%
2%
5%
5%
8%
2%
5%
0.00%
Free from AF after 12 months
Complication Rate
From the below table 5 we can observe that the Q and likewise the I2 is lower
in the case of Fixed effect model suggesting that the studies conducted are
done in similar conditions as well as with similar patients which is definitely
the case while it should be noted that the random effect would have required
even more and larger database analysis and is usually best for the
researches which includes several researches rather than only 4 with small
sized data as a whole although random effect model is sometimes preferred
because fixed model is quite rigid in assuming that every participant is
15
similar as well as the procedure was similar which is not the case in true
sense as discussed above.
Table 5: Fixed and Random Effect Models
Hetrogenity Q
I2
ES (fixed)
SEes (fixed)
CI (fixed)
Fixed
Random
0.1019
0.176
(28.44)
(16.09)
0.4945
0.491
0.0139
0.006
0.4673
0.480
We can also observe from the below table the respective combined outcome
of and standard error along with CI of the respective studies:
Study
S.No
1
2
3
4
Kuck et al (n=762)RD
Hunter et al (n= 157RD
Luik et al
(nRD
Perez et al (n= 50)RD
Summary
Combined
Odd Ratio
0.933
0.875
0.920
0.800
0.8821
CI lower
0.835508
0.66751
0.769775
0.449385
0.873003
CI upper
1.031343
1.082723
1.070863
1.150615
0.891427
As we can observe that combined OR value of 1 would suggest that the

success rate would be extremely high and the treatment would be
successful, which below 1 would mean that there are chances of
complications respectively and as can be observed from the below forest plot
that there are instances of lower than 1 values suggesting that there may be
complication in both the treatments.
16
Kuck et al
Hunter et al.
Luik et al
Perez et al.
0.95
0.2
Odd Ratio
While if we analyse the treatments with respect to the studies we can

observe that two studies suggest that radiofrequency ablation would have
higher success rate while one of the study suggest that cryp ablation would
be a better choice one of the study remained inconclusive from this regards.
Table 6: Odd Ratios
Study
Kuck et al (n=762)RD
Kuck et al (n=762)Cryo
Hunter et al (n= 157RD
Hunter et al (n= 157Cryo
Luik et al
(nRD
Luik et al
(nCryo
Perez et al (n= 50)RD
Perez et al (n= 50)Cryo
Summary/Average
Odd Ratio
0.4680
0.4654
0.4346
0.4406
0.4647
0.4556
0.4000
0.4000
0.441108
17
Limitations:
There are several limitation identified as the formula which was used to
derive Median and IQR is not clear as well as there is ambiguity in the use of
combined effect due to which we restrained ourselves to utilize the
respective values.
Further the success of PV isolation and the deaths from arrhythmia are not
mentioned in all the studies and it can be argued that the meta-regression
results are not comparable as Kuck et al. (2016) utilized the Cox proportional
Hazard Regression while other emphasized on logistical regression which
may reduce the comparability of the results.
Moreover Hunter et al. (2015) used two different size of catheters in cryo
group including 28mm in 57/78 and 23mm in 13/78 and both in 8/78 while
we observed that with respect to the 30/78 all the respective PVs were
isolated with only two applications, thus increasing it to 54/78 with further
applications respectively.
Luikket. al(2015) & Perez et al. (2013) advocated the use of 28mm and
23mm for Cryo device while we observed that for each PV, two applications
of cryo energy for 1st generation CBs it was done two times for 300 seconds
and for 2nd generation CBs it was done again two times for 240 seconds.
Hence the differences between the procedures again reduces the
comparability between the studies as well as Kuck et al(2016) does not
mentioned the rationale behind the selection of CB1 ablation time which was
300seconds and CB2 which was 240seconds respectively.
Discussion:
Statement of principal findings
From the analysis of the results we can observe that PV cryoballoon ablation
is an efficacy and safer technique for the respective treatment of paroxysmal
as the mean total procedure time is quite lesser than radiofrequency
procedure although the total mean fluoroscopy time is higher in two studies
by 30.7% and 24.39% while in the remaining two studies there were no
fluoroscopy procedure time differences respectively.
Further from the analysis it can be argued that due to the reduced total
procedure time duration Cryballon would be the most efficacy procedure with
18
respect to the time but in order to truly assess which is the most safe and
effective treatment of Paroxysmal Atrial Fibrillation we have to analyse the
complication rates as well as the freedom from AF after 6 months and 12
months.
Although the 6 months data with respect to the freedom from AF is not ready
available in all the studies under evaluation but Luik et al (2015) argues that
the 6 months freedom rate were 13% higher (Refer to Table 3) in the case of
RF although since the p-value of the results are 0.13 i.e. above 0.05 and due
to high p-value we should use this comparison with caution as there is
possibility of the sampling effect.
We also analysed that higher level of expertise are required for
radiofrequency ablation while crypballons learning curve is shorter which
may the reason that the complication rates are 4 and 2.44 times higher as
compared to the radiofrequency group in Luik et al. (2015) and Prez et al.
(2013) although from table 1 we can observe that the data with respect to
Previous strokes, heart failure, Hyperlipidemia , Valve-Diseases etc. are notpresent, thus it would be difficult for us to be conclusive in this regards.
However the p-values in both the cases are below 0.05 suggesting that the
results are substantial and hence reliable.
Moreover we also observed that the PV isolation for paroxysmal AF was quite
faster with the cryoballoon which may be argued to have higher procedural
success rate as compared to RF although this conclusion may not be highly
conclusive but if we analyze the combined approach CRYO seems to be
superior to the RF (Hunter et al. (2015).
Further from the analysis of the combined pooling results of all trials by the
authors we observed that cryoballoon ablation reduced the respective
fluoroscopic time as well as the total procedure time by a weighted mean of
20.5 minutes at 95 percent confidence interval as compared to the
radiofrequency ablation.
While the cryoballoon ablation is also analysed to have longer as well as nonsignificant ablation time than radiofrequency ablation which can argued to
be due to the small sample sizes of clinical trials in some cases as well as
due to hetroelasticity because of the presence of divergent results, thus
overestimating the overall results.
19
Moreover we can also observe from the above table 5 in the result section
that the heterogeneity Q is low due to which we preferred the fixed effect
model as more data would be required for random effects models which may
help us to achieve the same statistical power as the fixed effects model
respectively hence we are assuming that the studies conducted are done in
similar conditions as well as with similar patients as well as the effect size of
fixed model is also larger than the effect size of Random Effect Model
respectively.
As we know that the higher OR value would suggest a higher success rate
while lower OR value suggest lower success rate of the respective treatment
and we can also analyse from the odd ratios in table 6 that in the studies
conducted by Kuck et al. and Luike et al. radiofrequency ablation treatment
is preferred although Huner et al. suggest that Cryp would be more
advantageous.
Strengths and weaknesses of the study

From the above analysis we observed that there are mixed results with
respect to the freedom from AF after a year as Kuck et al (2015) and Luil et
al(2015) suggesting similar success rate with only marginal differences while
the studies conducted by Hunter et al(2015) and Perez et al (2013) suggest
extreme results; Hunter suggesting Cryo is more effective while Perez
suggest that RF would be more effective treatment but it should be noted
that both of the latter studies have quite lesser sample size than the former
which may be the reason for biases apart from the biases discussed in the
above sections.
Hence the above is a weakness in the sense that the figures we utilized for
the research can be argued to be incomparable due to the differences and
sampling size etc. while it should be noted that since we have used four
separate researches who already analysed the respective matter from four
different dimensions, therefore it is the strength of our research that it
depicts the case matter from wider perspective respectively.
Strengths and weaknesses in relation to other studies
20
One of the weakness of our study as compared with other studies is that we
restrained to use the combined values for the respective cases because of
lack of data although combined figures can be quite helpful especially to
generalize the results for comparison respectively.
Meaning of the study: possible explanations and implications

for clinicians and policymakers
We can analyze that the fluoroscopic time and total procedure durations for a
trial fibrillation patients for cryoballoon ablation are quite lesser as compared
to radiofrequency ablation as cryoballoon is more advanced and latest
procedure.
The policy makers should supervise the efficacy levels of cryoballoon
practitioners as if the higher proportion of procedures result in complications
then the respective practitioner should be re-assessed of his level of
expertise.
Therefore actions should be taken by the supervisory authorities to minimize
the complication rates by proper licensing and continuous monitoring of the
level of expertise respectively.
Further the freedom from the AF after 12 months is generally same or have
very marginal differences suggesting that both the procedures have almost
similar success rate although regarding the cryoablation it can be argued
that it may not be the safest treatment of paroxysmal atrial fibrillation
because of higher complication rates while regarding the radiofrequency
ablation the reason for low complication rate may be due to the reason that
high level of expertise like-wise the training and experience is required,
which is not compulsory for cryoablation practitioner. Therefore the
radiofrequency ablation would be the most safer and effective treatment
from this dimension respectively.
Un-answered questions and future research

In future researches it would be more beneficial to emphasize on the most
effective treatment other than the ones analysed in this report as well as the
predictor variables need to be analysed which can increase or decrease the
overall efficacy and safety of the procedure.
21
Further this research also failed to answer whether the pre-medication can
have any impact on the respective treatment and therefore should be
researched in future studies.
Conclusion:
From the above analysis can conclude that lesser fluoroscopic time and total
procedure duration can be achieved using the cryoballoon ablation as
compared to radiofrequency ablation, although the freedom from the AF
after 12 months is generally same suggesting that both the procedures have
almost similar success rate but with respect to the cryoablation it can be
argued that it may not be the safest treatment of paroxysmal atrial
fibrillation because of higher complication rates thus suggesting that the
radiofrequency ablation is more safer and effective treatment as if the
procedural duration is low and it can be done fast it cannot be considered
efficient if the results are not positive.
Hence the efficacy of the PV cryoablation is non-inferior to PV isolation
using open-irrigated radio frequency catheters with electro physiological and
electro anatomical guidance but radio frequency ablation can be rightly
considered safer treatment due to less complications observed respectively.
References
Hunter, RJ, Victoria Baker, MCFERD, Lovell, MJ, Tayebjee, MH, Ullah, W,
Siddiqui, MS, Mclean, A & Richmond, L 2015, 'Point-by-Point Radiofrequency
Ablation Versus the Cryoballoon or a Novel Combined Approach: A
Randomized Trial Comparing 3 Methods of Pulmonary Vein Isolation for
Paroxysmal Atrial Fibrillation (The Cryo Versus RF Trial)', J Cardiovasc
Electrophysiol, vol 26, pp. 1307-1314.
Kuck, K-H & Josep Brugada, MD,AFMMD,FOMD,KRJCAEMD,PDTAMD,KBJPPD,JPACT 2016, 'Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial
Fibrillation', The England Journal of Medicine, Massachusetts Medical Society.
Luik, A, Radzewitz, A, Kieser, M & Walter, M 2015, 'Cryoballoon Versus Open
Irrigated Radiofrequency Ablation in Patients With Paroxysmal Atrial
FibrillationThe Prospective, Randomized, Controlled, Noninferiority Freeze AF
Study', Arrhythmia/Electrophysiology.
22
Prez, N, Cavazos, RF, Moreno, J, Caadas, V, Conde, A, Gonzlez-Ferrer, BJJ,

Macaya, MC & Prez-Villacastn, J 2013, 'The COR trial: A randomized study
with continuous rhythm monitoring to compare the efficacy of cryoenergy
and radiofrequency for pulmonary vein isolation', Unidad de Arritmias,
Instituto Cardiovascular, Hospital Clnico San Carlos,Investigacin Sanitaria
del Hospital Clnico San Carlos (IdISSC), Instituto de Madrid, Spain., vol 11,
no. 1.
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Is Cryoablation Safer And Effective Than Radiofrequency Ablation In The Treatment Of Paroxysmal

Is Cryoablation Safer And Effective Than

Date: August 29th, 2016

Presented by: Farrukh Hameed Khan

Un-answered questions and future research..............................................20

Design: By undertaking a systematic review and meta-analysis of the

Data sources: A detailed search of relevant trials, published in English,

Eligibility criteria for selecting studies: The studies were (only)

Results: The overall analyses showed that the patients randomised to

Conclusions: Our findings report clearly a non-inferiority of cryoablation

However, the approach mandates extensive training which is time

The researches were filtered which fulfils the following requirements:

a) Drug refractory patients with only paroxysmal atrial fibrillation,

Data extraction and data items:

FIRE and ICE

The continuous outcomes extracted were fluoroscopy time, total procedure

Table 4: Intervention Characteristics

Risk of bias in individual studies:

While the combined odd ratio is as follows:

Synthesis of Results & Additional Analysis:

Furthermore we will measures the respective heterogeneity with in the

There were a total of 637 patients randomised to radiofrequency arm and

FIRE and ICE

Table 2: Methodological characteristics

Mean FU-Duration (months)

Risk of bias in individual studies:

Risk of bias across studies:

Perez et al (n= 50)

Mean age +SD

use of antiarrhythmic drugs is generally considered a failure as the primary

As we can observe that combined OR value of 1 would suggest that the

While if we analyse the treatments with respect to the studies we can

Strengths and weaknesses of the study

Strengths and weaknesses in relation to other studies

Meaning of the study: possible explanations and implications

Un-answered questions and future research

Prez, N, Cavazos, RF, Moreno, J, Caadas, V, Conde, A, Gonzlez-Ferrer, BJJ,

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Systematic Review & Meta Analysis-Final Proof Reading-Final Checked-Improved

Systematic Review & Meta Analysis-Final Proof Reading-Final Checked-Improved