We thank Yan Qu and colleagues for their interest in our
publication.1 In our systematic review we concluded that caffeine exposure
was not associated with increased AF risk. We also have performed a
qualitative evaluation of dose-response, which uses the relative
proportions of caffeine exposure within each study and the risk of atrial
fibrillation (AF). Pooling the relative risk (RR) of low caffeine intake
from each st...
We thank Yan Qu and colleagues for their interest in our
publication.1 In our systematic review we concluded that caffeine exposure
was not associated with increased AF risk. We also have performed a
qualitative evaluation of dose-response, which uses the relative
proportions of caffeine exposure within each study and the risk of atrial
fibrillation (AF). Pooling the relative risk (RR) of low caffeine intake
from each study showed that the exposure to such doses was associated to
significantly lower AF risk, without statistical heterogeneity (I2=0%).1
Yan Qu and colleagues provided data from multivariate random-effect meta-
regression of these data.2 They found a linear dose-response with a modest
reduction of relative risk for each increase of 200 mg of caffeine intake
per day (RR 0.98, 95%CI: 0.94-1.01). Despite the gradual risk reduction
with progressive higher caffeine dose intake, the 95% confidence intervals
becomes wider, meaning that results become less precise.2 These results as
ours need to be clarified in further studies.
To conclude, Yan Qu and colleagues overall reinforce and corroborate the
main results of our systematic review, concluding that caffeine exposure
is not associated with increased risk of atrial fibrillation irrespective
of the amount of caffeine.1,2
References
1. Caldeira D, Martins C, Alves LB, et al. Caffeine does not increase the
risk of atrial fibrillation: a systematic review and meta-analysis of
observational studies. Heart 2013;99:1383-1389
2. Yan Qu, Dan Hu, Junqian Huang, et al. Dose-response relationship
between caffeine and risk of atrial fibrillation" Heart. 2013.
Dear Editor,
We read with great interest the recent meta-analysis showing that low-dose
caffeine may have a protective effect on risk of atrial fibrillation,
while no favorable effect was found for high dose of caffeine, and a
sketch of a J-shape curve was speculated on the association of caffeine
with risk of atrial fibrillation.1 Therefore, to clarify the dose-response
relationship on caffeine and risk of atrial fibrilla...
Dear Editor,
We read with great interest the recent meta-analysis showing that low-dose
caffeine may have a protective effect on risk of atrial fibrillation,
while no favorable effect was found for high dose of caffeine, and a
sketch of a J-shape curve was speculated on the association of caffeine
with risk of atrial fibrillation.1 Therefore, to clarify the dose-response
relationship on caffeine and risk of atrial fibrillation, the restricted
cubic spline model and multivariate random-effect meta-regression2 was
performed, which was described in detail in our previous paper. 3-4 In
brief, a restricted cubic spline model with three knots at the 25, 50, and
75th percentiles of the caffeine levels, was estimated using generalized
least square regression taking into account the correlation within each
set of published relative risk (RR). Then the study-specific estimates
were combined using restricted maximum likelihood method in a multivariate
random-effects meta-analysis. A P value for nonlinearity was calculated by
testing the null hypothesis that the coefficient of the second spline is
equal to 0.
Among the seven observational studies included in the meta-analysis,1
three reported the association of caffeine with atrial fibrillation (the
reference numbers are 35-37), while the other four reported association of
coffee with atrial fibrillation (the reference numbers are 31-34).
Therefore, data from the three prospective cohort studies on caffeine and
atrial fibrillation were used in this dose-response analysis, including
1,796 atrial fibrillation cases and 91,290 participants. A linear dose-
response relationship of caffeine with risk of atrial fibrillation was
found (P for non-linearity=0.86), and the risk of atrial fibrillation
decreased by 2% [RR (95 CI %) =0.98 (0.94-1.01), P=0.21] for every 200
mg/day increment of caffeine consumption. The RR (95 CI%) of atrial
fibrillation was 0.99 (0.95-1.02), 0.97 (0.91-1.04), 0.96 (0.87-1.06),
0.95 (0.85-1.07), 0.94 (0.84-1.04), 0.93 (0.83-1.04), 0.93 (0.82-1.04),
0.92 (0.80-1.05), 0.91 (0.77-1.07) and 0.90 (0.75-1.09) for 100, 200, 300,
400, 500, 600, 700, 800, 900 and 1000 mg/day of caffeine intake,
respectively. In our opinion, readers should have a better understanding
regarding the important results by Caldeira et al.,1 taking into account
the aforementioned findings.
References
1 Caldeira D, Martins C, Alves LB, et al. Caffeine does not increase the
risk of atrial fibrillation: a systematic review and meta-analysis of
observational studies. Heart 2013;99:1383-1389.
2 Orsini N, Li R, Wolk A, et al. Meta-analysis for linear and nonlinear
dose-response relations: examples, an evaluation of approximations, and
software. Am J Epidemiol 2012;175:66-73.
3 Jiang W, Wu Y, Jiang X. Coffee and caffeine intake and breast cancer
risk: an updated dose-response meta-analysis of 37 published studies.
Gynecol Oncol 2013;129:620-629.
4 Wang Y, Yu X, Wu Y, et al. Coffee and tea consumption and risk of lung
cancer: a dose-response analysis of observational studies. Lung Cancer
2012;78:169-170.
Dorresteijn et al, (Heart 2013;99:866-872), presented a new tool, the
SMART risk score, for predicting 10 year risk of recurrence in patients
with established cardiovascular disease. This enables clinicians for the
first time to differentiate treatment within the hitherto broadly assumed
recurrence rate of at least 20% leading to guidelines that, so far, advise
maximal drug treatment for elevated risk factors for all patie...
Dorresteijn et al, (Heart 2013;99:866-872), presented a new tool, the
SMART risk score, for predicting 10 year risk of recurrence in patients
with established cardiovascular disease. This enables clinicians for the
first time to differentiate treatment within the hitherto broadly assumed
recurrence rate of at least 20% leading to guidelines that, so far, advise
maximal drug treatment for elevated risk factors for all patients alike.
Surprisingly, the authors seem to restrict its clinical use to those with
the highest risks (presumably the 23% of their cohort with remaining risks
of over 26%, fig. 2) thus aiming at correcting 'undertreatment'. With this
choice they miss the opportunity to use it also to revise possible
'overtreatment', which may have occurred in 21% of their cohort with risk
levels of 15% or lower.
We like to illustrate the relevance of an extended strategy with a
hypothetical example wherein a GP is consulted by a healthy 70 year old
male asking her support to stop his daily aspirin and statin medication.
He has been using this for 11 years, after a percutaneous coronary
intervention. He has never had an elevated blood pressure or any
cardiovascular complaints since and his Smart risk score is 15%. The GP
tells him that his age, being irreversible, has now lowered the
attributable risk of his reversible risk factors to such an extent (to
approx. 5%) that the harm of stopping his medication (leading to a
relative increase in attributable risk of approx. 35% ,or 2-3% absolute)
will not lead to an sizeable extra risk. Moreover continuing the
medication won't prevent the increasing risk of concurrent events from
other diseases. The patient, content to have overgrown most of his
corrigible risk, decides to stop.
Our problem with this example is that the argumentation around
attributable risk and remaining risk after minimising or maximizing
treatment has to come from educated guesses.
We would therefore urge the authors of the SMART risk score to support
potential users by providing more easily accessible data on these items in
order to enable them to further clarify the abstract thinking of
prevention statistics for their patients
Messori et al [1] present a very interesting matter (the difference
between inconclusive results and demonstrating non-inferiority) concerning
our recently published meta-analysis of dabigatran vs. warfarin in the
setting of catheter ablation of atrial fibrillation [2] that merits a
practical reflection.
First, proving that two treatments are equal in performance is impossible
with statistical tools; at most, one can show...
Messori et al [1] present a very interesting matter (the difference
between inconclusive results and demonstrating non-inferiority) concerning
our recently published meta-analysis of dabigatran vs. warfarin in the
setting of catheter ablation of atrial fibrillation [2] that merits a
practical reflection.
First, proving that two treatments are equal in performance is impossible
with statistical tools; at most, one can show that they are equivalent
using statistical test that aims at showing that two treatments are not
too different in characteristics, where "not too different" is defined in
a clinical manner.
In our paper, non-significant results were obtained when comparing
dabigatran with warfarin for thromboembolic complications and major
bleedings. Thus, we cannot claim that dabigatran is different in
performance than warfarin, which is our conclusion. We have evaluated the
validity of our meta-analysis and tried to control for heterogeneity of
data using several sensitivity analysis. These have shown similar results
in the differently tested scenarios [2]. Moreover, we have gathered a
great body of evidence and presented reassuring results supporting the
absence of marked differences between the two studied anticoagulant
options.
With negative results, the question is always to know if such finding is
due to lack of power or whether the new treatment is likely to be similar
to the other. Negative results often occur because the sample size is too
small, and thereby the probability of making a type II error is too large.
Trial sequential analysis (TSA) is a recently introduced statistical tool
that may be "applied to determine the optimal information size required to
reach a conclusive result". This tool has suggested in a study that
between 80 to 90% of all assessed non-significant meta-analysis might
eventually have been underpowered to that purpose [3]. This is such a big
issue.
According to the results of the Messori et al. [1], the TSA methods
applied to our meta-analysis failed in showing conclusive result because
the number of events were insufficient to construct the boundaries of
futility ('no effect'). Moreover, Messori and colleagues' estimations
would suppose to conduct a trial with more than 18.000 patients to compare
the two drugs, which is unrealistic and in face of the very low incidence
of events. Also, according to their opinion, this problem would occur to
any of the other novel anticoagulants to be tested. For example, "A Study
Exploring Two Treatment Strategies in Patients With Atrial Fibrillation
Who Undergo Catheter Ablation Therapy "(VENTURE-AF trial), comparing
rivaroxaban and warfarin, estimates an enrollement of 200 patients [4].
Additionally, the "Catheter Ablation vs Anti-arrhythmic Drug Therapy for
Atrial Fibrillation Trial" (CABANA), one of the largest catheter ablation
of atrial fibrillation trials to date, will enrol 3000 subjects during
more than 6 years [5]. However, based on the event rates observed in our
meta-analysis, for a non-inferiority trial intending to show that the
effect of a dabigatran is not worse than that of warfarin by more than a
specified margins (0.5% for thromboembolic and 0. 7% for major bleedings)
the inclusion of 4782 patients, as done in our meta-analysis, allow to
achieve around 80% power (beta=0.2) at alpha=0.05.
Final and robust answer to this important issue may be given in the next
few years, with data available from a larger number of patients included
in future trials that will allow us to make a more powerful meta-
analysis. In the meantime, with the limitations of meta-analysis
methodology previously discussed, our study shows that there is no
significant difference between dabigatran and warfarin in patients
undergoing catheter ablation of atrial fibrillation.
References:
1. Messori A, Fadda CV, Maratea D, Trippoli S. Comparing dabigatran vs
warfarin in patients with atrial fibrillation undergoing catheter
ablation: inconclusiveness of the results concerning thromboembolic
complications and major bleedings. Heart.2013 Sep 16. [EPub]
2. Providencia R, Albenque JP, Combes S, Bouzeman A, Casteigt B, Combes N
et al. Safety and efficacy of dabigatran versus warfarin in patients
undergoing catheter ablation of atrial fibrillation: a systematic review
and meta-analysis.Heart.2013 Jul 22. [Epub ahead of print]
3. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis
reveals insufficient information size and potentially false positive
results in many meta-analyses. J ClinEpidemiol. 2008;61(8):763-9.
4. A Study Exploring Two Treatment Strategies in Patients With Atrial
Fibrillation Who Undergo Catheter Ablation Therapy (VENTURE-AF) ,
available at http://clinicaltrials.gov/show/NCT01729871
5. Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial
Fibrillation Trial (CABANA) , available at
http://clinicaltrials.gov/ct2/show/NCT00911508
Conflict of Interest:
RP has received honoraria for serving as a speaker and consultant for Boheringher-Ingelheim and as a co-investigator in the ENGAGE-AF TIMI 48 trial.
We have read with interest the comments by Bin Abdulhak and
colleagues [1] to our recently published article [2]. We share the same
opinion concerning the use of dabigatran in this setting. Thus, in our
paper we have proposed the same posology in face of the similar findings:
despite the lack of conclusive evidence in support of any particular
dabigatran dosage or timing for interrupting or restarting drug therapy,
like...
We have read with interest the comments by Bin Abdulhak and
colleagues [1] to our recently published article [2]. We share the same
opinion concerning the use of dabigatran in this setting. Thus, in our
paper we have proposed the same posology in face of the similar findings:
despite the lack of conclusive evidence in support of any particular
dabigatran dosage or timing for interrupting or restarting drug therapy,
like Bin Abdulhak and colleagues [1], we also suggested skipping 1 or 2
doses of dabigatran before the procedure (or maybe more if renal function
was compromised) and restarting the drug 3 to 4 hours after assuring
haemostasis [2]. However, we admit that the ideal drug regimen is still an
unsolved matter, since the role of uninterrupted dabigatran may yet need
further clarification.
We agree that a randomized controlled trial of dabigatran versus warfarin
in these patients may provide further evidence and guidance. However, we
know not of any such study that is either ongoing or planned at the
moment. Furthermore, the sample of patients treated with dabigatran that
was gathered in our study (1,823 patients) provides already a reasonable
support towards the safety and efficacy of the drug.
According to the last Venice Chart international consensus document on
atrial fibrillation ablation, the use of transoesophageal echocardiography
preablation should be considered as supplementary to a backup strategy to
anticoagulation, independently of the drug used. The document also
proposes that a cardiac computed tomography scan (routinely performed in
most of the patients for anatomical purposes) may be reasonable as an
alternative [3]. This is reinforced by data of a recent meta-analysis
reporting a very high reliability and accuracy for thrombus detection
namely when delayed imaging was performed (99% sensitivity and 100%
specificity) [4]. Therefore, preprocedural imaging for exclusion of
thrombus may be justifiable, even in face of the favorable data from the
RE-LY cardioversion sub-study.
References:
1. Bin Abdulhak, A., Khan, AR. ,Tleyjeh,I.,et al. Response to: Safety and
efficacy of interrupted dabigatran for peri-procedural anticoagulation in
catheter ablation of atrial fibrillation: a systematic review and meta-
analysis. Heart. 2013 (In Press)
2. Providencia, R., Albenque, J-P., Combes, S.,et al. Heart Published
Online First: 2013 Jul 22 doi:10.1136/ heartjnl-2013-304386
3. Raviele A, Natale A, Calkins H et al. Venice Chart international
consensus document on atrial fibrillation ablation: 2011 update. J
Cardiovasc Electrophysiol. 2012;23(8):890-923. doi: 10.1111/j.1540-
8167.2012.02381.x
4. Romero J, Husain SA, Kelesidis I et al. Detection of left atrial
appendage thrombus by cardiac computed tomography in patients with atrial
fibrillation: a meta-analysis. Circ Cardiovasc Imaging. 2013;6(2):185-94.
doi: 10.1161/CIRCIMAGING.112.000153
Conflict of Interest:
RP has received honoraria for serving as a speaker and consultant for Boheringher-Ingelheim and as a co-investigator in the ENGAGE-AF TIMI 48 trial. No conflicts of interest for other co-authors.
In the interpretation of clinical trials or meta-analyses that show
no significant difference between the two comparators, one controversial
issue is the need to differentiate between "no proof of difference"
(inconclusive result) and "proof of no difference" (or demonstrated non-
inferiority). For this purpose, trial-sequential analysis (TSA) is
considered to be an appropriate statistical tool (1-4).
In the interpretation of clinical trials or meta-analyses that show
no significant difference between the two comparators, one controversial
issue is the need to differentiate between "no proof of difference"
(inconclusive result) and "proof of no difference" (or demonstrated non-
inferiority). For this purpose, trial-sequential analysis (TSA) is
considered to be an appropriate statistical tool (1-4).
In the meta-analysis by Providencia et al. comparing dabigatran vs
warfarin in patients with atrial fibrillation undergoing catheter ablation
(5), one limitation that the authors themselves have pointed out is that
"some comparisons [were] limited by the low event rates". As shown in
Figure 2 of Providencia's paper, the overall event rate in the two
patient groups was 0.3% (15/4782) for thromboembolic complications and
1.4% (67/4782) for major bleedings.
In the light of these findings, the conclusion that "the rate of
thrombolembolic complications and/or major bleeding in patients on
dabigatran.... is similar to that seen with warfarin" is not justified by
any statistical proof. In fact, if a TSA is applied to determine the
optimal information size required to reach a conclusive result from these
data, the analysis clearly shows that the number of patients actually
enrolled in the available trials (N=4,782) is much lower than the optimal
number required for evaluating thromboembolic complications (N=18,767) or
major bleedings (N=17,461); see Figure 1 at
www.osservatorioinnovazione.net/supplement/dabigatran-ablation.pdf .
Hence, the best interpretation of these results is that no conclusion
can be made on these two end-points.
References
1. Messori A, Fadda V, Maratea D, Trippoli S. Erythropoietin in
patients with acute myocardial infarction: no proof of effectiveness or
proof of no effectiveness? Clin Cardiol. 2013 Aug 8. doi:
10.1002/clc.22187. [Epub ahead of print] PubMed PMID: 23929820.
2. Messori A, Fadda V, Maratea D, Trippoli S. Intra-aortic balloon
pump in high-risk percutaneous coronary interventions without cardiogenic
shock: Trial sequential analysis of outcomes. Int J Cardiol. 2013 Jul 23.
doi:pii:S0167-5273(13)01155-8. 10.1016/j.ijcard.2013.06.098. [Epub ahead
of print] PubMed PMID: 23890904.
3. Messori A, Fadda V, Maratea D, Trippoli S. Erythropoiesis-
stimulating agents in heart failure: no proof of effectiveness or proof of
no effectiveness? Eur J Heart Fail. 2013 Aug;15(8):944-5.
4. Messori A, Fadda V, Maratea D, Trippoli S. ?-3 Fatty acid
supplements for secondary prevention of cardiovascular disease: from "no
proof of effectiveness" to "proof of no effectiveness". JAMA Intern Med.
2013 Jun 17:1-2. doi:10.1001/jamainternmed.2013.6638.
5. Providencia R, Albenque JP, Combes S, Bouzeman A, Casteigt B,
Combes N, et al. Safety and efficacy of dabigatran versus warfarin in
patients undergoing catheter ablation of atrial fibrillation: a systematic
review and meta-analysis. Heart Published Online First: 2013 Jul 22
doi:10.1136/ heartjnl-2013-304386
We read with interest the study by Providencia et al. which
demonstrated that dabigatran had a similar efficacy and safety profile as
warfarin in the setting of catheter ablation (CA) of atrial fibrillation
(AF) (1). These findings concur with two other meta-analyses on the same
topic (including one from our group) which have been recently published
(2,3). All the published meta-analyses on this...
We read with interest the study by Providencia et al. which
demonstrated that dabigatran had a similar efficacy and safety profile as
warfarin in the setting of catheter ablation (CA) of atrial fibrillation
(AF) (1). These findings concur with two other meta-analyses on the same
topic (including one from our group) which have been recently published
(2,3). All the published meta-analyses on this topic were limited by the
hierarchy of evidence, which was mostly derived from observational
studies. These observations warrant validation by a randomized controlled
trial. However, patients will probably undergo the procedure while on
dabigatran based on the current available evidence until a controlled
study is carried out. How to manage the drug peri-procedurally and
minimize the risks of bleeding and thromboembolism are importance points
to be considered. A reasonable approach based on the importance of
limiting interruption to peri-procedural anticoagulation and considering
the pharmacokinetics of dabigatran is to hold 1-2 doses of dabigatran and
resume the medication a shortly after achieving post-procedural hemostasis
at the vascular access site. Indeed, in our analysis limited to studies
that held 1-2 doses of dabigatran and resumed the drug on the same day as
the procedure, we not only found no significant difference in bleeding or
thromboembolic events between interrupted dabigatran and uninterrupted
warfarin, but importantly there was zero to mild in between studies
heteterogenity. Also, it is reasonable to consider transesophageal
echocardiography (TEE) before CA of AF in patients on dabigatran given the
relatively lesser experience with the drug and the fact that most reported
studies have used TEE before the ablation procedure.
References:
1.Providencia, R., Albenque, J-P., Combes, S.,et al. Heart Published
Online First: 2013 Jul 22 doi:10.1136/ heartjnl-2013-304386
2.Bin Abdulhak, A., Khan, AR. ,Tleyjeh,I.,et al.Safety and efficacy
of interrupted dabigatran for peri-procedural anticoagulation in catheter
ablation of atrial fibrillation: a systematic review and meta-
analysis.Europace. 2013 August 16 doi: 10.1093/europace/eut239
3.Hohnloser, S., Camm, A. Safety and efficacy of dabigatranetexilate
during catheter ablation of atrial fibrillation: a meta-analysis of the
literature.Europace. 2013 August 16 doi:10.1093/europace/eut241
We thank Dr Cohn for pointing out that our description[1] of the
POISE dosage described only the first dose. The general maintenance dose
was 200 mg extended release once a day (equivalent to 50 mg immediate
release three times a day). If systolic pressure dropped below 100 mmHg,
or heart rate below 50 bpm, beta-blockade was paused and later restarted
at 100 mg od.
We thank Dr Cohn for pointing out that our description[1] of the
POISE dosage described only the first dose. The general maintenance dose
was 200 mg extended release once a day (equivalent to 50 mg immediate
release three times a day). If systolic pressure dropped below 100 mmHg,
or heart rate below 50 bpm, beta-blockade was paused and later restarted
at 100 mg od.
Moreover, as Dr Cohn points out, the metoprolol was given twice. The
first was 2 - 4 hours before surgery. The surgery then lasted a variable
time. During the first 6 hours of recovery, if the heart rate was above 80
bpm and the blood pressure above 100 mmHg, the second dose was given. If
the blood pressure was above 100 mg but the heart rate only between 50 and
80, the second dose was given only at the end of the 6 hours.
No patients received the protocol permitted theoretical dosage of 400
mg in the initial 24 hours[2].
Causation
We can see Dr Cohns' point that causation can never really be proved
in medicine. The statistically significant increased mortality was merely
the result of the randomised controlled trial data.
Dr Cohns' Conclusions
We thank Dr Cohn for encapsulating more elegantly than we managed
ourselves, the conclusions of our paper.
References
1. Bouri S et al. Meta-analysis of secure randomised controlled
trials of ?-blockade to prevent perioperative death in non-cardiac
surgery. Heart 2013. doi: 10.1136/heartjnl-2013-304262.
2. Poldermans D, Devereaux P J. The experts debate:Perioperative beta
-blockade for noncardiac surgery - proven safe or not? CCJM 2009;76: S84-
92]
In non-cardiac surgery, the role of beta-blocakde to prevent
perioperative death is extremely controversial. While it is now agreed
that the results from the DECREASE family of trials cannot be trusted (1),
the evidence from the remaining 9 "secure" trials is somewhat difficult to
interpret. The recent meta-analysis by Bouri et al. (1) has concluded
that, according to these 9 trials, beta-blockade significantly increases...
In non-cardiac surgery, the role of beta-blocakde to prevent
perioperative death is extremely controversial. While it is now agreed
that the results from the DECREASE family of trials cannot be trusted (1),
the evidence from the remaining 9 "secure" trials is somewhat difficult to
interpret. The recent meta-analysis by Bouri et al. (1) has concluded
that, according to these 9 trials, beta-blockade significantly increases
mortality (risk ratio=1.27; 95% confidence interval: 1.01 to 1.60;
p=0.04), but this result was at the limits of statistical significance.
Since trial-sequential analysis (TSA) can contribute to better
interpret controversial findings from meta-analyses (2-4), we employed
this statistical technique to re-examine the results from the 9 secure
trials. The end-point was mortality. We assumed two-sided testing, type-
1 error=5%, power=80%, event frequency for controls=2.5% (i.e. the
arithmetic cumulative event rate in the 9 control groups), and relative
risk reduction (RRR)=25%. Boundaries for superiority, inferiority or
futility were calculated according to the O'Brien-Fleming alpha-spending
function. The graph of TSA was plotted according to a specific software
(User Manual for TSA, Copenhagen Trial Unit 2011).
Figure 1 summarises our analysis (9 trials; 10,529 patients). Our
results essentially confirm the conclusion by Bouri et al. (1). On the one
hand, our trial-sequential graph showed that 17,495 patients would be the
optimal sample size to show a relative difference of +/-25%. On the other
hand, the z-curve based on the 9 trials reached an area very close to the
boundary of inferiority. Although this boundary was not crossed, the
pattern of the curve indicated that these results demonstrate at least
futility (i.e. proof of no effectiveness), while they also tend to
approach the demonstration of inferiority.
On the basis of this TSA, the use of beta-blockade in non-cardiac
surgery is statistically proven to be ineffective (futility) and,
additionally, is very likely to be harmful. Since futility of this
pharmacological intervention is statistically demonstrated, in our view no
further trials should be carried out to study the potential benefit in
these patients; furthermore, in consideration that a preliminary evidence
supports the hypothesis of a harmful effect, this is another reason why
beta-blockade in non-cardiac surgery should be abandoned also in clinical
practice.
References
1. Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis
of secure randomised controlled trials of ?-blockade to prevent
perioperative death in non-cardiac surgery. Heart. 2013 Jul 31. doi:
10.1136/heartjnl-2013-304262.
2. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential
analysis may establish when firm evidence is reached in cumulative meta-
analysis. J ClinEpidemiol. 2008 Jan;61(1):64-75.
3. Messori A, Fadda V, Maratea D, Trippoli S. ?-3 Fatty Acid
Supplements for Secondary Prevention of Cardiovascular Disease: From "No
Proof of Effectiveness" to "Proof of No Effectiveness". JAMA Intern Med.
2013 Jun 17:1-2.
4. Messori A, Fadda V, Maratea D, Trippoli S. Erythropoiesis-
stimulating agents in heart failure: no proof of effectiveness or proof of
no effectiveness? Eur J Heart Fail. 2013 Aug;15(8):944-5.
Figure 1. Trial sequential analysis of 9 "secure" randomized trials.
In the z-curve (represented in blue), individual trials correspond to
individual segments; trials are plotted in chronological order (from left
to right). The x-axis indicates the cumulative number of patients; the
starting point of the z-curve is at x=0, i.e. inclusion of no trials.
Abbreviations and symbols: red lines are the boundaries for superiority or
inferiority while green lines are the boundaries for futility;
T=treatment; C=controls.
Availability: this Figure can be downloaded from
the following Internet address:
http://www.osservatorioinnovazione.net/supplements/messori-eletter-heart-
2013.pdf
after reading with great interest your paper I started to perform
the Five-minute heart rate variability test to all patients in my daily
cardiology practice. I'm using for spectral analysis of HRV a PC-ECG
Workstation manufactured by Contec Medical Systems.
I'm stimulated from the results of ARM-CAD study to use the Five-
minute heart rate variability test as a new clinical tool t...
after reading with great interest your paper I started to perform
the Five-minute heart rate variability test to all patients in my daily
cardiology practice. I'm using for spectral analysis of HRV a PC-ECG
Workstation manufactured by Contec Medical Systems.
I'm stimulated from the results of ARM-CAD study to use the Five-
minute heart rate variability test as a new clinical tool to predict, in
unselected cardiology stable patients, the burden of coronary
atherosclerothic disease (in the range from normal coronary vessels to
multi-vessel obstructive disease) for better cardiac global risk
stratification.
A LF HRV value less than 250 ms2 , as a alternative marker of
significant angiographic coronary isease, is clearly also an indication to
treat the clinically stable patients with a optimal medical therapy (OMT)
in the effort to increase, with drugs and lifestyle changes, the value of
LF HRV.
The evidencies for better outcomes in stable CAD patients treated
with OMT versus PCI are increasing.1,2,3
I suggest that LF HRV value, as result of balance of both arms
(parasympathetic and sympathetic) of autonomic cardiac system on
myocardium, sino-atrial node and vasculature,can be considered as an
indicator of the global status of the heart, not only of the coronary
vessels.
Few days ago I performed the Five-minute heat rate variability test
to a 54 year old patient with dilated cardiomyopathy (EF of 30%) and a
previous recent negative coronary angiography (epicardial coronary vessels
free of lesions). The value of LF HRV of this patient was 40.89 ms2.
Regards
Giovambattista Scarfone, MD
1. Gyenes GT, Ghali WA. Should all patients with Asymptomatic but
significant (>50%) left main coronary artery stenosis Undergo surgical
revascularization? Circulation 2008;118:422-5
2. Stergiopoulos K, Brown DL. Initial coronary stent implantation
with medical therapy vs medical therapy alone for stable coronary artery
disease. Arch Intern Med 2012; 172:312-319.
3.Boden WE. Mounting evidence for lack of PCI benefit in stable
coronary heart disease. Arch Intern Med 2012; 172: 319-321.
We thank Yan Qu and colleagues for their interest in our publication.1 In our systematic review we concluded that caffeine exposure was not associated with increased AF risk. We also have performed a qualitative evaluation of dose-response, which uses the relative proportions of caffeine exposure within each study and the risk of atrial fibrillation (AF). Pooling the relative risk (RR) of low caffeine intake from each st...
Dear Editor, We read with great interest the recent meta-analysis showing that low-dose caffeine may have a protective effect on risk of atrial fibrillation, while no favorable effect was found for high dose of caffeine, and a sketch of a J-shape curve was speculated on the association of caffeine with risk of atrial fibrillation.1 Therefore, to clarify the dose-response relationship on caffeine and risk of atrial fibrilla...
Dorresteijn et al, (Heart 2013;99:866-872), presented a new tool, the SMART risk score, for predicting 10 year risk of recurrence in patients with established cardiovascular disease. This enables clinicians for the first time to differentiate treatment within the hitherto broadly assumed recurrence rate of at least 20% leading to guidelines that, so far, advise maximal drug treatment for elevated risk factors for all patie...
Messori et al [1] present a very interesting matter (the difference between inconclusive results and demonstrating non-inferiority) concerning our recently published meta-analysis of dabigatran vs. warfarin in the setting of catheter ablation of atrial fibrillation [2] that merits a practical reflection. First, proving that two treatments are equal in performance is impossible with statistical tools; at most, one can show...
We have read with interest the comments by Bin Abdulhak and colleagues [1] to our recently published article [2]. We share the same opinion concerning the use of dabigatran in this setting. Thus, in our paper we have proposed the same posology in face of the similar findings: despite the lack of conclusive evidence in support of any particular dabigatran dosage or timing for interrupting or restarting drug therapy, like...
In the interpretation of clinical trials or meta-analyses that show no significant difference between the two comparators, one controversial issue is the need to differentiate between "no proof of difference" (inconclusive result) and "proof of no difference" (or demonstrated non- inferiority). For this purpose, trial-sequential analysis (TSA) is considered to be an appropriate statistical tool (1-4).
In the met...
To The Editor:
We read with interest the study by Providencia et al. which demonstrated that dabigatran had a similar efficacy and safety profile as warfarin in the setting of catheter ablation (CA) of atrial fibrillation (AF) (1). These findings concur with two other meta-analyses on the same topic (including one from our group) which have been recently published (2,3). All the published meta-analyses on this...
Metoprolol Dosing
We thank Dr Cohn for pointing out that our description[1] of the POISE dosage described only the first dose. The general maintenance dose was 200 mg extended release once a day (equivalent to 50 mg immediate release three times a day). If systolic pressure dropped below 100 mmHg, or heart rate below 50 bpm, beta-blockade was paused and later restarted at 100 mg od.
Moreover, as Dr C...
In non-cardiac surgery, the role of beta-blocakde to prevent perioperative death is extremely controversial. While it is now agreed that the results from the DECREASE family of trials cannot be trusted (1), the evidence from the remaining 9 "secure" trials is somewhat difficult to interpret. The recent meta-analysis by Bouri et al. (1) has concluded that, according to these 9 trials, beta-blockade significantly increases...
Dear Dr. Kotheca,
after reading with great interest your paper I started to perform the Five-minute heart rate variability test to all patients in my daily cardiology practice. I'm using for spectral analysis of HRV a PC-ECG Workstation manufactured by Contec Medical Systems.
I'm stimulated from the results of ARM-CAD study to use the Five- minute heart rate variability test as a new clinical tool t...
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