Ascertaining the correct dose of antiplatelet therapy is vitally
important, because dosage adjustment is simple, inexpensive and has the
potential to bring about large effects at a population level.
It is true that the available literature does not give us a
definitive answer, and conventional levels of significance has not been
achieved with p=0.10. But one should not rely on hypothesis testing and
take P<0.05 as the sole criterion when making inferences.(1) The point
of our paper was to argue that just because the two doses are not seen to
be significantly different it does not follow that they are equivalent.(2)
The evidence base is limited and the confidence intervals are wide, but
the data offer some suggestion that medium dose may be better.
Both Dr Grant and Dr Myerson believe that our paper should not have
been published because there was not a statistically significant
difference between the doses. This argument might have had some validity
had we suggested that medium dose was superior to low dose, but it has
none at all when we are arguing that the data do not support a conclusion
of equivalence.
Dr Myerson asserts that there were over 3000 patients. There was in
fact less than half this number of whom just 385 had events, this is not a
large number. The word “trend” is given in inverted commas but it is Dr
Myerson’s term - we did not use the word. Who is being creative here?
Trying to extrapolate results of a 'large body of evidence' in native
coronary arteries to patients undergoing coronary surgery is injudicious.
Incisions into the coronary arteries and conduits exposes collagen and
stimulates platelet aggregation under conditions of intense platelet
activation due to trauma and extracorporeal circulation, these events do
not occur naturally in native coronary arteries.
Indirect comparison meta-analysis is not “dubious” but a valid
statistical technique(3). Of course, additional assumptions are made when
comparing two sets of trials, as we explained in some detail. Whether the
indirect analysis is justified is a matter of judgment. The same applies
to the marginally significant heterogeneity between the two medium dose
trials.
Dr Cates draws our attention to the occlusion rates in the placebo
arms of the trial by Gavaghan being 6% (average of 7 days) compared to
Sanz of 18% (average of 10 days) in the early stage. However, the early
occlusion rates of the placebo arm in Goldman’s study (average 9 days)
were visually estimated to be 14% (figure 4 of his paper), results that
are broadly comparable with Sanz. Also, the baseline characteristics
appear similar in terms of coronary risk factors as a measure of the risk
for graft occlusion (we accept that information on smoking was sparse).
The tables provided in the full manuscript are the correct version.
In summary, there is a lack of evidence that low and medium dose
regimens are equivalent and a suggestion that medium dose may be superior.
It is important not to confuse the issue by reference to lack of
conventional statistical significance, unfamiliarity with indirect
comparison meta-analysis, or trying to invoke the results from trials that
clearly do not apply to this subset of patients. The uncertainty can only
be resolved by head to head comparison.
Eric Lim [1] & Douglas G Altman [2]
[1] Department of Cardiothoracic Surgery, Papworth Hospital,
Cambridge CB3 8RE, [2] Cancer Research UK/NHS Centre for Statistics in
Medicine, Institute for Health Sciences, Oxford OX3 7LF
References
1. Altman DG, Machin D, Bryant TN, Gardner MJ. (eds) Statistics with
confidence. 2nd Edition: BMJ Books, 2000.
2. Altman DG, Bland JM. Absence of evidence is not evidence of
absence. BMJ 1995;311:485.
3. Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect
comparison for estimating efficacy of competing interventions: empirical
evidence from published meta-analyses. BMJ 2003; 326: 472-4.
Rapid Response:
Authors' Reply
Editor,
Ascertaining the correct dose of antiplatelet therapy is vitally
important, because dosage adjustment is simple, inexpensive and has the
potential to bring about large effects at a population level.
It is true that the available literature does not give us a
definitive answer, and conventional levels of significance has not been
achieved with p=0.10. But one should not rely on hypothesis testing and
take P<0.05 as the sole criterion when making inferences.(1) The point
of our paper was to argue that just because the two doses are not seen to
be significantly different it does not follow that they are equivalent.(2)
The evidence base is limited and the confidence intervals are wide, but
the data offer some suggestion that medium dose may be better.
Both Dr Grant and Dr Myerson believe that our paper should not have
been published because there was not a statistically significant
difference between the doses. This argument might have had some validity
had we suggested that medium dose was superior to low dose, but it has
none at all when we are arguing that the data do not support a conclusion
of equivalence.
Dr Myerson asserts that there were over 3000 patients. There was in
fact less than half this number of whom just 385 had events, this is not a
large number. The word “trend” is given in inverted commas but it is Dr
Myerson’s term - we did not use the word. Who is being creative here?
Trying to extrapolate results of a 'large body of evidence' in native
coronary arteries to patients undergoing coronary surgery is injudicious.
Incisions into the coronary arteries and conduits exposes collagen and
stimulates platelet aggregation under conditions of intense platelet
activation due to trauma and extracorporeal circulation, these events do
not occur naturally in native coronary arteries.
Indirect comparison meta-analysis is not “dubious” but a valid
statistical technique(3). Of course, additional assumptions are made when
comparing two sets of trials, as we explained in some detail. Whether the
indirect analysis is justified is a matter of judgment. The same applies
to the marginally significant heterogeneity between the two medium dose
trials.
Dr Cates draws our attention to the occlusion rates in the placebo
arms of the trial by Gavaghan being 6% (average of 7 days) compared to
Sanz of 18% (average of 10 days) in the early stage. However, the early
occlusion rates of the placebo arm in Goldman’s study (average 9 days)
were visually estimated to be 14% (figure 4 of his paper), results that
are broadly comparable with Sanz. Also, the baseline characteristics
appear similar in terms of coronary risk factors as a measure of the risk
for graft occlusion (we accept that information on smoking was sparse).
The tables provided in the full manuscript are the correct version.
In summary, there is a lack of evidence that low and medium dose
regimens are equivalent and a suggestion that medium dose may be superior.
It is important not to confuse the issue by reference to lack of
conventional statistical significance, unfamiliarity with indirect
comparison meta-analysis, or trying to invoke the results from trials that
clearly do not apply to this subset of patients. The uncertainty can only
be resolved by head to head comparison.
Eric Lim [1] & Douglas G Altman [2]
[1] Department of Cardiothoracic Surgery, Papworth Hospital,
Cambridge CB3 8RE, [2] Cancer Research UK/NHS Centre for Statistics in
Medicine, Institute for Health Sciences, Oxford OX3 7LF
References
1. Altman DG, Machin D, Bryant TN, Gardner MJ. (eds) Statistics with
confidence. 2nd Edition: BMJ Books, 2000.
2. Altman DG, Bland JM. Absence of evidence is not evidence of
absence. BMJ 1995;311:485.
3. Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect
comparison for estimating efficacy of competing interventions: empirical
evidence from published meta-analyses. BMJ 2003; 326: 472-4.
Competing interests:
None declared
Competing interests: No competing interests