The Lancet reported the results of the Progress trial in which Perindopril was used to lower the blood pressure of patients following strokes in 2001. There were some problems in the analysis of the results from this trial because the investigators were allowed to choose one of two alternative regimens for the patients. In one group the patients were randomised to Perindopril or placebo, and in the other group where the doctors felt it was appropriate to use a thiazide diuretic as well as Perindopril the patients were randomised to Perindopril and Indapamide or double placebo.
In the analysis of the trial results the combination of Perindopril and Indapamide resulted in statistically significant benefits to the patients in terms of prevention of stroke and of major vascular events, whereas Perindopril alone did not reach statistical significance. It is already known that Indapamide improves clinical outcomes so it is possible that the main benefit in the combined drug group comes mostly from the Indapamide, and it is not possible to separately assess the added benefit of Perindopril.
If the second group had been randomised to all get Indapamide and then either Perindopril or Placebo on top it would have been reasonable to combine the results from all the included patients to make an overall assessment of the benefit attributable to Perindopril. The combined results presented in the paper are seriously confounded by the addition of Indapamide in some of the patients and are therefore uninterpretable.
I am grateful to the GP Trainers in Kingston (London) who suggested looking at this paper in a Critical Appraisal Workshop. When we asked what question this study was trying to answer it became clear that the two regimens were addressing different questions: the first is assessing the benefit of Perindopril against placebo, the second Perindopril and Indapamide against double placebo. These are quite distinct and if these were two separate studies I would not be happy to combine them into a single result in a Meta-analysis (as the trialists have done in the paper). What is more they carry out a test for heterogeneity (difference) between the two regimens and find highly significant differences in outcome for both stroke and all adverse events (p< 0.001 in Figure 5 of the original paper).
We concluded that a thiazide diuretic is worth considering to lower the blood pressure of all patients following a stroke, but the case for Perindopril is unproven. The editorial team at the Lancet seem to think this is a fair criticism as they have published my letter making this point, and if you want to look for yourself at the paper or the letters they are both available on the Lancet Website.
The lowering of blood pressure after stroke. Cates C. The Lancet – Vol.358, Issue9297, 08 December 2001,Page1993
In the study of the perindopril protection against recurrent stroke study (PROGRESS) Collaborative Group (Sept 29, p 1033), the first group were given perindopril alone and did not differ significantly from the combination therapy group in rate of stroke or major vascular events by comparison with placebo. The second group were given perindopril and indap amide, but this treatment was compared with double placebo.
If all patients in the second group were given indapamide and randomly assigned perindopril or placebo, it would make sense to combine the results from both groups, on the basis that both were placebo comparisons of perindopril, but with different co-interventions. Use of the second placebo means that the two groups are actually answering separate questions of the efficacy of perindopril’s alone (group one) and in combined treatment (group two).
Pooling the results of the two groups makes little sense to me under these circumstances, since the known efficacy of indapamide is a serious confounding factor. Moreover, the question arises of how much benefit perindopril adds to use of indapamide alone. In view of the 10% of patients taking perindopril who withdrew in the run-in period and the surprising lack of efficacy in relation to the average fall in blood pressure noted by Jan Staessen and Jiguang Wang, my take-home message from this report would be to start patients on a thiazide diuretic after a stroke or transient ischaemic attack. Addition of perindopril might be beneficial, but, unfortunately, the double placebo in this study makes the study design unsuitable to address that question directly.”
Response to: PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.Lancet 2001;358:1033-1111