The PROGRESS trial three years later: time for a balanced report of effectiveness
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.329.7472.968 (Published 21 October 2004) Cite this as: BMJ 2004;329:968
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I am very glad to see the excellent review of the PROGRESS trial by
Richard Wennberg, and Camilla Zimmermann. Ever since my review of this
study for our pharmacy journal club it had been clear to me that the
author’s conclusions were not a clear summary of the trial results. There
is no acknowledgment of the possibility that the diuretic may be the main
reason for the reduction in stroke. There is also no acknowledgment of the
weakness of the study for not including a diuretic alone arm. Instead all
of this is passed over for the (rightly named) “illogical and misleading”
conclusion that all stroke patients should be on “perindopril-based”
therapy. The reviewers are to be congratulated for shining a clear light
on these murky conclusions.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
The criticisms of the PROGRESS trial by Wennberg and Zimmermann [1]
are fully justified. Too often, the flaws in large-scale trials are lost
in the mists of time, leaving the original results fixed in the medical
literature unsullied by any hint of doubt regarding their validity. The
fact is that the data from the PROGRESS trial fail to demonstrate that
perindopril by itself is of benefit to patients with cerebrovascular
disease.[2] Moreover, as clearly shown by Wennberg and Zimmermann, the
presentation of data in the published paper is misleading.
Similar criticisms, however, may be applied to other large-scale
trials. As a prime example, consider the GISSI-3 trial [3] which, like
PROGRESS, involved an ACE inhibitor and presented an interpretation of the
data which was patently misleading in terms of attributing a beneficial
effect to a single drug when the data supported an effect only in
combination. In a multi-centre, open, randomised controlled trial, 19,394
patients with myocardial infarction received lisinopril, nitrates, both
drugs or neither drug, the 2x2 factorial design allowing various
comparisons to be performed. The abstract focussed on the results of
comparisons between all patients allocated to lisinopril (with or without
nitrates) and two “control” groups comprising either patients allocated to
no treatment or to nitrates alone, or to no treatment. With regard to the
first comparison, the authors stated that “Lisinopril, started within 24
hours from AMI symptoms, produced significant reductions in overall
mortality (odds ratio 0.88 [95%CI 0.79-0.99]) and in the combined outcome
measure of mortality and severe ventricular dysfunction (0.90 [0.84-
0.98]).” The second comparison produced similar results, 0.83 (0.70-0.97)
and 0.85 (0.76-0.94), respectively. Although these results refer to a
mixed group of patients receiving lisinopril – about half allocated to
nitrates, the remainder to controls – the implication in the abstract and
in the discussion section is that lisinopril alone, as well as in
combination with nitrates, reduces the frequency of unfavourable outcomes
in patients with myocardial infarction.
However, unlike the PROGRESS trial, data were available in the GISSI-
3 paper which challenge the claims for efficacy of lisinopril alone. Table
7 reported the results of the four treatment arms individually. [3] A
comparison of patients allocated to lisinopril without nitrates (n = 4713)
and controls allocated to no treatment (n = 4729) showed that there was no
difference in the overall mortality (0.91[0.78-1.07]) or the combined
outcome (0.96 [0.86-1.07]). Interestingly, there was no mention of this
finding in the abstract, in the text of the results section which referred
to Table 7, or in the discussion. Surely such data should have been given
more prominence in order to avoid the misunderstanding that lisinopril
alone was shown to be of benefit in patients with acute myocardial
infarction?
The GISSI-3 trial exhibits much that is bad about the current fashion
for large-scale randomised trials. The substantial proportion of eligible
patients (55%) excluded from the study raises legitimate questions
concerning the external validity. The absolute treatment differences for
either endpoint were trivial: with respect to overall mortality, the
absolute reduction reported with lisinopril +/- nitrates was 0.8% (P=0.03)
and with lisinopril alone was 0.6% (NS). Furthermore, the size of the
absolute treatment difference was conveniently omitted from the abstract
and the discussion – unwelcome results, it seems, are best buried amongst
a mass of opaque data. But worst of all, it is the blatant manipulation of
data in order to make the case favoured by the authors and the sponsors of
the study that brings medical research into disrepute.
By re-visiting previously published large-scale trials and reminding
the medical community of their flaws, Wennberg and Zimmermann have
performed a service.
[1] Wennberg R & Zimmermann C. The PROGRESS trial three years
later: time for a balanced report of effectiveness. BMJ 2004;329;968-70.
[2] PROGRESS Collaborative Group. Randomised trial of perindopril-based
blood-pressure-lowering regimen among 6,105 individuals with a previous
stroke or transient ischaemic attack. Lancet 2001;358;1033-41.
[3] GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate
singly and together on 6-week mortality and ventricular function after
acute myocardial infarction. Lancet 1994:343;1115-22.
Competing interests:
None declared
Competing interests: No competing interests
I am writing in support of the recent excellent commentary on PROGRESS by Professor Wennberg and Dr Zimmermann.
Like the authors, I am troubled by the interpretation of the results of PROGRESS published in the original Lancet article and reiterated by others; by the almagamation of the perindopril and perindopril/indapamide arms under the rubric "perindopril-based therapy"; and by the chief conclusions about such therapy attributed by the trialists.
Interestingly, this has affected my own work. A neurologist referee of a recent article on secondary stroke prevention I published in the Canadian Journal of Neurological Sciences strongly criticized our paper for simply noting the difference in efficacy between the two active treatment arms of PROGRESS; this anonymous reviewer adamantly stated that the trial was not sufficiently powered to show a distinction. Perhaps the best way to look at PROGRESS is that it is really two parallel but different randomized trials with the same control group. Therefore, combining these two very different treatment arms for analysis may be an oversimplification.
Moreover, the article by Wennberg and Zimmermann does not at all distract from implementation of the trial results, as argued by the PROGRESS trialists. With combination ACE inhibitor-diuretic therapy, we get the best of both worlds, and a combination indapamide-perindopril regimen does exist and is manufactured by Servier. I also find it interesting that a higher dose of perindopril monotherapy (8 mg) did not prevent stroke in the recent massive EUROPA study, despite a reduction in blood pressure of 5/3 mm Hg.
Competing interests:
None declared
Competing interests: No competing interests
Dear colleagues,
First, I thank you for this very accurate analysis of the PROGRESS
study.
However, some questions remain unresolved.
Like many other publications, the PROGRESS Study confirms the need to
treat a pathology, which has been perfectly known and accepted about
fifteen or twenty years ago.
Like many others, it is inaccurate in its conclusions, and in the use made
by the sponsor to promote a drug neither better, nor more cost-effective
than others.
It is extremely unfortunate that guidelines like JNC7 rely on this kind of
work to set indisputable recommendations.
I dare not ask any questions about the impartiality of the education in
our medical schools, when I read the litany of financial disclosures.
I also see that the overall mortality is currently a tertiary or minor
endpoint in most publications. The difference of mortality between the
patients who received drugs and those who received placebo is often
ridiculously thin, or null, like in PROGRESS Study.
I thought the life of my patients was my main concern, but now I have the
satisfaction to see that patients die quite as much, but since they are
treated, they die cured.
Competing interests:
None declared
Competing interests: No competing interests
There is a strong evidence base for many aspects of stroke care
particularly secondary prevention. Stroke units significantly reduce death
and disability regardless of severity but only 50% of UK patients receive
this care. The risk of stroke is greatest within the first few days
following transient ischaemic attack yet waiting times for neurovascular
clinics may be weeks or months even if a local service is available.
Hypertension is the most important risk factor for the primary
prevention of stroke but prior to publication of the perindopril
protection against recurrent stroke study (PROGRESS ) in 2001 there was
uncertainty as to the benefits of blood pressure lowering for secondary
prevention (1). Since then the debate has changed as to whether the
substantial reduction in stroke risk seen in this trial (RRR 43% (95% CI
30-54) is due: to specific effects of the combination of perinodopril and
indapamide; indapamide alone; a class effect of these drugs; or blood
pressure lowering per se. These views are strongly held as can be seen
papers by Wennberg and Zimmermann and MacMahon and colleagues (2,3).
Surely the time has come to move on and look at the bigger picture which
is ensuring that blood pressure lowering and other effective measures are
widely and appropriately implemented e.g. aspirin, cholesterol lowering,
carotid endarterectomy for carotid stenosis, warfarin for atrial
fibrillation. Cost effective implementation strategies are required not
endless academic debate. Some will use perindopril and indapamide others
will use other blood pressure lowering drugs –three years on we need to
agree to disagree and move on as suggested by MacMahon and colleagues (3).
This important issue is that only 65% of hypertensive patients are on
treatment at follow up following discharge (4). Surely our patients
deserve better?
1. PROGRESS Collaborative Group.
Randomised trial of perinopril-based blood pressure lowering regimen among
6105 individuals with previous stroke or transient ischaemic attack.
Lancet 2001;358:1033-1041.
2. Wennberg R Zimmerman C.
The PROGRESS trial three years later: time for a balanced report of
effectiveness.
BMJ 2004;329:968-970.
3. MacMahion S Neal B Rodgers A Chalmers J.
The PROGRESS trial three years later:time for more action and less
distraction.
BMJ 2004;329:970-971.
4. Intercollegiate Working Party for Strokre.
Concise report on the National Sentinel Audit for Stroke, 2001-2002.
London: Royal College of Physicians 2001.
Competing interests:
HR was a site investigator for PROGRESS and has received lecture fees from Servier. She is a member of the Intercollegiate Stroke Working Party.
Competing interests: No competing interests
It is indeed somewhat simplistic, and potentially misleading, to
interpret PROGRESS as indicating that stroke patients benefit from the
combination of perindopril and indapamide. In applying these results
clinically, one needs to know whether the benefit in stroke reduction is
due mainly to indapamide or to some synergistic effect of the two. After
all, given the prevalence of polypharmacy and the cost, why give two
medications when one might suffice? To sort out this question, it is
helpful to compare the results of PROGRESS(1)with those of HOPE(2).
The HOPE trial was a 2x2 factorial, randomised, placebo controlled
trial testing vitamin E and ramipril in 9297 high-risk patients, defined
as those over 55 who had a history of vascular disease (coronary artery
disease, stroke, or peripheral vascular disease), or had diabetes with at
least one other cardiovascular risk factor. After a mean follow-up of 5
years, the ramipril group had a relative risk reduction (RRR) of death
from cardiovascular causes of 26% (95% CI: 14 to 30%), a RRR of myocardial
infarction of 20% (95% CI: 10-30%), and a RRR of stroke of 32% (95% CI: 16
-44%) compared to placebo, all significant at p<_.001. this="this" reduction="reduction" was="was" sustained="sustained" for="for" fatal="fatal" and="and" non-fatal="non-fatal" strokes="strokes" ischemic="ischemic" strokes3="strokes3" _.="_." p="p"/> How are clinicians to reconcile the beneficial effect of ramipril
monotherapy in HOPE, with the non-significant effect of perindopril
monotherapy in PROGRESS? There are a number of possible explanations to
explore:
1. Perhaps there are differences in patient populations and absolute
risk of stroke. HOPE enrolled a high risk population; although only 11%
had had a previous stroke or TIA (vs 100% in PROGRESS), 39% had diabetes
(vs 13% in PROGRESS), and 80% had a history of ischemic heart disease (vs
16% in PROGRESS). Could PROGRESS reflect a lower risk population than
HOPE, making it more difficult to detect an effect? This does not appear
to be the case. The stroke rate in the HOPE placebo arm was 4.9% vs 12.9%
in the PROGRESS placebo arm; if anything the event rate was higher in
PROGRESS making it easier to detect a potential beneficial effect,
consistent with the fact that it is usually easier to detect a effect in
secondary prevention studies compared to primary prevention. In addition,
subgroup analysis in HOPE indicates that the beneficial effect is
consistent in those with and without a previous stroke (p for
interaction=0.21).
2. Perhaps the degree of blood pressure reduction was greater in HOPE
than in PROGRESS? This does not appear to be the case; the average blood
pressure reduction in the HOPE trial was 4/3 vs 5/3 in the PROGRESS trial
(systolic/diastolic). This is despite the fact that HOPE was not aiming
primarily at blood pressure reduction, and centres were encouraged to
control hypertension before enrollment; this is reflected in the fact that
the starting blood pressure was lower in HOPE (139/79) than in PROGRESS
(147/86).
3. Perhaps the dose of ACE inhibitor was insufficient? HOPE aimed
for a 10 mg daily dose of ramipril, which represents the maximum
recommended dosage. PROGRESS aimed for a 4 mg daily dose of perindopril,
which represents one quarter to one half the maximum recommended dosage.
This seems a moot point given that the blood pressure reduction was
virtually identical. One would have to surmise that the stroke prevention
effect was due to a mechanism other than blood pressure lowering, a
possibility which the HOPE investigators also raise. They argue that the
risk reduction seen in the trial is much greater than that expected from
the degree of blood pressure lowering. However, this is not supported by
2 recent meta-analyses. The Blood Pressure Lowering Treatment Trialists’
Collaboration(4)and Staessen et al.(5) both concluded that for the same
degree of blood pressure lowering, ACE inhibitors showed no advantage over
diuretics or beta-blockers; odds ratios were centred narrowly around one
for outcomes of stroke, and cardiovascular morbidity and mortality.
4. Perhaps the effect of ramipril is not a class effect of all ACE
inhibitors? This seems highly unlikely, given the similar reduction in
blood pressure in both trials, and the fact that both agents have tissue
ACE activity and similar pharmacokinetics.
5. Perhaps the difference between the 2 trials is simply the play of
chance? Although the confidence intervals for the effect sizes in HOPE
and PROGRESS overlap by 7%, one reflects a hazard ratio and the other
reflects a relative risk, making direct comparisons invalid. A Q test,
checking heterogeneity of hazard ratios for stroke between the 2 studies,
is significant (p=0.02). This means that the observed difference is
unlikely to be due simply to chance.
So how are we to make sense of these conflicting results? The answer
may lie in the profile of those enrolled in PROGRESS. Since this was an
Australian, New Zealand, and Southeast Asian collaboration, almost 40% of
those in PROGRESS were Oriental. The profile of cardiovascular disease
among Orientals is very different than among Caucasians(6). Ischaemic
heart disease predominates in Caucasians; the age-standardised, gender-
specific mortality rates per 100,000 population for Australian Caucasian
males is 104.6, vs 26.3-45.5 for Japanese and Chinese males. By contrast,
cerebrovascular disease predominates in Orientals; the age-standardised,
gender-specific mortality rates per 100,000 population for Japanese and
Chinese males is 44.0-102.6 vs. 19.3 for Australian males. This may
reflect an underlying difference in genetic make-up, environmental
influences, or both. The relative contributions of genes and environment
in this group are starting to be dissected using migration studies,
e.g.(7). Such ethnic variations in blood pressure and response to anti-
hypertensive agents has been noted before in other groups, e.g. African
Americans(8). Thus, it seems likely that at least part of the disparity
between HOPE and PROGRESS may be due to potentially different mechanisms
of vascular disease in Orientals vs Caucasians, and perhaps differing
response to ACE inhibitors.
Rather than being a source of confusion and debate, such conflicting
results should prompt new hypotheses, in this case, that potential ethnic
variation should be explored. Using the methods of genetic epidemiology
in this setting may hold the key to greater understanding of the genetic
and environmental factors in vascular disease.
John Attia, senior lecturer, epidemiology, and academic consultant
Catherine D’Este, associate professor, biostatistics
Christopher R. Levi, conjoint senior lecturer, and staff neurologist
Centre for Clinical Epidemiology and Biostatistics,
University of Newcastle,
Newcastle, NSW, Australia
And
Clinical Neuroscience Program
Hunter Medical Research Institute
John Hunter Hospital
Newcastle, NSW Australia
1. 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; 358:1033-041.
2. The Heart Outcomes Prevention Evaluation Study Investigators.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145-
53.
3. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala et al.
Use of ramipril in preventing stroke: double blind randomised trial. BMJ
2002; 324:1-5.
4. Blood Pressure Lowering Treatment Trialists’ Collaboration.
Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-
lowering drugs: results of prospectively designed overviews of randomised
trials. Lancet 2000; 356:1955-64.
5. Staessen JA, Wang J-G, and Thijs L. Cardiovascular protection and
blood pressure reduction: a meta-analysis. Lancet 2001 358:1305-15.
6. Menzies Centre for Population Health Research. Profile of
cardiovascular diseases, diabetes mellitus and associated risk factors in
the western pacific region. Manila, World Health Organisation, 1999.
7. Fang J, Madhavan S, Alderman MH. Cardiovascular mortality of
Chinese in New York City. J Urban Health 1999; 76:51-61.
8. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS,
et al. Single-drug therapy for hypertension in men. A comparison of six
antihypertensive agents with placebo. N Engl J Med 1993; 328:914-21.
Competing interests:
None declared
Competing interests: No competing interests
Treating the patient in front of you
The debate of how to manage blood pressure (BP) after stroke has been
going on for years and will probably continue for many more, as new agents
and regimens are being developed and tested (e.g. combining ACE Inhibitors
and Angiotensin Receptor Antagonists). Whilst these academic debates and
new clinical trials take place, it is vital for clinicians to concentrate
on the patient in front of them, and tailor the BP lowering regimen
according to the patient's clinical background and co-morbidities.
For the majority of patients, it is probably appropriate to lower the
BP as much as possible, as long as it can be safely tolerated. However,
some patients may not warrant such an aggressive regimen, e.g. those with
bilateral severe carotid stenosis [1], or those with a history of falls
due to orthostatic hypotension. Some groups of patients may particularly
warrant an ACE Inhibitor, such as those who have a history of myocardial
infarction, cardiac failure, diabetes [2], or stable coronary heart
disease [3]. On the other hand, diuretics should be used with caution or
avoided in certain groups of patients such as those with urinary
incontinence or poor renal function.
Some clinicians might choose Perindopril purely for its
pharmacological properties (e.g. its high trough-peak ratio and ease of
dose escalation) [4]. Indpamide is also meant to have a different
pharmacological profile from Thiazides [5], but no head-to-head comparison
trials have yet been performed amongst stroke patients. Clinicians might
also choose other ACE Inhibitors and diuretics for other reasons in order
to suit the patient in front of them.
MacMahon et al [6] and Rodgers [7] are correct in emphasising the
importance of not delaying the implementation of effective BP lowering for
all stroke patients. Due to the complexity and diversity of the patient
group, clinicians need to be clever in exercising the art of medicine to
find the appropriate regimen for each patient.
References:
1. Rothwell PM, et al; Carotid Endarterectomy Trialists'
Collaboration. Relationship between blood pressure and stroke risk in
patients with symptomatic carotid occlusive disease. Stroke
2003;34(11):2583-90.
2. Ruggenenti P, et al; Bergamo Nephrologic Diabetes Complications
Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2
diabetes. N Engl J Med 2004;351(19):1941-51.
3. Fox KM; EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease Investigators. Efficacy of
perindopril in reduction of cardiovascular events among patients with
stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial (the EUROPA study). Lancet
2003;362(9386):782-8.
4. Sica DA. Dosage considerations with perindopril for systemic
hypertension. Am J Cardiol 2001;88(7A):13i-18i.
5. Ames RP. A comparison of blood lipid and blood pressure responses
during the treatment of systemic hypertension with indapamide and with
thiazides. Am J Cardiol 1996;77(6):12b-16b.
6. MacMahon S, et al. The PROGRESS trial three years later: time for
more action, less distraction. BMJ 2004;329:970-971.
7. Rodgers H. The PROGRESS trial three years later: All aspects of
secondary prevention after stroke need to be improved. BMJ 2004;329:1404-
1405.
Competing interests:
Dr Joseph Kwan has received one lecture fee from Servier in 2002.
Competing interests: No competing interests