Use of ramipril in preventing stroke: double blind randomised trial
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7339.699 (Published 23 March 2002) Cite this as: BMJ 2002;324:699
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In the comments on the HOPE stroke substudy1 a parallel is made with
PROGRESS to stress the blood pressure-independent stroke-protective effect
of ACE inhibitors, and argue for the potential cerebrovascular deleterious
effect of angiotensin II (AII). We think however that these 2 trials
should rather be opposed.
In PROGRESS, perindopril alone comparatively to placebo actually did
not reduce the risk of stroke recurrence in spite of a BP-decrease greater
than that obtained with ramipril in HOPE. In contrast in the PATS trial 2,
indapamide alone decreased the risk of stroke recurrence by 29% for the
same BP-decrease as with perindopril alone. Since indapamide stimulates
AII-formation, its superiority over perindopril in preventing stroke
challenges the concept that AII is solely deleterious by acting through
AT1-receptors, and justifies to recall that AII has experimentally proven
stroke-protective effects, mediated by non-AT1-receptors which promote
collateral circulation recruitment to the ischemic brain 3.
The recent LIFE trial 4 showing that in hypertensive patients, the
AT1-receptor-blocker (ARB) losartan had a greater BP-independent stroke-
protective effect than atenolol without greater cardiac complications
prevention, strongly supports the clinical relevance of non-AT1-receptor
-mediated stroke-protective effects, since ARBs increase AII-formation.
Indeed there is no reason why a greater AT1-receptor blockade with ARB,
proven by the greater reduction of LVH should be more apparent at the
level of the cerebral than of the coronary arteries, the incidence of new
atrial fibrillation being the same.
The unique BP-independent stroke prevention with ramipril among ACEI, in
spite of the blunting of these non-AT1 receptors, should therefore be
explained. In this trial with an initial prevalence of coronary heart
disease (CHD) of 80%, the cardiac complications overrided stroke by a
factor 5 in contrast to the other trials where the reverse was observed,
in relation to a much lower prevalence of CHD (<16%). Furthermore the
absolute prevention of cardiac complications overrided that of stroke by a
factor 3. Since cardiac complications are per se strong risk factor of
strokes 5, we propose that a significant part of stroke prevention in HOPE
was actually secondary to cardiac protection. It would therefore be
interesting to have more details on the nature of the ischemic strokes in
HOPE.
The likelyhood that ACEI or betablocker have lower BP-independent stroke-
protective effect than diuretics or ARB in different populations at higher
risk of stroke than of cardiac complication, justifies a large trial
comparing ARB to ACEI to demonstrate the superiority of ARB in these
populations.
Albert Fournier,Hakim Mazouz, Roxana Oprisiu, Michel Andrejak
Nephrology and Pharmacology department-CHU-80054 AMIENS CEDEX 1 – France
e.mail Fournier.Albert@chu-amiens.fr
Jean Miche Achard
Physiology department – CHU – Limoges - France
References
1. Bosch J, Yusuf S, Pogue J, Sleight P. On behalf of the HOPE
investigations. Use of ramipril in preventing stroke : double blind
randomised trial;. BMJ 2002;324:699-702.
2. PATS collaborating group. Post-stroke Antihypertensive Study. Chinese
Med J 1995;108:710-717.
3. Dalmay F, Mazouz H, Allard J, Pesteil F, Achard JM, Fournier A. Non-
AT(1)-receptor-mediated protective effect of angiotensin against acute
ischaemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst
2001;2(2):103-6.
4. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et
al. Cardiovascular morbidity and mortality in the Losartan Intervention
For Endpoint reduction in hypertension study (LIFE): a randomised trial
against atenolol. Lancet 2002;359(9311):995-1003.
5. Mooe T, Olofsson BO, Stegmayr B, Eriksson P. Ischemic stroke. Impact of
a recent myocardial infarction. Stroke 1999;30(5):997-1001.
Competing interests: No competing interests
Dear Editor,
We owe a debt of thanks to the BMJ for publishing the paper, “Use of
ramipril in preventing stroke: double blind randomised trial”. At our
practice journal club last week it provided the perfect focus for a
discussion about study methodology and data presentation. It allowed our
past and present registrar to display their carefully honed skills in
critical reading.
Apart from the obvious problems with the data (as examples, about 10%
of patients recruited dropped out and no assessment of their impact on the
analysis was offered; the fact that a higher percentage of stroke
survivors who had been taking placebo had no functional impairment yet
this escaped discussion), the paper was interesting in two other principal
ways. It suggested that (BMJ) rules are there to be broken. The data was
presented without reference to numbers needed to treat (66 for all
strokes, 166 for fatal strokes and 111 for non-fatal strokes) and without
the clarifying benefit of any flow diagrams. It also clearly demonstrated
the pro-drug bias so prevalent in medical literature (no data about
adverse effects).
At least, however, the policy of the BMJ to insist that authors
declare competing interests came into its own….”All authors have acted as
consultants and have received funding for research from the above
sponsors, as well as having attended and presented papers at symposia with
support from the sponsoring agencies”.
Yours sincerely,
Lesley Morrison, on behalf of the Journal Club, Teviot Medical
Practice.
Competing interests: No competing interests
Sir,
In the comments on the HOPE stroke substudy1 a parallel is made with
PROGRESS to stress the blood pressure-independent stroke-protective effect
of ACE inhibitors, and argue for the potential cerebrovascular deleterious
effect of angiotensin II (AII). We think however that these 2 trials
should rather be opposed.
In PROGRESS, perindopril alone comparatively to placebo actually did
not reduce the risk of stroke recurrence in spite of a BP-decrease greater
than that obtained with ramipril in HOPE. In contrast in the PATS trial 2,
indapamide alone decreased the risk of stroke recurrence by 29% for the
same BP-decrease as with perindopril alone. Since indapamide stimulates
AII-formation, its superiority over perindopril in preventing stroke
challenges the concept that AII is solely deleterious by acting through
AT1-receptors, and justifies to recall that AII has experimentally proven
stroke-protective effects, mediated by non-AT1-receptors which promote
collateral circulation recruitment to the ischemic brain 3.
The recent LIFE trial 4 showing that in hypertensive patients, the
AT1-receptor-blocker (ARB) losartan had a greater BP-independent stroke-
protective effect than atenolol without greater cardiac complications
prevention, strongly supports the clinical relevance of non-AT1-receptor
-mediated stroke-protective effects, since ARBs increase AII-formation.
Indeed there is no reason why a greater AT1-receptor blockade with ARB,
proven by the greater reduction of LVH should be more apparent at the
level of the cerebral than of the coronary arteries, the incidence of new
atrial fibrillation being the same.
The unique BP-independent stroke prevention with ramipril among ACEI, in
spite of the blunting of these non-AT1 receptors, should therefore be
explained. In this trial with an initial prevalence of coronary heart
disease (CHD) of 80%, the cardiac complications overrided stroke by a
factor 5 in contrast to the other trials where the reverse was observed,
in relation to a much lower prevalence of CHD (<16%). Furthermore the
absolute prevention of cardiac complications overrided that of stroke by a
factor 3. Since cardiac complications are per se strong risk factor of
strokes 5, we propose that a significant part of stroke prevention in HOPE
was actually secondary to cardiac protection. It would therefore be
interesting to have more details on the nature of the ischemic strokes in
HOPE.
The likelyhood that ACEI or betablocker have lower BP-independent stroke-
protective effect than diuretics or ARB in different populations at higher
risk of stroke than of cardiac complication, justifies a large trial
comparing ARB to ACEI to demonstrate the superiority of ARB in these
populations.
References
1. Bosch J, Yusuf S, Pogue J, Sleight P. On behalf of the HOPE
investigations. Use of ramipril in preventing stroke : double blind
randomised trial;. BMJ 2002;324:699-702.
2. PATS collaborating group. Post-stroke Antihypertensive Study. Chinese
Med J 1995;108:710-717.
3. Dalmay F, Mazouz H, Allard J, Pesteil F, Achard JM, Fournier A. Non-
AT(1)-receptor-mediated protective effect of angiotensin against acute
ischaemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst
2001;2(2):103-6.
4. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et
al. Cardiovascular morbidity and mortality in the Losartan Intervention
For Endpoint reduction in hypertension study (LIFE): a randomised trial
against atenolol. Lancet 2002;359(9311):995-1003.
5. Mooe T, Olofsson BO, Stegmayr B, Eriksson P. Ischemic stroke. Impact of
a recent myocardial infarction. Stroke 1999;30(5):997-1001.
Competing interests: No competing interests
Dear sirs,
Beyond the obvious criticisms of this trial (1) such as the typical
presentation of the relative risk reduction (RRR) and absolutely no
mention of the absolute risk reduction (ARR) and the number needed to
treat (NNT) the central question remains. Is it blood pressure lowering,
or is it the ace inhibitor that lead to the 32% RRR in stroke with a NNT
of 67.
The authors conclude that all patients at high risk for stroke should
be placed on ramipril irrespective of their initial blood pressure. This
is based on the fact that the pressure in the ramipril group had only a
3/2 blood pressure lowering and this could not explain the beneficial
effects seen. They also site the PROGRESS trial (2) as supporting the
benefits of ace inhibitors in both primary and secondary prevention even
in patients without hypertension.
These arguments have flaws. In the PROGRESS trial a secondary
prevention trial involving patients who had either a stroke or TIA, 1280
patients on just perindopril vs placebo had no benefit despite an average
blood pressure drop of 5/3. In the combination group of perindopril and
indapamide vs placebo 1770 patients in the active treatment group saw a
43% RRR, with a NNT of 17 for reduction of stroke with an average blood
pressure reading drop of 12/9. this is hardly a ringing endorsement for
the ace inhibitor.
The 10 mg dose of ramipril was given at bedtime and the blood
pressure was checked at an unspecified time in the day after lying down
for 5 minutes. Why was the pressure taken this way? According to our 1999
Canadian recommendations for the management of hypertension,(3) blood
pressure should be taken sitting with both the back and the arm supported.
It is done in this standardized way to emulate the technique used in older
hypertension trials. According to a HOPE substudy (4) using ambulatory bp
monitoring 10 mg of ramipril reduced 24 hour ambulatory blood pressure a
highly significant 10/4 mm Hg with much of the benefit seen at night. This
could go a long way in explaining the benefits seen in this trial.
The only way to resolve the question of is it the ACE inhibitor or is
it the blood pressure lowering is to compare 2 active agents. This in fact
has been done in the CAPPP trial (5). In this randomized trial of 10985
patients with diastolic hypertension comparing captopril to beta blockers
and diuretics fatal and non fatal strokes were more common in the
captopril group (1.25; p=.044). This trial is conveniently ignored in the
discussion section.
From the accumulating evidence the concept of the J curve appears
dead and lower is better for blood pressure targets. The appropriate
target for blood pressure will be arrived at with due consideration of the
"event rate" in the untreated group and the NNT to make a rational cost
effective decision. Industry driven calls for widespread use of an ACE
inhibitors without compelling evidence is not useful.
References
1 J. Bosch et al, Use of ramipril in preventing sroke: double blind
randomised trial. BMJ 2002, 324:1-5
2 PROGESS Collaborative Group, Randomized trial of perindopril-based blood
-pressure-lowering regimen among 6105 individuals with previous stroke or
transient ischaemic attack. Lancet 2001, 358:1033-1041
3 1999 Canadian recommendations for the management of hypertension.
Supplement to CMAJ 1999; 161 (12 Suppl)
4 Per Svensson et al, Comparative effects of ramipril on ambulatory and
office blood pressures A HOPE Substudy. Hypertension 2001;38:e28-e32
5 L. Hansson et al, Effect of angiotensin-coverting-enzyme inhibition
compared with conventional therapy on cardiovascular morbity and mortality
in hypertension: the Captopril Prevention Project randomized trial. Lancet
1999,353:611-616.
Competing interests: No competing interests
When explaining the reduction in stroke rate by ramipril, the authors
of the HOPE study assume that ramipril may have multiple mechanisms in
addition to blood pressure lowering, by which “atherosclerotic events’ may
be prevented [1,2]. Atherothrombosis, however, is not the only cause of
stroke. Stroke may also have an embolic cause, most frequently atrial
fibrillation. Atrial fibrillation is an independent risk factor for stroke
and about 16% of ischemic strokes are associated with atrial fibrillation
[3]. Although the HOPE investigators reported electrocardiographic
findings, the prevalence of atrial fibrillation has not been indicated by
them [1,2]. It can be expected that the prevalence of atrial fibrillation
in the patients of the HOPE-study is high, since the same risk factors,
which were inclusion criteria for the HOPE study, have been identified by
epidemiological studies to be also risk factors for the development of
atrial fibrillation: increased age, hypertension, coronary heart disease,
elevated serum cholesterol levels and smoking [4,5]. Uninformed about the
prevalence of atrial fibrillation and its distribution among the placebo-
and the ramipril-group, it can be speculated that differences in the
prevalence of atrial fibrillation might have contributed to the
differences in stroke incidence. Possibly the prevalence of atrial
fibrillation was higher in the placebo- than in the ramipril-group thus
contributing to the lower incidence of stroke in the ramipril group.
In atrial fibrillation patients, stroke prevention can be achieved
effectively by antithrombotic therapy, either by oral anticoagulation with
70% reduction of the relative risk or by aspirin with 20% reduction of the
relative risk [3]. Uninformed about the rate and kind of antithrombotic
therapy in the atrial fibrillation patients and about their distribution
among the placebo- and the ramipril-group, it can be speculated that
differences thereof might have contributed again to the differences in
stroke incidence.
Therefore, in order to understand better the mechanisms of stroke
prevention in the HOPE study and to assess the effect of ramipril on
stroke prevention, it would be helpful to know the prevalence of atrial
fibrillation and the antithrombotic therapy provided to the patients.
References
1. Bosch J, Yusuf S, Pogue J, Steight P, Lonn E, Rangoonwala B, et al. Use
of ramipril in preventing stroke: double blind randomised trial. BMJ
2002;324:1-5.
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. Hart RG, Sherman DG, Easton JD, Cairns JA. Prevention of stroke in
patients with nonvalvular atrial fibrillation. Neurology 1998;51:674-81.
4. Wilhelmsen L, Rosengren A, Lappas G. Hospitalizations for atrial
fibrillation in the general male population: morbidity and risk factors. J
Intern Med 2001;250:382-9.
5. Stewart S, Hart CL, Hole DJ, McMurray JJ. Population prevalence,
incidence, and predictors of atrial fibrillation in the Renfrew/Paisley
study. Heart 2001;86:816-21.
Competing interests: No competing interests
In the abstract of their paper, Bosch and colleagues (1) state that
the objective of the analysis was "To determine the effect of the
angiotensin converting enzyme inhibitor ramipril on the *secondary
prevention* (our emphasis) of stroke". Our understanding of this term is
prevention of recurrence after a previous stroke or TIA but less than 11%
(1013/9297) of patients had a previous event.
Later in the abstract the authors claim that "Benefits were
consistent.....in subgroups defined by the presence or absence of previous
stroke, coronary artery disease, peripheral arterial disease, diabetes, or
hypertension."
No numeric data are provided on the 1013 patients with previous
stroke but Figure 3 shows clearly a non-significant effect of ramipril on
stroke risk in this sub-group with wide confidence intervals crossing one.
Despite the low numbers of patients - probably insufficient to show a
difference if one exists - the effect, or lack or it, is remarkably
consistent with that reported for perindopril given alone in much larger
PROGRESS trial of secondary prevention of stroke (2).
We conclude that blood pressure lowering - by at least 9/4 mmHg (as
achieved in those given active treatment in the PROGRESS trial) - and
irrespective of the type of agent used - is the is the single most
important factor in secondary prevention of stroke. Unless ACE inhibition
as monotherapy achieves this target, it cannot be recommended.
(1) Use of ramipril in preventing stroke: double blind randomised
trial. Jackie Bosch, Salim Yusuf, Janice Pogue, Peter Sleight, Eva Lonn,
Badrudin Rangoonwala, Richard Davies, Jan Ostergren, and Jeff Probstfield
BMJ 2002; 324: 699
2. Randomised Trial of a Perindopril-Based Blood-Pressure-Lowering
Regimen among 6,105 Individuals with Previous Stroke or Transient
Ischaemic Attack. Lancet 2001; 358: 1033-41
No competing interests.
Competing interests: No competing interests
Dear Editor,
I was a bit surprised to see that the BMJ has published a trial (1)
that has presented the results in a way, which exaggerates the findings.
Stroke prevention, the topic under discussion in this paper is important
for the patients, physicians and funders of care. Hence the results should
have been presented in way that would help the practicing clinicians;
Numbers needed to treat (NNT) along with relative risk reduction (RRR).The
authors report a 32% RRR in all strokes and a 61% RRR in fatal strokes.
For total strokes this translates in to a NNT of 67 for 4 and a half years
treatment with Rimapril.
There is evidence to show that the way results of clinical trial are
presented influences both physicians (2-3) and funders 4 of health care.
In the randomised controlled trial by Bucher et al (2), physicians gave
higher ratings for the effectiveness of the drug and were more inclined to
prescribe lipid lowering drugs when the results are presented as relative
risks. Naylor et al (3) observed that method of reporting trial results
alter the perception of therapeutic effectiveness and adds that
clinicians' views of drug therapies are affected by the common use of
relative risk reductions in both trial reports and advertisements. A study
(4) from a UK health authority reported that Health authority members'
willingness to purchase services was influenced by the methods used to
present results. Interestingly two of the above three paper were published
in the BMJ.
The problem of biased reporting clinical trials is not a new
phenomenon. Pocock et al (5) in their survey of three medical journals in
1987 found that overall, the reporting of clinical trials appears to be
biased toward an exaggeration of treatment differences. What do the
CONSORT guidelines say? These two lines from the revised recommendations
of the CONSORT statement (6) may be relevant here. “For both binary and
survival time data, expressing the results also as the number needed to
treat for benefit (NNTB) or harm (NNTH) can be helpful”. Ironically the
two references (7-8) supporting this statement are from the BMJ.
What can be done to improve the quality of reporting of results of
RCTs?. It has been pointed out that both reduction in relative risk and
reduction in absolute risk should be reported in medical papers because
exclusive emphasis on the reduction in relative risk may overstate the
effectiveness of a treatment 2. If there is general agreement then the
next CONSORT guidelines should include a statement that wherever
applicable the results of clinical trials should include NNTs.
Although the BMJ has taken the lead by publishing many studies on the
appropriate way to present results and its impact, in future if it
emphasises to the authors of clinical trials to present NNTs, this will
greatly help the BMJ readers and avoid criticisms of both the authors,
reviewers and editors.
Reference
1) Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B,
Davies R, Ostergren J and Probstfield J on behalf of the HOPE
Investigators. Use of ramipril in preventing stroke: double blind
randomised trial BMJ (2002) 324: 699-702
2) H C Bucher, M Weinbacher, K Gyr. Influence of method of reporting
study results on decision of physicians to prescribe drugs to lower
cholesterol concentration. BMJ 1994;309:761-764.
3) Naylor CD, Chen E, Strauss B. Measured enthusiasm: does the method
of reporting trial results alter perceptions of therapeutic effectiveness?
Ann Intern Med 1992;117:916-21
4) Fahey T, Griffiths S, Peters TJ. Evidence based purchasing:
understanding results of clinical trials and systematic reviews. BMJ
1995;311:1056-1059
5) SJ Pocock, MD Hughes, and RJ Lee. Statistical problems in the
reporting of clinical trials. A survey of three medical journals. N Engl J
Med. 1987317:426-432
6) David Moher, MSc, Kenneth F. Schulz, PhD, Douglas G. Altman, DSc,
for the CONSORT Group*. The CONSORT statement: revised recommendations for
improving the quality of reports of parallel group randomized trials.
http://www.consort-statement.org/examples17.htm Accessed on 8th April
2002.
7) Cook RJ, Sackett DL. The number needed to treat: a clinically
useful measure of treatment effect. BMJ. 1995;310:452-4.
8) Altman DG, Andersen PK. Calculating the number needed to treat for
trials where the outcome is time to an event. BMJ. 1999;319:1492-5.
Competing interests: None
Acknowledgements: I am grateful to Dr. Kev Hopayian, General
Practitioner, Leiston, Suffolk, UK for bringing this issue to my attention
through a posting in the evidence based health discussion list.
Dr.P.Badrinath M.D,M.Phil,(Epid)PhD(Cantab)DFPHM(UK),MPH
Clinical Assistant Professor & Hon Consultant in Preventive Medicine,
Department of Community Medicine,
UAE University, PO Box 17666, Al Ain,
United Arab Emirates.
Competing interests: No competing interests
Bosch et al. are keen to stress the potential public health benefits
from widespread use of ramipril, but fail to mention the potential harms
and discomforts that patients will have to endure while taking ramipril.
Sadly, this paper presents no information on adverse effects in the trial,
and is another example of how the medical literature is biased towards
detailed descriptions of therapeutic benefit, but regularly glosses over
the less pleasant side of things.[1] This is unfair to both patients and
their doctors who are trying to weight up the pros and cons of therapy.
At the very least, the authors should have mentioned that this
particular paper was a substudy of existing data, and that adverse effects
data was available from the original publication.[2] It would have made it
much easier for us to find out that ramipril increased the absolute rate
of withdrawals due to cough by 5.5% (number-needed-to harm 18), and
hypotension or dizziness by 0.4% (number-needed-to harm 250), as compared
to placebo. These adverse events occurred despite there being an
unspecified number of intolerant patients being initially excluded during
the run-in phase prior to randomization. The published adverse effects
rates are therefore likely to be be a gross underestimate of what will
occur in clinical practice.
In order to fully informed, patients need to know that the 1.5%
decrease in the absolute rate of stroke is counterbalanced by this 5.5%
(or greater) risk of persistent cough, and that they will have to live
with this cough while hoping that some future stroke will probably (but
not definitely) be averted. It would be very helpful if Bosch et al. had
considered the data in this light before making a sweeping recommendation
on the public health benefits of ramipril.
Finally, journal editors should ensure that manuscripts provide a
balanced view, instead of just concentrating on new and exciting
beneficial effects. Whilst new and exciting may be fashionable, journals
have a duty to their readers to also warn them of any potential problems
that may arise.
1. Loke YK, Derry S. Reporting of adverse drug reactions in
randomised controlled trials – a systematic survey. BMC Clinical
Pharmacology 2001, 1:3.
2.Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects
of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med. 2000 ;342:145-53.
Competing interests: No competing interests
Sir, I am amazed how this article ever passed peer review. The numbers in table 1 simply do not add up.
In the breakdown of non-fatal strokes, the authors seem to claim that: 49+85 =139; 108+80=182; 52+12=63; 16+65=78.
Also, the total numbers of subtypes of stroke(ischaemic and non-ischaemic)do not match the total stroke numbers: 78+157=235 and not 226; 63+101=164 and not 156.
Furthermore, some conclusions drawn in the discussion are not supported by the data in Fig 2.
Fig 2 clearly shows the 95% CI of diastolic BP <_79 _80-89="_80-89" and="and" systolic="systolic" bp="bp" _130-139="_130-139" touching="touching" on="on" relative="relative" risk="risk" of="of" _1.0.="_1.0." therefore="therefore" it="it" can="can" not="not" be="be" concluded="concluded" that="that" benefit="benefit" was="was" seen="seen" at="at" all="all" values="values" diastolic="diastolic" blood="blood" pressure="pressure" because="because" the="the" true="true" value="value" is="is" somewhere="somewhere" along="along" _95="_95" _="_" ci="ci" might="might" well="well" _1="_1" i.e.="i.e." no="no" effect="effect" ramipril="ramipril" whatsoever.="whatsoever." p="p"/>The authors do not report on how many patients with 'strokes of uncertain aetiology' (not confirmed on scan) had 'no functional impairment'. Could it be that all of these patients in fact had a TIA rather than a stroke, and therefore the number of strokes in this study is much lower?
Even with the data presented the numbers needed to treat, per year, are roughly 415(judged by prevented fatal strokes (44-17=27) and strokes causing some functional impairment (108-85=23)), what sounds a lot less spectacular than
32%/61% reduction of RR of all/fatal strokes.
Competing interests: No competing interests
A trial's entire data-set should be publically available
Dear Editor,
The authors of the HOPE study have touted the value of ramipril
therapy in the prevention of stroke by stating that
ramipril reduced the relative risk of a stroke by 32% in high risk
patients. A number of BMJ respondents have stated that the RRR figure of
32% is clinically meaningless, and that one needs to calculate the
absolute risk reduction (ARR) figure and the number-needed-to-treat (NNT)
figure to determine the true clinical value of ramipril therapy. The
calculated ARR figure is 1.5% over a time period of 4.5 years, which
translates to a NNT figure of 67 over 4.5 years. That suggests that 67
patients would have to be treated with ramipril for a duration of 4.5
years to prevent ONE stroke, which is near-equivalent to suggesting that
approximately 300 patients would have to be treated yearly to prevent ONE
stroke event per year. Many respondents have used those NNT figures to
argue that ramipril would not be cost-effective therapy if the baseline
yearly risk of a stroke was only 1%.
There is another problem that relates to clinical trials involving
patients who have low control event rates -- chance events can have
have a large effect on the trial's results and either diminish, or
magnify, the "apparent" efficacy of the drug. In their HOPE substudy
article, [1] the authors state "In the first year 36 (0.8%) stroke events
occurred in the ramipril group and 53 (1.1%) in the placebo group (0.68,
0.45 to 1.04). By year two 77 (1.7%) stroke events had occurred in the
ramipril group and 112 (2.4%) in the placebo group (0.69, 0.51 to 0.92).
At year three 113 (2.4%) patients taking ramipril had had a stroke
compared with 163 (3.5%) taking placebo (0.69, 0.54 to 0.88), and by the
fourth year 142 (3.1%) patients in the ramipril group and 207 (4.5%) in
the placebo group had had a stroke (0.68, 0.55 to 0.84)". Those figures
suggest that ramipril was EQUALLY efficacious throughout the trial's 4.5
year time period, that the average placebo patient's stroke event rate was
~1% per year, that the average ramipril patient's stroke event rate was
~0.7% per year, resulting in an average yearly ARR of ~0.3% (NNT = 333).
Many clinicians would intuitively accept the fact that ramipril could have
a consistent therapeutic effect over a time period of 4.5 years, and they
would readily accept the accuracy of those figures.
However, would those clinicians readily accept the accuracy of those
figures if they knew the following facts. At the start of the trial,
patients were randomized to ramipril therapy or placebo therapy, and
patients were excluded from trial participation if they were currently
taking an angiotensin converting enzyme inhibitor (ACEI). One would
therefore presume that no placebo patients would be taking an ACEI at the
start of the trial. However, as the trial proceeded the number of placebo
patients taking an ACEI increased, while the number of treated patients
taking ramipril (or another ACEI) decreased. [2]
From those figures, it can be seen that the available "ACEI efficacy
power" was only ~65% as great in the last years of the trial compared to
the time of trial inception. Knowing that fact, does it make sense that
the yearly ARR due to ACEI-activity would remain constant at ~0.3%/year
throughout the trial?
There is another fact that doesn't make sense. At the time of
randomization, approximately 28% of the HOPE trial's patients were taking
statins (28.4% of ramipril active patients, 28.8% of placebo patients). By
year 2, the numbers were approximately 38% (38.1% of ramipril active
patients, 38.4% of placebo patients) and at the time of the penultimate
visit, the numbers were approximately 49% (49.1% of ramipril active
patients, 49.3% of placebo patients). That means that towards the end of
trial, the number of placebo patients taking a statin was approximately
20% greater than at the time of trial inception (49.3% minus 28.8%) and
the number of placebo patients taking an ACEI was approximately 10%
greater (10.8% minus 0.0%). If both statins and ACEIs have the power to
reduce the risk of a subsequent stroke by ~30%, then why was the absolute
stroke event rate in placebo patients the same in the 4th year (1.0%) as
it was in the 1st two years (1.0-1.1%)?
I personally don't know the answer to those questions, and I strongly
suspect that the phenomenon was due to chance effects and/or low event
rates. It is well known that chance events plays havoc in clinical trials
that have low event rates, and that the final trial results are therefore
less reliable. It is also interesting to note that although the HOPE trial
showed a 32% RRR in stroke prevention due to use of an ACEI, that a meta-
analysis of the SAVE, AIRE, and TRACE trials showed no benefit in stroke
prevention secondary to use of an ACEI (stroke events in ACEI patients =
4%, stroke events in control patients = 3.7%). [3] How does one explain
the marked difference in results between those ACEI trials and the HOPE
trial? Could chance be playing a major role?
There is another matter of great import. Can one infer that ramipril
would have a similar benefit in patients with a
recent stroke (who have an "average" yearly stroke event rate in the range
of 3-8%) if one presumes that ramipril's RRR figure of 32% for high-risk
patients (recent MI patients, PID patients, diabetic patients with CAD
risk factors) is scientifically valid and accurate? I would argue that one
cannot automatically infer that ramipril would produce a 32% RRR in
recurrent stroke events in patients who have suffered a recent stroke --
just because the drug produced a 32% RRR in other high risk patients (eg.
recent MI patients, PAD patients, diabetic patients with CAD risk
factors). My reasoning would be two-fold. First of all, I noted in my
analysis of the CAPRIE trial [4] that clopidogrel had no benefit over
aspirin in preventing a stroke event in patients with a recent MI (0.73%
yearly stroke events - clopidogrel, 0.72% yearly stroke events - aspirin)
compared to its slightly positive effect in recent stroke patients (5.2%
yearly stroke events - clopidogrel, 5.65% yearly stroke events - aspirin).
That example shows that a drug's stroke preventative efficacy may be
different in recent stroke patients compared to other high-risk patients,
who have a significantly smaller risk of a subsequent stroke. Secondly, I
noted that figure 3 in the authors article [1] indicates that ramipril had
a RR of approximately 0.85 in the 1,013 HOPE trial patients, who had a
previous history of stroke/TIA, and that the placebo patients in that
subgroup had a control stroke event rate of 9.9%. Those figures would
suggest that ramipril is not equally effective in patients with a recent
stroke (RR = 0.85) compared to other high-risk patients (RR figure =
0.68). Are those figures in figure 3 accurate, and do they apply to
patients with a recent stroke/TIA, or do they apply to patients with any
history of a prior stroke/TIA? I noted in the FDA's briefing document [2]
that the following figures applied to 1,013 patients who had a previous
history of cerebrovascular disease:- 500 were randomized to the ramipril
group and 513 to the placebo group. It is my understanding that the figure
of 1,013 patients applies to randomized patients who had a previous
stroke/TIA and not specifically to patients with a recent stroke. Perhaps
the HOPE trial's investigators could provide further details to make this
distinction much clearer.
Finally, it is my belief that a clinician-interpreter needs to have
access to a trial's complete data set in order to
accuratedly interpret a trial's results, and that he shouldn't be limited
to the amount of raw data routinely
published in a medical journal article. For example, the CURE trialists
claimed in their journal article report on
the CURE trial that clopidogrel produced a 20% RRR for the composite
endpoint of MI/stroke/CV death in ACS patients. However, after obtaining
more detailed information from the FDA, my personal analysis of the trial
[5] revealed that clopidogrel had far less efficacy after 30 days compared
to the <_30 day="day" time="time" period="period" and="and" that="that" the="the" nnt="nnt" figures="figures" were="were" much="much" higher="higher" for="for"/>30 day time period (NNT = 125 [composite primary outcome of CV
death/MI/stroke]; NNT = 285 [MI -- fatal or not]; NNT = 500 [Stroke --
fatal or not]). Therefore, I believe that the editors of the major medical
journals should refuse to publish the results of any clinical trial unless
they obtain access to the trial's entire data-set. Although there is
obviously no space to post the entire data-set in the paper version of the
journal article, the online version of the published article could have
inbuilt links to the entire data-set, so that interested readers can more
thoroughly examine the trial's raw data.
Jeff Mann.
jmannemg@earthlink.net
References:
1. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B,
Davies R, Ostergren J and Probstfield J on
behalf of the HOPE Investigators. Use of ramipril in preventing stroke:
double blind randomised trial BMJ(2002) 324: 699-702.
2. HOPE trial - FDA briefing document
Available at
http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3612b1d.pdf
3. Flather MD, Yusuf S, et al. Long-term ACE-inhibitor therapy in
patients with heart failure of left-ventricular
dysfunction: a systematic overview of data from individual patients.
Lancet 355 (May 6, 2000) pages 1575-1581.
4. Mann J. The cost-effectiveness of clopidogrel in the prevention of
heart attacks and ischemic stroke: weighing
the evidence from the CAPRIE trial.
Available online at http://www.homestead.com/emguidemaps/files/de-clopidogrel.html
5. Mann J. Controversies in the interpretation of the CURE trial's
results.
Available online at http://www.homestead.com/emguidemaps/files/de-CUREtrial-Jeff.html
Competing interests: Time of visit--Number of ramipril-active patients taking an ACEI--Number of placebo patients taking an ACEI1 year -- 87.4% -- 3.4%2 year -- 85% -- 6.0%3 year -- 82.2% -- 8.1%4 year -- 75.1% -- 10.8%Final visit -- 78.9% -- 12.3%