Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients
In this controlled clinical trial of an ACE inhibitor, ramipril, in patients with significant risk factors for cardiovascular disease, but mostly without left ventricular dysfunction, the drug reduced a broad array of cardiovascular outcomes and overall mortality by about 20%. This represents a significant benefit, and also represents a fairly large expansion of the population known to benefit from ACEI therapy.
Does this study really apply to patients with cardiovascular risk factors and normal left ventricular function? Perhaps, but the entry criteria of EF > 40% is not exactly a normal ejection fraction (50% or 55% would be normal). Although the authors state that their results were valid in patients whose EF was in fact greater than 40%, they do not give any data on subgroups with truly normal ejection fractions and they do not indicate what the mean baseline ejection fraction was in those patients in whom it was measured. Some of the benefit that was found may have been due to a beneficial effect in patients with mildly impaired left ventricular function.
The authors imply in the results and in the discussion section of the article that their results also applied to patients with diabetes but without overt cardiovascular disease, whereas their figure 2 demonstrates that the benefit in this subgroup did not reach statistical significance. A more honest and direct statement of the results in this subgroup would have been appropriate.
Do the results demonstrated here apply to other ACE inhibitors, or even to angiotensin receptor blockers? The authors refrain from speculating on this issue, but in an accompanying editorial Dr. Gary Francis of the Cleveland Clinic suggests caution when extrapolating to other drugs, and mentions ramipril's "well-known heightened ACE-inhibitory activity in tissue" (I must confess that tissue-ACE inhibition is not so well-known to me). Pharmacologically how far to extrapolate the results of any trial is a question that comes up frequently. All else being equal, it is nice to use the specific agent that has been tested, but all else is seldom equal. There are variations in price, availability and similarity of patients to the study population. How far to extrapolate ends up being a judgement call, to be made by the prescriber.
February 12, 2000
ReferencesReferences related to this article from the NLM's PubMed database.
From: samim celebi chalab [firstname.lastname@example.org]
They did not discuss the problem of high drop out of patients because of side effects
(the major one is cough) and the problems of benefits vs problems of prolonged use to get these
benefits. Also, what about the effect of vit E ?
June 29, 2000
[The following letter (minimally shortened here) was sent to me in February by Dr. Salim Yusuf, corresponding author of this paper. I have not been updating this website for the past few months, because of time constraints and other activities, thus the delay in posting it. -- mj]
Dear Dr. Jacobson,
Because of space restrictions we could not provide too many subgroup analyses or discuss further details at greater length in the New England Journal paper. You would perhaps be reassured that the mean ejection fraction in the people that we measured was .55 and there was benefit in this subgroup. This will be the basis of a further paper.
I have some reservations about the third paragraph and it perhaps shows some naivete. We have shown the data fully, regarding the subgroup of those with diabetes but without overt cardiovascular disease in figure 2 and it's transparent to the world what the results are. This was a subgroup that was relatively small and had lower event rates. Not surprisingly, although the relative risk reduction was identical to that of the rest of the patients in the trial, it did not reach statistical significance. No trial is designed to show statistical significance in every subgroup examined.
Salim Yusuf, Dphil, FRCPC
August 22, 2000
1. During the last year four important trials have been published regarding pharmacological treatment of cardiovascular disease, three of them dealing with heart failure (bisoprolol, metoprolol, spironolactone). However, the basis for a change in practice must rely on the robustness of the recommendation. The external validity depends on the representativity of included patients. In Evidence-Based-Medicine it is important to translate findings of controlled trials into practice to answer the question if the result is relevant to an individual patient. As was pointed out in a commentary on the MERIT-HF trial, neither of the bisoprolol and metoprolol trials were properly reported according to the CONSORT guidelines for reports of randomised controlled trials. This was not implemented in the presentation of the RALES study and not in the presentation of the HOPE study. How were patients basically recruited and which patients did not take part?
2. In the HOPE study the incidence of the primary outcome and of deaths from any cause were given in Table 3 with estimates of relative risk and 95 % CI. For practical purposes, the table could also have contained information on NNT and corresponding CI. Exploring this opportunity, data could be presented as follows.
n.a. = not applicable
We suggest that it would add to the understanding of the outcome of the trial if these figures (with their CI) had been presented in the original paper.
3. Major studies on ACE-inhibitors stress the importance of using target doses of the drugs as some studies have shown a better result of higher doses than of lower doses. In the HOPE study ramipril was also tested at two dose levels, 2.5 mg and 10 mg. For the composite outcome no difference was found between the groups, comprising only 488 patients. This result could of course be due to a large type II error. In fact, the calculated power (post hoc) seem to be only 4 %. What is the dose-response relation of ramipril regarding end points such as those in HOPE?
Hans Liedholm, MD PhD, Agneta Björck Linné, B Pharm
Juan Merlo, MD PhD
Malmö University Hospital
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