Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7274.1440 (Published 09 December 2000) Cite this as: BMJ 2000;321:1440
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Before making clinical decisions based on the results of
this article it's important to not focus exclusively on
disease oriented evidence (DOE), but to instead interpret
the results in the context of the patient-oriented evidence
that matters (POEMs) (1). The authors of this study have
nicely shown that the combination of two types of
renin-angiotensin inhibitors decreases both microalbuminuria
and hypertension better than either agent alone. However,
neither the two agents given concomitantly nor either agent
separately has been clearly shown to be superior to
conventional and much cheaper agents (diuretics,
beta-blockers) in decreasing either disease related or all
cause related morbidity and/or mortality for type 2
diabetics with hypertension. In fact, the UKPDS trial found
no difference between ACE inhibition and beta-blockers in
treatment of hypertension in Type 2 diabetes (2).
It is crucial that the distinction between DOEs and POEMs be
considered, since clinicians are not at all being detailed
by pharmaceutical representatives to use cheap (generic) and
useful medication, but instead the more expensive
medications. This is even more important in the US where we
don't yet offer basic medical coverage and each year, as the
cost of delivering health care rises mainly due to the
rising costs of pharmaceuticals, more patients forego
medical coverage (rationing people instead of rationing
health services) (3).
References:
1. Slawson DC, Shaughnessy AF, Bennett JH. Becoming a
medical information master: Feeling good about not knowing
everything. J Fam Pract 1994;38:505-13.
2. UKPDS 39. BMJ 1998;317:713-20.
3. Slawson DC, Shaughnessy AF. 2001 Becoming an Information
Master: Using "medical poetry" to remove the inequities in
health care delivery. J Fam Pract 50:51-6.
Competing interests: No competing interests
The role of Angiotensin converting enzyme inhibitors in the prevention of diabetic nephropathy in...
EDITOR - Mogensen et al in their study (1) suggest dual blockade of
the renin-angiotensin system by Angiotensin converting enzyme inhibitors
and angiotensin receptor blockers is more effective in reducing blood
pressure and, to some extent, albuminuria in Type 2 diabetic patients with
hypertension and microalbuminuria.
Blockade of the renin-angiotensin system by Angiotensin converting enzyme
inhibitors (ACE-I) shown to prevent diabetic microvascular complications,
especially nephropathy in many studies. Most of the studies were done
with European patients with few in Japanese, Chinese and Indian patients.
No study done on black populations.
Further studies should be conducted on black diabetic patients and
compare their response to ACE-I for many reasons:
Firstly, diabetic renal disease behaves differently in different
ethnic groups (2).
Secondly, When Angiotensin converting enzyme inhibitors are used as
an antihypertensive there is a big ethnic difference in response to it.
Patients of Afro-Caribbean origin show diminished response to ACE-I as an
antihypertensive compared to whites (3).
Thirdly, to optimise the use of ACE-I and to individualize it, the
enthusiasm for the use of ACE-I as nephroprotective agents should not
overshadow the potential of these agents to promote an acute deterioration
in renal function, especially in patients with occult renovascular
disease.
Alia El-Kadiki MClin Sci student.
University of Leicester,
University Road
Leicester, LE1 7RH
1. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW,
Cooper ME. Randomised controlled trial of dual blockade of renin-
angiotensin system in patients with hypertension, microalbuminuria, and
non-insulin dependent diabetes: the Candesartan and Lisinopril
microalbuminuria (CALM) study. BMJ 2000,321:1440-4. (9 December.).
2. Cowie CC. Diabetic renal disease: racial and ethnic differences
from an epidemiological perspective. Transplant Proc. 1993,25:2426-30.
3. Gibbs CR, Beevers DG, Lip GY. The management of hypertensive
disease in black patients. QJM. 1999,92:187-92.
Competing interests: No competing interests
Mogensen et al interpret their results as demonstrating that the
combination of lisinopril plus candesartan was more effective than either
agent alone at lowering blood pressure and reducing the urinary
albumin:creatinine ratio over 24 weeks in patients with type 2 diabetes.
They state “our results …support this new and potentially highly
beneficial therapeutic approach [combination therapy] for the prevention
of diabetic renal and vascular disease”. Their interpretation of the
renoprotective effect of the combination and its superiority in lowering
blood pressure do not appear to be supported by the results and
methodological issues limit its interpretation. In particular:
1) The authors state in the abstract that “the reduction in urinary
albumin:creatinine ratio with combination treatment was greater than with
either candesartan or lisinopril”. However, in table 4, the authors report
that the the difference in the urinary albumin:creatinine ratio between
lisinopril and the combination was not significant (p>0.20). In other
words, they did not show that the combination was more effective than
lisinopril alone. The p value for the difference between candesartan and
the combination was 0.04. As numerous statistical tests were done, and no
correction for multiple testing was applied, we question whether a p value
of 0.04 is significant.
2) The authors report that the combination produced increases in
creatinine and urea and a decrease in creatinine clearance at 24 weeks.
These changes at best should be going in the opposite direction, or at
least be no different if the combination is touted as being more
renoprotective.
3) From a methodological perspective, first, patients received
combination therapy only from week 12-24. Inexplicably, the authors
compared the effects of the combined therapy (at 24 weeks) to baseline
data (week 0). Second, 53 patients (27%) enrolled in the trial were
excluded from these comparisons because their diastolic pressures had been
reduced to <80mm Hg at week 12 on single therapy. In essence, the
authors compared the combination (including carry-over effects from 12
weeks of single therapy) to patients who had the least response to single
therapy. This is a biased comparison, and the authors should have compared
single and combination therapy from 12 to 24 weeks, not from baseline.
Presumably, the 53 patients were excluded because it was deemed unsafe or
unnecessary to further reduce their blood pressures. It would therefore
be of concern if clinicians concluded from this study that it is
beneficial to use the combination at the outset of therapy.
Competing interests: No competing interests
Statistical flaws?
In appraising the article, the following 2 questions came to mind:
1) The authors stated that they needed 220 patients to provide
sufficient power to the study. But they only evaluated 197 patients in the
end. Does this invalidate or weaken the statistical analysis?
2) What was the purpose of using the log scale in calculating the
urinary albumin excretion and the use of geometric means in determining
the urinary albumin:creatinine ratio of the treatment groups (tables 1 and
3)? Without the log scale, would not the change in urinary albumin
excretion be significant enough?
Competing interests: No competing interests