(Circulation. 2000;102:e43.)
© 2000 American Heart Association, Inc.
Correspondence |
Effects of Acute Angiotensin II Type 1 Receptor Antagonism and Angiotensin Converting Enzyme Inhibition on Plasma Fibrinolytic Parameters in Patients With Heart Failure
Department of Medicine and Pharmacology, Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee
To the Editor:
We read with interest the study by Goodfield et al1
comparing the effects of the acute administration of a single
dose of enalapril or losartan on fibrinolytic
parameters. We would like to raise several concerns about
the design of this study that we believe should temper the authors’
interpretation of their results. First, a well-described diurnal
variation exists in plasminogen activator
inhibitor-1 (PAI-1) antigen and activity. In this study,
subjects received oral doses of enalapril and losartan at 10:00
AM; blood samples were drawn before drug administration and
at 4:00 PM. However, in carefully controlled studies, we
have shown that in subjects with an activated
renin-angiotensin system (RAS), plasma PAI-1 antigen levels
fall spontaneously by 
50% over that same time period.2
Although the decrease in PAI-1 after losartan was greater than
that measured after enalapril, it is possible that neither reduction
was different from that which would have been measured during placebo.
Second, the authors studied patients with congestive heart failure who
were taking other medications that could affect the RAS. Without data
on renin or aldosterone concentrations during each study
day, it is impossible to exclude the possibility that the degree of
stimulation of the RAS differed on the 2 study days. Third, because
blood was sampled at only one time point after drug administration, the
authors cannot exclude the possibility that they measured a
pharmacokinetic rather than a pharmacodynamic effect. Finally, the
relatively low affinity of enalapril for tissue
angiotensin-converting enzyme may explain the apparent
reduced potency of this drug in reducing PAI-1. However, the more
likely explanation is that neither drug had any real effect on plasma
fibrinolytic balance, with the reported results merely reflecting
predicted diurnal changes and the effects of confounding
variables.
References
1.
Goodfield NER, Newby DE, Ludlam CA, et
al. Effects of acute angiotensin II type 1
receptor antagonism and angiotensin converting enzyme
inhibition on plasma fibrinolytic parameters in patients
with heart failure. Circulation. 1999;99:2983–2985.
2.
Brown NJ, Agirbasli M, Kerins DM, et al. Effect of
activation and inhibition of the renin-angiotensin system
on plasma PAI-1. Hypertension.. 1998;32:965–971.
Response
Prof Christopher A. Ludlam, University of Edinburgh Royal Infirmary, Lauriston Place, Edinburgh, Scotland
We are grateful to Drs Vaughan and Brown for their comments and are pleased that they found our article of interest. They raise 4 relevant issues relating to our preliminary findings.
The diurnal variation of plasma tissue plasminogen activator and plasminogen activator inhibitor type 1 concentrations is important, well described, and considered in the discussion of our article. However, the comparison between enalapril and losartan is valid, and the crossover design enhances the power of such a comparison. Given the close proximity of the study days (48 hours) and the clinical stability of the patients enrolled, it is unlikely that there was a significant difference in the activation of the renin-angiotensin system between the losartan and enalapril phases of the study. A time order effect was not observed, and the order of enalapril and losartan was randomized. However, we are currently in the process of determining the baseline plasma renin activity, angiotensin II concentration, and aldosterone concentration on the 2 study days.
We do not believe that the observed differences between enalapril and losartan are due to a pharmacokinetic effect because, as we stated in the Methods section of our article, the 6-hour sampling time point was chosen to coincide with the peak plasma concentrations of the active metabolites, enalaprilat, and E3174. The interpretation that our findings reflect the relatively low affinity of enalapril for tissue angiotensin converting enzyme is an interesting hypothesis, and comparisons with more tissue-specific angiotensin-converting enzyme inhibitors, such as quinapril, would be of value.
Finally, in keeping with our submission as a Brief Rapid Communication, our article indicates "the need for further validation of the observations, elaboration of associated findings, and additional experimental trials." Many issues remain unresolved, such as the effects of chronic dosing, the influence on diurnal variation, drug or class action, etc. However, we believe our preliminary findings suggest that, in patients with heart failure, a significant difference may exist in the effects of angiotensin-converting enzyme inhibitor therapy and angiotensin-1 receptor antagonism on plasma fibrinolytic parameters.
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