Angiotensin receptor blockers and myocardial infarction

Sir,

The editorial by Verma and Strauss(1) on the VALUE trial highlights
an important emerging area of clinical practice(2). The authors raise
several important points, namely the increased incidence of myocardial
infarction and stroke in this study, and the non-superiority of
angiotensin receptor blockers over ACE inhibitors in other trials. However
we believe that several key points merit further discussion.

The VALUE trial design focused primarily on the vasculoprotective
effect of both drugs through their antihypertensive properties. The
editorial points out that there was an increased incidence of myocardial
infarction and stroke in the group taking valsartan, however the
respective antihypertensive effects of the doses of each drug used were
clearly in favour of amlodipine(3). Meta-analysis based arguments have
questioned whether the observed small difference in blood pressure with
amlodipine could account for the difference in the observed rate of
myocardial infarction(4). These arguments, however, were based on the mean
difference in blood pressure over the whole trial and fail to take into
account the fact that the difference in BP favouring amlodipine was much
greater in the first 3 – 6 months following randomisation. This period
coincided with the period of excess risk for myocardial infarction in the
group assigned to valsartan thus we believe that an explanation for this
excess risk based on blood pressure differences cannot yet be discounted.

Two studies ELITE II(5) (utilising losartan) and VALIANT(6)
(utilising valsartan and the largest angiotensin receptor 2 blocker trial
yet reported) have demonstrated that angiotensin receptor blockers were
equivalent to the ACE inhibitor captopril in patients with heart failure
or myocardial infarction in terms of progression of heart failure and
also, importantly, in recurrent myocardial infarction. In addition the
superior tolerability of angiotensin receptor blockers in heart failure,
an effect which has significant implications in everyday clinical
practice, has been demonstrated repeatedly in these and other clinical
trials, most notably in the CHARM-Alternative programme a study which the
authors quote themsleves(7).

While we would therefore argue that an effect of angiotensin 2
receptor blockers in promoting myocardial infarction independent of
effects on blood pressure remains to be established, it should be
acknowledged that there is a plausible biological basis for such an
effect. ACE inhibition may modulate some of its beneficial effects through
raised levels of bradykinin: an effect which is absent with angiotensin 2
receptor blockers(8,9). In addition recent work in murine models suggests
that the unopposed stimulation of ATII receptors caused by angiotensin
receptor blockers may in fact have a pro-inflammatory effect and induce
inappropriate apoptosis in cardiac myocytes.

Based on the above arguments, we would suggest that ACE inhibitors
should still be the drugs of choice in blockade of the renin-angiotensin
system. Nonetheless, it is important to recognise that many of the
concerns regarding the angiotensin 2 receptor blockers arise from post-hoc
sub-group analysis of trials which overall have demonstrated beneficial
clinical effects of this class of drugs together with excellent
tolerability.

Yours faithfully

A Arumainathan
Senior House Officer

B Patel
SpR in Cardiology

WJC Hobbs
Consultant Cardiologist

M Fisher
Consultant Cardiologist

University Department of Cardiology,
Link 7Z,
Royal Liverpool University Hospital,
Prescott Street,
Liverpool
L7 8XP

References:

1. Verma S, Strauss M. Angiotensin receptor blocker and myocardial
infarction. BMJ 2004; 329: 1248-49

2. Julius S, Kjedlsen, Weber M et al. Outcomes in hypertensive
patients at high cardiovascular risk treated with regimes based on
valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363:
2022-31

3. Eguchi K, Kario K, Hosihide Y. Comparison of valsartan and
amlodipine on ambulatory and morning BP in hypertensive patients. American
Journal of Hypertension 2004; 17:112-227

4. Staessen JA, Thijs L, Birkenhäger WH. Value: Analysis of Results.
Lancet 2004; 364: 931

5. Pitt B, Poole-Wilson PA, Segal R. Effect of losartan compared with
captopril on mortality in patients with symptomatic heart failure- the
Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-87

6. Pfeffer MA, McMurray JJV, Velazquez EJ et al. Valsartan,
captopril, or both in myocardial infarction complicated by heart failure,
left ventricular dysfunction, or both. New England Journal of Medicine
2003; 349: 1893-1904

7. Granger CB, McMurray JJV, Yusuf S et al. Effects of candesartan in
patients with chronic heart failure and reduced left ventricular systolic
function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM
-alternative trial. Lancet 2003; 362: 772-6

8. Weber MA. The angiotensin II receptor blockers: opportunities
across the spectrum of cardiovascular disease. Reviews in Cardiovascular
Medicine 2002; 3: 183-91

9. Levy BI. Can angiotensin II type 2 receptors have deleterious
effects in cardiovascular disease? Implications for therapeutic blockade
of the renin-angiotensin system. Circulation 2004; 109: 8-13

Competing interests:
None declared