Volume 1, Number 2, June 2000

The renin angiotensin system and cardiovascular disease: hope or hype?
Bryan Williams

The HOPE study has provided important new data with regard to cardiovascular protection for patients at high risk of cardiovascular disease. Its results demonstrate that ACE-inhibition and the associated blood pressure reduction are unequivocally beneficial in high risk patients and any strategy that imparts benefit in a high risk group, whatever the mechanism, should be deployed. Nevertheless, the pathophysiological basis for this benefit is not unimportant. If there is a benefit that is independent of blood pressure reduction, related to blockade of the RAAS or potentiation of bradykinin by ACE-inhibition, then this represents a key advance and should prompt further study into the pathophysiological basis of this effect in order that it may be optimised. It also raises important questions. For instance, what is the dose of ACE-inhibition required for maximal benefit? Is bradykinin important in this response? If so, would the benefit be reproduced by angiotensin II receptor antagonists?
In contrast, if the benefit observed in the HOPE study is largely related to systemic blood pressure reduction, it questions the validity of the concept of "normotension" in patients at high risk of cardiovascular disease. It would also pose the question as to whether blood pressure thresholds for intervention with drug therapy and targets on therapy should be lowered beyond current guidance for patients at high cardiovascular risk.
The HOPE study results were heralded by much hype in the lay press and have been followed by an almost evangelical embracing of the RAAS hypothesis. In today's clinical research environment this has become inevitable, but should not replace the need for objective appraisal of the data and their scientific and clinical implications. I strongly support the view that inappropriate activation of the RAAS and other neurohumoral mediators contributes to premature cardiovascular morbidity and mortality, and that blockade of the RAAS will most likely provide cardiovascular benefits beyond blood pressure reduction. However, when clinical studies, such as HOPE, are designed in which an RAAS blocking agent challenges placebo, some blood pressure reduction is inevitable. It may seem trivial but in high risk patients, over a long duration of study, its impact cannot be considered less relevant or less important than the non-haemodynamic actions of RAAS blockade. The mechanism of benefit of ramipril in the HOPE study is unresolved. Nevertheless, this important study has broadened the spectrum of cardiovascular diseases amenable to intervention by blockade of the RAAS. In so doing the hype may be justified in that it offers high risk patients improved hope of prolonged survival, whatever the mechanism. The clinical pragmatist might rightly conclude that is enough.

JRAAS 2000;1:142-146.

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