Blocking the renin-angiotensin system – history and controversies

Abstract

Division of Nephrology, St Michael’s Hospital, University of Toronto, Toronto, Ontario Correspondence: Dr Phil McFarlane, Division of Nephrology, St Michael’s Hospital, University of Toronto, 61 Queen Street East, 9th Floor, Toronto, Ontario M5B 1W8. Telephone 416-867-3702, fax 416-867-3709, e-mail phil.mcfarlane@utoronto.ca Received for publication August 27, 2010. Accepted September 4, 2010 The renin angiotensin system (RAS) was identified more than 100 years ago, and agents to block its actions have been available for clinical use in Canada for approximately 30 years. The RAS was initially identified as a potent pressor; its ability to cause vasoconstriction, and salt and water retention can significantly raise blood pressure. However, as the constituents of this system were better characterized, it became clear that RAS activation may have effects beyond raising blood pressure. Due to differential distribution of the angiotensin II receptor within the intrarenal vasculature, RAS activation can raise intraglomerular pressure and preserve glomerular filtration at times of dehydration. In disease states, RAS activation contributes to end-organ damage through its effects as a growth factor and proinflammatory mediator. Early clinical trials in nephrology and cardiology suggested that RAS blockade could meaningfully reduce progressive organ damage and improve patient outcomes in people with high cardiorenal risk, and that these benefits extended beyond the ability of these drugs to lower blood pressure. As clinical trial experience accumulated, medications that block the RAS appeared in Canadian clinical practice guidelines. Currently, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are indicated as first-line agents for the treatment of individuals with uncomplicated hypertension, those with left ventricular hypertrophy, those with hypertension and diabetes who are free of chronic kidney disease, and in those who have diabetic or nondiabetic chronic kidney disease (1,2). People with diabetes and high cardiovascular risk should receive an ACEI or an ARB even if their blood pressure is within the normal range (3). ACEIs are recommended for the treatment of left ventricular systolic dysfunction, and ARBs are indicated to be added to an ACEI in those who are at higher risk of hospitalization due to heart failure (4). ARBs are indicated as first-line agents for isolated systolic hypertension (1). It is recommended that an ACEI or an ARB be combined with a beta-blocker in people with hypertension and recent myocardial infarction (1). A combination of an ACEI and a diuretic are recommended for those with hypertension and cerebrovascular disease (1). This array of indications is dizzying, and reflects the culmination of a tremendous amount of work performed by basic scientists and clinical trialists over decades. Not surprisingly, the use of ACEIs and ARBs in Canada has risen. Initially, they were generally used only by specialists in restricted, high-risk populations, but have gained in popularity to become some of the most heavily prescribed drugs in Canada, with ACEIs and ARBs having a combined prescription rate of approximately one in every 10 Canadians (5). Interest in the RAS continues to expand, and the arrival of direct renin inhibitors has led to new methods of blocking the RAS and has stimulated new clinical research. In the present supplement, we examine important issues relating to RAS blockade in Canada. Drs Nantel and Rene de Cotret review the history and evolution of RAS blockade, and highlight selected clinical trials that had a meaningful impact on clinical practice guideline development in Canada. Looking forward, Dr Burgess ventures into the highly controversial area of whether the positive results from clinical trials of RAS blockade can be extended to all agents of a given class, or whether they are specific to a particular molecule. Finally, Drs Ducharme and Schiffrin examine the evolving understanding of the role of RAS blockade in people with atrial fibrillation. RAS blockade will remain a central component of end-organ protection for Canadians at risk. Because research in this area remains very active, Canadian clinicians will await with interest further evolutions in this field. RAS BLOCKADE IN THE MANAGEMENT OF CARDIOVASCULAR DISEASE