Dual renin-angiotensin system blockade

Some 30 years ago, captopril became the first angiotensin converting enzyme (ACE) inhibitor available for clinical use. Since then, several other ACE inhibitors have been introduced, as well as drugs from the angiotensin II type 1 receptor blocker (ARB) family. More recently, an orally active renin inhibitor, aliskiren, has become available. It is now possible to block renin itself, to inhibit the conversion of angiotensin I into angiotensin II, and to block the main target receptors of angiotensin II in a single patient. In the linked systematic review and meta-analysis of randomised controlled trials (doi:10.1136/bmj.e42), Harel and colleagues examined the safety of dual blockade of the renin-angiotensin system using the renin inhibitor aliskiren and an ACE inhibitor or ARB.1

Many investigators have evaluated whether delivering a combination of drugs that interfere with specific functions of the renin-angiotensin system would be more effective at reducing blood pressure or protecting target organs (or both) than giving one drug only. Both dual and triple renin-angiotensin blockade have been investigated. Most trials did not consider the potential pathophysiological consequences of blocking the system at multiple levels. A meta-analysis that compared combinations of an ACE inhibitor and ARB with single drug treatment—mainly in patients with diabetes or kidney disease—showed that, among other positive findings, patients on dual treatment had a greater reduction in proteinuria than those taking a single drug.2 However, the authors cautioned that most of the included studies were small, varied in quality, and did not provide reliable data on adverse drug reactions.2 At the same time concerns about the safety of combination treatment with an ACE inhibitor and an ARB, particularly in patients with left ventricular dysfunction, emerged from another meta-analysis.3 Hypotension, worsening kidney function, and an increase in serum potassium were the most worrying adverse events. Two large randomised trials evaluating dual treatment in high risk patients reported similar adverse findings.4 5 The combination of an ACE inhibitor and an ARB seems to affect potassium values more than it affects overall renal function, which suggests that raised serum potassium is only marginally related to a reduction in glomerular filtration rate, if at all. ACE inhibitors and ARBs have opposite effects on angiotensin II concentrations, and a reduction in glomerular filtration rate in response to one of the agents may be partially offset by the other. Both drugs, however, lower plasma aldosterone, and the combination of a fall in plasma angiotensin II together with adrenal angiotensin receptor blockade could possibly induce a state of relative hypoaldosteronism, leading to a rise in plasma potassium.

Less is known about safety when the new renin inhibitor aliskiren is combined with an ACE inhibitor or an ARB, which is why Harel and colleagues analysed the risk of acute kidney injury and hyperkalaemia when various blockers of the renin-angiotensin system are combined. One message that emerged from their analysis of a large number of studies is that the risk of renal impairment associated with dual treatment with aliskiren and an ACE inhibitor or ARB is smaller than many clinicians might believe. However, their definition of acute kidney injury was fairly liberal, with a cut-off value that many nephrologists would consider too high, and it did not take into account baseline creatinine. Moreover, it is not certain that reported cases of renal impairment were truly related to kidney damage because a rise in creatinine can sometimes be explained entirely by intrarenal haemodynamic factors.

An important message from the current study is that use of a combination of aliskiren and an ACE inhibitor or ARB increases the risk of hyperkalaemia. This adverse effect could again be explained by suppression of endogenous aldosterone. The patient’s clinical background is important, but the current study did not show a clear association between the risk of hyperkalaemia and the patient’s clinical state. Although the authors tried to differentiate between low risk and high risk patients when estimating the risk of hyperkalaemia, they were not able to show a significant difference between the two groups for this outcome. It is therefore not clear whether or not clinicians should exercise caution in prescribing dual treatment in the subgroup of patients with hypertension but no other risk factors for hyperkalaemia. Another drawback is that ACE inhibitors and ARBs were considered together as a single class. The authors understandably wished to simplify the analysis of data, but unfortunately this reduces the usefulness of the study’s findings from a pharmacological perspective. The two drug classes have divergent effects on angiotensin II concentrations and receptor occupancy, and their effects may also differ when combined with aliskiren. Finally, it is not clear whether the patients who were included in the various studies were representative of the general population of patients with hypertension. Indeed, there was a preponderance of men and younger people in the included trials. The risk estimates from the current meta-analysis may not accurately reflect risk in “real life”—the risk of developing severe hyperkalaemia may be greater still.

It is noteworthy that the ALTITUDE trial, which was designed to explore whether dual blockade with aliskiren combined with an ACE inhibitor or ARB would reduce morbidity and mortality in a broad range of high risk patients with type 2 diabetes,6 was stopped prematurely in December 2011. The trial’s data safety monitoring board advised against continuing the study because “the active treatment group experienced an increased incidence of non-fatal stroke, renal complications, hyperkalaemia, and hypotension over 18 to 24 months of follow-up.” The committee concluded that patients were unlikely to benefit from aliskiren on top of standard antihypertensive treatment.7

Given these concerns, clinicians should avoid using a combination of renin-angiotensin system blockers in high risk patients and be extremely cautious when using combination treatment in low risk patients. Another lesson may be that sound pathophysiological data rather than logical reasoning should guide the design of large and costly trials. Future work should concentrate on how different renin-angiotensin system blockers interact and in which types of patients the combination can be used safely.