ACE inhibitors, angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.

Keywords: :

• Aliskiren
• Angiotensin-converting enzyme
• Angiotensin receptor blockers
• Direct renin inhibitor
• Hypertension
• Renin–angiotensin–aldosterone system

Transparency

Declaration of funding

This analysis and the publication of this article were supported by Novartis Pharma AG, Basel, Switzerland. F.S. performed the initial literature searches. Both authors contributed to: the design and content of the review article; the development of an initial outline; comments on and modifications to additional drafts; approval of the final draft.

Declaration of financial/other relationships

R.D. has disclosed that he has been the recipient of honoraria for scientific presentations and participation in advisory board meetings from Novartis. F.S. has disclosed that she is an employee of Oxford PharmaGenesis™ Ltd, which has received project funding from Novartis Pharma AG, Basel, Switzerland.

All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 and Peer Reviewer 2 have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors would like to acknowledge the assistance of Dr Richard White (Oxford PharmaGenesis™ Ltd), who managed the incorporation and editing of comments to produce a final draft manuscript for submission.