Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events: do the latest trials challenge existing evidence?

Table 2 Overview of large outcome trials investigating dual RAS inhibition

Study name or author	Study population	ACE inhibitor	ARB	DRI	Impact of combined therapy versus monotherapy
ONTARGET^®[33, 63]	Patients at high risk of CV events	Ramipril	Telmisartan		No improvement in CV outcomes; increased incidence of renal events due to acute renal failure caused by concomitant diseases (tumour, pneumonia, severe diabetes and others)
ALOFT [64]	HF	Standard therapy		Aliskiren	Addition of aliskiren to standard treatment reduced NT-proBNP. Combined therapy had no effect on UACR
ALLAY [65]	Hypertensive patient with LVH		Losartan	Aliskiren	No additional benefit over and above monotherapy
ALTITUDE [66]	T2DM patients	Standard therapy		Aliskiren	Increased incidence of AEs in the combination arm (including non-fatal stroke, renal dysfunction, hyperkalaemia and hypotension)
AVOID [12]	T2DM patients		Losartan	Aliskiren	Significantly reduced UACR versus losartan monotherapy
ASPIRE [67]	Patients following acute MI	Standard therapy		Aliskiren	Combined therapy did not further attenuate left-ventricular remodelling
ASTRONAUT [68]	Haemodynamically stable, hospitalizations for heart failure patients	Standard therapy		Aliskiren	No reduction in CV death or HF rehospitalization at 6 months or 12 months after discharge
VA NEPHRON-D [61, 69]	Patients with diabetes and overt proteinuria	Lisinopril	Losartan		Terminated early due to greater number of observed acute kidney injury events and hyperkalaemia in the combination group

ACE, angiotensin-converting enzyme; AE, adverse event; ARB, angiotensin II receptor blocker; ALLAY, ALiskiren Left ventricular Assessment of hypertrophY; ALOFT, ALiskiren Observation of heart Failure Treatment; ALTITUDE, ALiskiren Trial in Type 2 diabetes Using carDio-renal Endpoints; ASPIRE, Aliskiren Study in Post-MI Patients to Reduce rEmodeling; ASTRONAUT, The AliSkiren TRial ON Acute heart failure oUTcomes; AVOID, Aliskiren in the eValuation of prOteinuria in Diabetes; CV, cardiovascular; HF, heart failure; LVH, left ventricular hypertrophy; MI, myocardial infarction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; ONTARGET^®, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; RAS, renin-angiotensin system; T2DM, Type 2 diabetes mellitus; UACR, urine albumin-creatinine ratio; VA NEPHRON-D, Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy.
Standard therapy: ALOFT and ASPIRE–ACE inhibitor (or ARB) and β-blocker; ALTITUDE–ACE inhibitor or ARB; ASTRONAUT–included diuretics, ACE inhibitors or ARBs, β-blockers and aldosterone blocking agents, unless contraindicated.

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