293severe bradycardia, particularly in patients with advanced CKD and if drugs like
atenolol and bisoprolol (which accumulate in CKD) are used. CCBs, particularly
non-dihydropyridines, also interfere with the metabolism and excretion of calcineu-
rin inhibitors (CNIs), as well as with the mammalian target of rapamycin (mTOR)
inhibitors. In patients taking such combinations, careful monitoring of CNIs and
mTOR inhibitor blood levels is required if drugs or dosages are changed [ 24 ].
Dual Blockade of the RAS
Although dual blockade of the RAS with ACEI + ARB or ACEI/ARB + direct
renin inhibitor (DRI) combinations may seem like a rational strategy for improv-
ing renal and cardiovascular outcomes, there is no conclusive evidence of the long-
term renal and cardiovascular benefit of such combinations in hypertensive CKD
patients [ 25 ].
In Ongoing Telmisartan Alone and in Combination With Ramipril Global
Endpoint Trial (ONTARGET) [ 40 ], investigators randomized patients ≥55 years of
age with cardiovascular disease or diabetes with end-organ damage to ramipril,
telmisartan, or the combination of both drugs. The primary outcome of interest was
the combined endpoint of dialysis, doubling of serum creatinine, or death. There
was no significant difference in this outcome between ramipril and telmisartan
alone, whereas combination therapy actually increased the risk. In addition, the
ONTARGET trial found no benefit of combination therapy over ramipril mono-
therapy in reducing the cardiovascular risk. The Veterans Affairs Nephropathy in
Diabetes (VA NEPHRON-D) trial [ 41 ] enrolled 1448 patients with diabetic
nephropathy, with or without hypertension. Subjects were randomized to losartan +
lisinopril versus losartan + placebo for prevention of a primary composite endpoint
of renal events or death. The trial was halted early because of lack of efficacy, as
well as because of increased risk of hyperkalemia and acute kidney injury in the
dual therapy group. Notably, BP was not different between groups.
The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial [ 42 ]
studied the DRI aliskiren in combination with the ARB losartan versus losartan
alone in 599 patients with type 2 diabetes and diabetic nephropathy. Combination
therapy reduced the urinary albumin/creatinine ratio by 20%, as compared with
losartan alone. There were only small differences in BP between the two groups and
no differences between the rates of adverse events. In contrast, the Aliskiren Trial in
Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE)
[ 43 ], involving the same combination of aliskiren + losartan in patients with diabe-
tes and CKD, has been terminated early due to an increased risk of adverse events
and no evidence of benefit in the dual therapy group. Consequently, the US Food
and Drug Administration (FDA) [ 44 ] and the ERBP guideline [ 35 ] have counseled
against the use of this combination.
18 Treatment of Hypertension in Light of the New Guidelines: Pharmacologic...