Inhibition of the renin-angiotensin system (RAS) by administration of either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) or a direct renin inhibitor (DRI) similarly reduces blood pressure (BP), when each is used as monotherapy in patients with hypertension [1, 2]. Both ACE inhibitors and ARBs also slow down the progressive decline in renal function, which marks renal injury, particularly in patients with diabetic nephropathy [3–5] with the renoprotective effects of these drugs, in part, relating to their capacity to reduce protein excretion [6]. Both ACE inhibitor and ARB therapy also decrease the high cardiovascular (CV) event rate common to high-risk cardiac patients [7–10]. Moreover, ACE inhibitors and ARBs are both of proven benefit in forms of heart failure (HF) characterized by a reduced ejection fraction (EF) [11, 12].

The pharmacologic actions of ACE inhibitors and ARBs and/or a DRI have been well characterized. BP reduction and/or tissue-based protection, achieved through interruption of the RAS , relates specifically to the distinctive pharmacodynamic properties of either an ACE inhibitor , a DRI, or an ARB [13, 14]. Factors that have some bearing on the final response to these drug classes include drug pharmacokinetic and pharmacodynamic half-life, the phenomenon of “angiotensin-II”, or “aldosterone escape” and/or interruption of the short feedback loop, which increases upstream components of the RAS—so-called reactive hyperreninemia [14, 15].

At the outset of therapy with an ACE inhibitor, both circulating and tissue concentrations of angiotensin-II (ang-II) drop. This fall in ang-II concentrations is to be expected given that ACE inhibition per se dose dependently lessens the enzymatic conversion of angiotensin-I (ang-I) to ang-II. Alternatively, with more long-term ACE inhibitor use, there is a gradual return of circulating and tissue ang-II concentrations to pretreatment levels, a process termed “angiotensin-II escape” [16]. One suggested explanation for ang-II escape focuses on the ability of tissue-based enzymes, such as chymase, cathepsin G, and CAGE (chymostatin-sensitive angiotensin-generating enzyme), to alternatively generate ang-II from a number of peptide substrates [17].

Since an ARB works by blocking the AT₁-receptor, it was initially presumed that this mechanism of action, in addition to possibly AT₂-receptor stimulation, would be additive to an ACE inhibitor effect by lessening the opposing BP effects that could in theory result from “angiotensin II escape.” The relevance of ang-II escape however remains unclear. In the treatment of hypertension and HF, there is scant evidence to support a role for ang-II escape in disabling the response to an ACE inhibitor [18]. If ang-II escape with ACE inhibitor use is ever to be clinically relevant, it will be on the basis of “suboptimal tissue protection,” a process that is not readily quantified. DRIs were originally held to offer incremental benefit for BP reduction in addition to what might be seen with an ACE inhibitor or an ARB, as they provide a more complete blockade of the RAS . It was posited that a DRI would suppress residual ang-II production and the counter-regulatory increase in plasma renin activity (PRA) observed in patients receiving ACE inhibitor and ARB monotherapy, and/or by blocking “aldosterone escape” that is seen with an ACE inhibitor or an ARB [19] .

ARAs can further reduce BP when given together with an ACE inhibitor, ARB, or a DRI . Fundamentally, nullifying the effect of aldosterone effect on BP with an ARA would be expected to further reduce BP beyond what would be seen with any of these classes given alone or together. Such BP reduction relates to an ARA effect on aldosterone/volume, which would not be mechanistically redundant as is the case when an ACE inhibitor is added to an ARB or a DRI [20–22].

The basis for combining an ACE inhibitor with an ARB or a DRI is to achieve a therapeutic outcome better than that seen with either drug given as monotherapy. Giving two RAS inhibitors together is not merely “giving two drugs” in that there are various pharmacologic considerations that influence the interpretation of the observed response. To accurately interpret the response to the combination of an ACE inhibitor and an ARB and/or a DRI requires that consideration be given to the pharmacologic profile of individual class members, time-of-day of dosing of each compound, the sequence with which the ARB or ACE inhibitor is added, and continuing dual therapy for a long-enough period of time to ensure that a long-term response has been identified [23].

There are more than 20 ACE inhibitors and ARBs, and one DRI marketed worldwide. There was one fixed dose combination of a DRI/ARB (aliskiren/valsartan [Valturna®]); however, it is off the market since 2012. Drugs within each of these classes have divergent durations of action; thus, the combination of the short-acting ACE inhibitor, captopril, with the long-acting ARB, candesartan, can produce a greater end-of-day response than if captopril were to be given with the more short-acting ARB, losartan. This can be mistakenly viewed as an additive response when it may simply reflect a more extended effect from the longer half-life compound. This is particularly the case with the long-acting compound, aliskiren [24]. When an ACE inhibitor and ARB are both long acting, meaningful additivity in BP reduction does not occur [25]. The timing of drug administration should also be accounted for in assessing a response to combination therapy in that, giving an ACE inhibitor and an ARB separated by several hours may conceivably prove more effective than if both medications were given simultaneously. Finally, the sequence in which these medications are given, such as whether an ACE inhibitor or an ARB is first given and when the alternative drug is added, may influence the final BP reduction and/or an end-organ effect such as a drop in urinary protein excretion [26].

The concept of dual blockade of the RAS being inherently better than a single agent-modifying activity in this class seemed quite logical with the early experimental evidence from Menard et al. and therein rapidly emerged as a therapeutically attractive option [27]. Much of the early enthusiasm for dual blockade of the RAS system, however, derived from beneficial changes in surrogate end points such as BP, proteinuria, and/or endothelial dysfunction; however, a not insignificant amount of this unbridled excitement about combined RAS inhibition proved to be unjustified as the results from various trials became available with studies such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), and the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) [28–30].

ONTARGET was a double-blind, randomized, parallel-group study involving 25,620 patients in 40 countries. Patients were 55 years of age or older with either a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes with end-organ damage. Subjects were randomized to telmisartan 80 mg/day, ramipril 10 mg/day, or telmisartan 80 mg/day plus ramipril 10 mg/day. The primary end points were CV mortality, nonfatal stroke, acute myocardial infarction (MI), and HF hospitalization. The secondary end points were newly diagnosed HF, diabetes mellitus, or atrial fibrillation; revascularization procedures, development of dementia/cognitive decline, and nephropathy. Study results showed that mean BP was lower in the telmisartan (0.9/0.6 mmHg greater reduction) and the combination therapy groups (2.4/1.4 mmHg greater reduction) than in the ramipril group. At study’s end, the primary end point had occurred in a similar number of patients in all three patient groups. Patients receiving combination treatment had higher rates of hypotensive symptoms, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of progressing to a need for dialysis. At its conclusion, ONTARGET provided the largest evidence base available to determine, if the combination of an ACE inhibitor/ARB could reduce CV disease-related events and mortality in high-risk patients, including those with diabetes [28].

In the ALTITUDE study, the utility of the renin inhibitor, aliskiren, was tested in 8561 high-risk type 2 diabetic patients, the majority of whom had albuminuria, who were adjunctively given aliskiren 300 mg/day or placebo in addition to treatment with an ACE inhibitor or an ARB. A composite CV and renal end point was selected. The trial was discontinued prematurely after 18.3 % of the aliskiren group had reached the primary end point compared to 17.1 % in the placebo group. About 41 % of patients had a baseline systolic BP > 140 mmHg, and 12 % had a diastolic BP > 85 mmHg. Oddly, BP actually increased about 3 mmHg in both groups, although this increase was less in the group given aliskiren. Glomerular filtration rate (GFR) decreased 5 ml/min over the 42 months of observation in both groups. Potassium increased in both groups but more so in the aliskiren group. Hyperkalemia (> 5.5 mmol/l) was both the most common adverse event reported by investigators and the lead cause of study drug discontinuation. The Data and Safety Monitoring Board terminated this study early citing issues of therapeutic futility as well as an increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension over the 18–24 months of follow-up [29].

The VA NEPHRON-D trial studied the effect on CKD progression of 100 mg of the ARB losartan with or without the ACE inhibitor lisinopril (10–40 mg/day) in 1448 mainly male veteran patients with type 2 diabetes and overt nephropathy (GFR 54 mL/min). The primary end point was a composite of a 50 % decline in eGFR, end-stage renal disease (ESRD) requiring dialysis, or death. Safety end points included mortality, hyperkalemia (serum potassium > 6.0 mmol/L or that required an Emergency Department visit, hospitalization, or dialysis), and acute kidney injury adverse events, which were episodes occurring during or requiring hospitalization. BP values were similar in the two groups at enrollment, during adjustment of the losartan dose, and at randomization. The combination group had slightly lower BP readings on treatment by 2 mmHg. A total of 152 primary end point events occurred in the monotherapy group and 132 in the combination therapy group, a nonsignificant difference (hazard ratio (HR) with combination therapy, 0.88; 95 % confidence interval [CI], 0.70–1.12; P = 0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (HR, 0.78; 95 % CI, 0.58–1.05; P = 0.10) decreased with time (P = 0.02 for nonproportionality). There was no benefit with respect to mortality (HR for death, 1.04; 95 % CI, 0.73–1.49; P = 0.75) or CVR events. Total mortality or CV end points were not different between treatments. This study was prematurely terminated for safety concerns. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P < 0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P < 0.001) [30].

There have been several areas where dual RAS inhibition has been considered as a suitable treatment option including difficult to manage hypertension, use in patients with high risk of vascular disease, post-MI, reduced EF forms of HF, and proteinuric forms of CKD. The use of dual RAS inhibitor therapy for resistant hypertension has not been studied in any sort of systematic manner and, as such, when used in this manner it has been empiric making it difficult to interpret observed responses [33]. There are currently no guidelines/treatment algorithms that support the use of dual RAS inhibitor therapy in the patient with resistant hypertension. Of note, as an example of the limited amount of information on this topic, patients with BP > 160/100 mmHg at entry were excluded from ONTARGET, thus limiting the applicability of these results to the treatment of significant hypertension [28].

Ramipril and telmisartan given together in ONTARGET did not afford a mortality or CVR benefit over and above ramipril therapy and, as such, did not provide any supporting data for the use of dual RAS inhibition in patients at high risk for vascular disease [28]. In addition, in the Valsartan in Acute Myocardial Infarction (VALIANT) trial, the combination of captopril and valsartan, together and individually given, was studied in a cohort within 10 days of acute MI. No additional survival benefits were seen with combination therapy, and the dual therapy group clearly experienced the greatest number of side effects [34].