Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

Abstract

European and United States regulatory agencies recently issued warnings against the use of dual renin–angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

The current regulatory environment

The renin–angiotensin system (RAS) has been a key therapeutic target in kidney and cardiovascular disease since the early nineties. Evidence of an escape from RAS inhibition and small clinical studies suggesting additive antiproteinuric effects of combining angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs, sartans) led to the proposal that concomitant use of both agents (dual RAS blockade) might improve patient outcomes. However, recent randomized clinical trials (RCTs) have emphasized the risks associated with dual RAS blockade. On 23 May 2014 the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) endorsed restrictions on combining ARBs, ACEIs and direct renin inhibitors such as aliskiren. The CHMP confirmed recommendations made by the Agency’s Pharmacovigilance Risk Assessment Committee in April 2014. This review supported the conclusions of a previous European Medicines Agency review relating specifically to aliskiren (http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/02/WC500122913.pdf). The CHMP opinion was forwarded to the European Commission, which issued final decisions valid throughout the EU in September 2014 (Box 1) (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Renin-angiotensin_system_(RAS)acting_agents/European_Commission_final_decision/WC500175069.pdf).

Box 1.

Summary of European Commission final decisions on dual RAS blockade, September 2014.

• Dual RAS blockade therapy through the combined use of ACEI, ARBs or aliskiren is not recommended in any patient

•  ACEI and ARBs should not be used concomitantly in patients with diabetic nephropathy

•  The use of aliskiren with either an ARB or an ACEI is contraindicated in patients with diabetes mellitus or chronic kidney disease stage 3–5 (GFR < 60 ml/min/1.73 m²)

• In individual cases where combined use of an ARB and ACEI is considered absolutely essential, it must be carried out under specialist supervision with close monitoring of renal function, electrolytes and blood pressure

•  This includes the licensed use of candesartan or valsartan as add-on therapy to ACEI in patients with heart failure.

•  In these patients, dual blockade should be limited to those intolerant to mineralocorticoid antagonists and with persistent symptoms despite other optimal therapy

• ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; GFR, glomerular filtration rate; RAS, renin–angiotensin system.

The document specifically cited evidence from the Ongoing Telmisartan Alone and in combination wiht Ramipril Global Endpoint trial, ONTARGET [Yusuf et al. 2008], Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints, ALTITUDE [Parving et al. 2012] and The Veterans Affairs Nephropathy in Diabete, VA NEPHRON-D [Fried et al. 2013] trials and from a meta-analyses of over 68,000 patients [Makani et al. 2013a] that concluded that dual RAS blockade through the combined use of ACEIs, ARBs or aliskiren is associated with an increased risk of adverse events, including hypotension, hyperkalemia and renal failure compared with monotherapy, in particular in patients with diabetic nephropathy. These studies supported that dual RAS blockade does not provide significant benefit in the general patient population, although some selected subpopulations may benefit. In patients with heart failure there is some evidence that the addition of a second RAS-acting agent may reduce hospital admissions. Similar warnings were issued by the US Food and Drugs Administration in 2012 and September 2014. Interestingly, these warnings did not refer to dual blockade of the renin–angiotensin–aldosterone system (RAAS) using a combination of a RAS and an aldosterone targeting drug. This may be due to both the demonstrated efficacy of dual RAAS blockade for heart failure [Pitt et al. 1999] and the safety profile of the combination in RCTs [Pitt et al. 1999], despite accumulating evidence of the higher risk for hyperkalemia when combining a RAS blocker and an aldosterone blocker than with dual RAS blockade [Preston et al. 2009; Van Buren et al. 2014] and the surge in severe and lethal hyperkalemia cases following the publication of the RALES trial [Juurlink et al. 2004]. RALES: Randomized Aldactone Evaluation Study.

We now critically review the evidence supporting a potential clinical benefit and the risks of dual blockade on hyperkalemia, hypotension and impaired renal function, discuss the role of mineralocorticoid receptor antagonists and provide a roadmap of future studies. Specifically, we set out to answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents (dual RAAS blockade)?

RAS and RAAS

RAS and RAAS refer to the some physiological pathway, but it is worth separating the concepts from a therapeutic point of view, since regulatory contraindications refer to dual RAS blockade but not to dual RAAS blockade (that is, when one of the components of the dual therapeutic regime targets aldosterone or the mineralocorticoid receptor). The RAAS regulates arterial pressure, tissue perfusion, extracellular volume, inflammation and fibrosis [Atlas, 2007].

Renin is secreted by juxtaglomerular cells in response to reduced renal perfusion pressure, low NaCl concentration in the tubular lumen, increased sympathetic discharge and lack of negative feedback by angiotensin II (AngII). Renin is also synthesized outside the kidney. Renin catalyzes the hydrolysis of angiotensin I (AngI) from angiotensinogen. The liver constitutively secretes angiotensinogen and glucocorticoids, estrogens, thyroid hormone and some cytokines like tumor necrosis factor or interleukin 1 may increase angiotensinogen release.

Angiotensin-converting enzyme (ACE) is mainly located on the plasma membrane of vascular endothelial cells, although other cells express ACE and there is a soluble form. ACE hydrolyzes AngI to yield AngII. AngII activates the Angiotensin 1 (AT1) receptor to promote vasoconstriction, NaCl reabsorption and renin inhibition in the kidney, hypertrophy in the cardiovascular system, aldosterone synthesis, oxidative stress and proliferative, proapoptotic, inflammatory and fibrogenic responses. By contrast, AngII activation of the AT2 receptor mediates vasodilation and has antiproliferation and antiapoptotic effects. The clinical consequences of activation of the AT3 and AT4 receptors are less well characterized. Additional RAS metabolites include AngIII, AngIV and Ang(1–7).Besides the classical pathway of angiotensin synthesis, ‘tissue RAS’ contributes to 40% of the total circulating AngII [Atlas, 2007].

Commercially available therapeutic agents that block the RAS are ACEIs, ARBs and aliskiren. ACEIs inhibit ACE and initially decrease AngII generation, aldosterone and vasopressin secretion and increase renin secretion. However, continuous ACEI usage is associated with normalization of AngII and aldosterone levels, the so-called ‘ACE escape’ [Atlas, 2007]. ARBs block the AT1 receptor for AngII. Therefore, the efficacy of these blockers is not limited by alternative (non-Angiotensin Converting Enzime (ACE)) tissue AngII generation. In contrast to ACEIs, the ARBs increase AngII levels, and as a result, AngII may bind to other receptors like AT2. Aliskiren is a direct renin inhibitor that blocks the synthesis of all angiotensin peptides (AngI, AngII), preventing the effects of the compensatory increase in renin secretion.

The adverse effect profile of ACEIs, ARBs and aliskiren is similar (hypotension, hyperkalemia deterioration of renal function and fetal abnormalities), although ACEIs additionally induce dry cough. While theoretically ACEIs and ARBs may have different actions depending on activation of non-AT1 receptors for AngII, in clinical practice they are used interchangeably for most indications. The existence of physiological escape routes to therapeutic targeting of the RAS system is the basis for dual blockade therapeutic approaches.

Aldosterone is a steroid hormone synthesized by adrenal glomerulosa cells in response to AngII, potassium ions and adrenalcorticoid hormone that promotes sodium reabsorption and potassium secretion in distal kidney tubules, inflammation and fibrosis through activation of the mineralocorticoid receptor [Brem et al. 2011; Brilla and Weber, 1992] Spironolactone and eplerenone are currently available mineralocorticoid receptor antagonists.

What safety issues are associated with dual RAS blockade?

The key safety issues associated with dual RAS blockade are hypotension that may lead to syncope, impaired kidney function that may lead to acute kidney injury (AKI) and hyperkalemia (Table 1) [Yusuf et al. 2008; Ellison and Ingelfinger, 2014; Fried et al. 2013; Makani et al. 2013a; Parving et al. 2012; Schrier et al. 2014; Torres et al. 2014].

Table 1.

Main recent randomized clinical trials and safety of dual renin–angiotensin system blockade.

Trial/drugs	Adverse events (dual blockade versus monotherapy)	Duration (months)	Study population*	Benefit	Mortality
HALT progression of Policystic Kidney disease (HALT-PKD) study A [Schrier et al. 2014] Lisinopril/telmisartan versus lisinopril/placebo	Syncope 0.4% versus 0.4%, ns AKI 4.8% versus 5.6%, ns Hyperkalemia 4% versus 1.8%, ns	96	N = 558, age 37 years eGFR 91 ml/min/1.73 m2 Albuminuria 18 mg/24 h Cause: PKD	Not on total kidney volume or eGFR	0.4% versus 0.4%, ns
HALT progression of Policystic Kidney disease (HALT-PKD) study B [Torres et al. 2014] Lisinopril/telmisartan versus lisinopril/placebo	AKI 9% versus 13.2%, ns Hyperkalemia 18.9% versus 16.9, ns	96	N = 486, age 49 years eGFR 48 ml/min/1.73 m2 Albuminuria 29 mg/24 h Cause: PKD	Not on total kidney volume or eGFR	1.6% versus 2.1%, ns
Ongoing Telmisartan Alone and in combination wiht Ramipril Global Endpoint trial (ONTARGET) [Yusuf et al. 2008] Telmisartan/ramipril versus telmisasrtan/placebo versus ramipril/placebo	Hypotension$ 4.8% versus 1.7%, p < 0.0001 Syncope$ 0.3% versus 0.2%, p = 0.03 Renal dysfunction 13.5% versus 10.2%, p < 0.001 Hyperkalemia 5.6% versus 3.3%, p = 0.001	56	N = 25,620, age 66 years eGFR 69 ml/min/1.73 m2 Albuminuria 927 mg/g Cause: 85% CV disease 69% hypertension 38% DKD	Not on death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure	12.5% versus 11.8%, ns
Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) [Parving et al. 2012] Aliskiren/ACEI or ARB versus placebo/ACEI or ARB	Hypotension 12.1% versus 8.3%, p < 0.001 ESRD, death attributable to kidney failure or loss of kidney function 2.8% versus 2.6%, p ns Hyperkalemia 11.2% versus 7.2%, p < 0.001	33	N = 8561, age 64 years eGFR 57 ml/min/1.73 m2 Albuminuria 14% < 20 mg/g, 26% ⩾ 20 to < 200 mg/g, 58% ⩾ 200 mg/g Cause: type 2 diabetes, CKD, CV disease	Not on cardiovascular death nor renal function	8.8% versus 8.4%, ns
The Veterans Affairs Nephropathy in Diabetes (VA-NEPHRON-D) [Fried et al. 2013] Losartan/lisinopril or losartan/placebo Losartán + lisinopril	AKI 12.2 versus 6.7 events/100 person-years, p < 0.001 Hyperkalemia 6.3 versus 2.6 events/100 person-years; p < 0.001	26	N = 1448, age 64 years eGFR 54 ml/min/1.73 m2 Albuminuria 862 mg/g Cause: DKD	Not on renal function or death	8.7% versus 8.3%, ns

^*Values are mean/median for the study population.

^$As a cause of discontinuation/

ACEI, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; ns, nonsignificant; PKD, polycystic kidney disease.

Hyperkalemia is defined as a plasma potassium level greater than 5.0–5.5 mmol/liter. Moderate (6.0–7.0 mmol/liter) or severe (7.0 mmol/liter) hyperkalemia may lead to cardiac arrhythmia and death [Ingelfinger, 2015]. In patients with hypertension without risk factors for hyperkalemia, the incidence of hyperkalemia (serum potassium >5.5 mmol/liter) with RAAS inhibitor monotherapy is up to 2% and with dual RAS blockade it is 5% [Weir and Rolfe, 2010]. However, the incidence of hyperkalemia increases in patients with chronic kidney disease (CKD) or heart failure.

The Makhani meta-analysis of 33 RCTs with 68,405 patients (mean age 61 years and mean duration of 52 weeks) concluded that dual RAS blockade (aliskiren, ACEI or ARB) was not associated with any significant benefit for all-cause or cardiovascular mortality compared with monotherapy. However, it reduced admissions to hospital for heart failure by 18% and increased the risk of hyperkalemia by 55%, the risk of hypotension by 66% (p < 0.001) and the risk of renal failure by 41% [Makani et al. 2013a]. It should be pointed out, however, that given the relatively short duration of follow up, it is unlikely that the putative long-term beneficial effects of dual RAS blockade could have been observed. Overall, rates of hyperkalemia or AKI were relatively low in the different studies, suggesting patient-related factors that predispose to complications. Box 1 provides some insights into factors that may contribute. In younger patients there were fewer differences between monotherapy and dual RAS blockade in terms of complications. However, studies in younger patients were smaller and age cannot be dissociated from underlying comorbidities, which were more frequent in older patients from clinical trials addressing cardiovascular risk or diabetic kidney disease (DKD) than in younger patients with polycystic kidney disease. Another issue with RCTs is the frequent use of fixed doses of the study drugs, which differs from clinical practice in which many physicians individualize and adjust the dose according to the therapeutic response and tolerance. As an example, a recent small RCT of dual RAS blockade versus monotherapy which failed to meet its primary endpoint of over 50% increase in baseline serum creatinine level, end-stage renal disease (ESRD) or death in older (mean age 66) patients with DKD, also did not find differences in hyperkalemia [Fernandez et al. 2013] However, in this study the dose was carefully titrated and early abnormalities in serum potassium were corrected by low potassium diet and cation exchange resins, which were used in 18% of patients.

Can the safety record of dual RAS blockade be improved?

The safety profile of dual RAS blockade may be improved by better selection of candidates for therapy, careful education of patients, families and physicians, and the use of add-on medications that decrease the risk of complications, such as oral potassium-lowering drugs.

Selection of candidates for therapy has two aspects: selection of those most likely to benefit and of those less likely to have adverse effects. The potential benefits of dual RAS blockade are discussed in the next section. However, one potential strategy to increase the likelihood of benefit is the use of -omics techniques to identify molecular signatures that identify early in the disease process those most likely to have progressive disease [Fernandez et al. 2012]. This would allow early therapy (i.e. before progression of CKD increases the risk of adverse effects) in a patient population with high risk of progression (i.e. that may obtain the greatest benefit from slowing disease progression). An example of this approach is the ongoing PRIORITY trial (Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention of Early Diabetic Nephropathy in Type 2 Diabetic Patients with Normoalbuminuria trial) (http://www.eu-priority.org/). PRIORITY stratifies patients with type 2 diabetes and normal albuminuria at low or high risk of having disease progressing to albuminuria based on the urinary proteomic classifier CKD273. In patients with diabetes and normoalbuminuria, the classifier CKD273 predicted the development of macroalbuminuria 5 years later with an area under the curve of 0.93 [Zurbig et al. 2012]. The CKD273 classifier is highly reproducible, as demonstrated for samples from different European centers [Siwy et al. 2014]. PRIORITY will assess the hypothesis that therapy with spironolactone on top of guideline-recommended treatment with ACEIs or ARBs may prevent development of microalbuminuria in this high-risk population. As discussed below, the use of spironolactone represents a modality of dual RAAS blockade. Proteomics of urinary exosomes or urinary metabolomics may also provide molecular signatures for patient stratification [Benito-Martin et al. 2013; Zubiri et al. 2013; Posada-Ayala et al. 2014].

Education of patients, families and physicians should emphasize the risks associated with excess potassium intake from diet or potassium-containing drugs, with volume depletion, especially in the context of diarrhea or vomiting, and the use of additional drugs that may increase serum potassium or promote volume depletion [Ben et al. 2014]. It is unclear to what extent these measures were implemented in recent large trials. Patients and their families (who may take primary responsibility for care, especially in older patients) should be familiar with dietary sources of potassium and with measures to decrease the potassium content of food and avoid binges on potassium-rich foods. Instructions should be given to stop dual RAS blockade in the case of diarrhea or vomiting and ambulatory blood pressure monitoring may be used to avoid hypotension.

Finally, the risk of hyperkalemia may be decreased by add-on medications. These include diuretics such as thiazides or loop diuretics when indicated because of hypertension, albuminuria or volume overload, and oral potassium-lowering agents such as ion exchange agents and potassium traps. Currently, only ion exchange resins such as sodium polystyrene sulfonate and calcium polystyrene sulfonate are commercially available potassium-lowering agents. However, these drugs are ill-fitted for chronic therapy. Compliance is usually poor due to palatability issues and gastrointestinal secondary effects, mainly constipation [Harel et al. 2013]. In addition, as exchange resins, they are a source of sodium or calcium respectively that may be undesirable in certain patients. Finally, although detailed epidemiological studies are lacking, they have been linked to the development of ischemic colitis and colon necrosis [Harel et al. 2013].

Two recent successful phase II trials will probably pave the way for phase III studies that may result in regulatory clearance of two new drugs to treat hyperkalemia: patiromer (RLY5016) and sodium zirconium cyclosilicate (ZS-9). Patiromer is a nonabsorbed oral polymer that exchanges potassium for calcium in the colon and effectively treated hyperkalemia in a phase II trial in patients with CKD under one or more RAAS inhibitor and with serum potassium 5.1–6.5 mmol/liter. Potassium was within normal limits in 76% of patients by week 4. Maintenance of patiromer for 8 more weeks decreased the recurrence of hyperkalemia from 60% to 15% [Weir et al. 2014]. Mild to moderate constipation was the most common adverse event. Patiromer is under study in diabetic nephropathy [ClinicalTrials.gov identifier: NCT01371747]. ZS-9 is an oral potassium trap 10 times more potent in vitro than current resins. In a phase II trial, 753 patients with hyperkalemia received 1.25–10 g ZS-9 or placebo three times a day for 2 days. At day 2, potassium significantly decreased in groups receiving 2.5–10 g doses compared with placebo. ZS-9 preserved normokalemia for 12 days [Packham et al. 2014].

Is it worth trying to improve the safety record of dual RAS blockade?

Attempts at improving the safety of RAS targeting monotherapy are indeed justified since these are life-saving interventions that delay CKD progression [K/DOQI Workgroup, 2005; Ruggenenti et al. 2012] and reduce the risk of mortality in chronic heart failure and decreased left ventricular ejection fraction [The SOLVD Investigators, 1991]. However, the European Community decision to advise against dual RAS blockade in diabetic nephropathy and most patients with heart failure was based as much on lack of efficacy as on safety issues. Thus, it could be argued that RCTs aimed at improving the safety of dual RAS blockade should wait until efficacy has been demonstrated for a particular indication. However, a focus on safety issues may have prevented the early termination of trials such as VA NEPHRON-D when there was a near-significant 37% reduction (p = 0.07) in the incidence of ESRD with dual RAS blockade versus monotherapy in patients with DKD [Fried et al. 2013]. Indeed, this study did not find differences in the incidence of hypotension between monotherapy and dual blockade, but the low target systolic blood pressure (110–130 mmHg) may have predisposed patients to AKI, while a detailed plan for management of hyperkalemia and compliance was not published.

Indeed, some patient subpopulations may benefit from dual RAS blockade, including patients with heart failure, in whom cardiovascular mortality and hospitalizations were reduced by candesartan and ACEIs compared with candesartan alone [McMurray et al. 2006]. Continuing with the prematurely terminated VA NEPHRON-D example, the hazard ratio for the primary endpoint was 0.78 CI (0.57–1.07) for those younger than 65 years CI (n = 667) and 0.78 (0.58–1.03) for white patients (n = 1051) for dual RAS blockade. Unfortunately, safety data for these predefined subpopulations are not available [McMurray et al. 2006]. Thus, the possibility of a positive efficacy/safety ratio for white patients under 65 years with DKD cannot be ruled out and merits further trials. In this regard, Table 1 suggests that AKI and hypotension were mainly found in studies including older patients with cardiovascular disease.

Is dual RAS blockade dead?

The question has been raised whether the end of dual RAS blockade has arrived [de, 2013]. From the nephrological point of view there is some evidence for a greater decrease in proteinuria with dual RAS blockade than with monotherapy [Fernandez-Juarez et al. 2006; Susantitaphong et al. 2013]. Proteinuria is an independent risk factor for progression of CKD [Hunsicker et al. 1997]. However, the evidence on dual RAS blockade and hard endpoints is tenuous. A key concept is therapy individualization, as opposed to fixed use in ONTARGET and ALTITUDE [Gentile et al. 2014]. Remuzzi and colleagues defend that a multidrug, individually tailored, antiproteinuric treatment based on combination therapy with maximum tolerated doses of ACEIs and ARBs (Remission Clinic protocol) reduced proteinuria and prevented ESRD more effectively than ACEI/ARB monotherapy in subjects with nondiabetic CKD. However, the only report to date is a single historic matched cohort comparing 56 patients, mean age 54 years, with CKD and heavy proteinuria (⩾3 g/24 h for ⩾ 6 months) despite conventional therapy (single blockade + statins). Treatment with dual RAS blockade plus statin with or without nondihydropyridine calcium channel blocker for a median follow up of 4 years further decreased proteinuria and reduced 8.5-fold the risk of progression to ESRD [Ruggenenti et al. 2008]. Forty-six percent of patients treated with dual blockade of the RAS achieved disease regression or complete remission. There were no cases of AKI and serum potassium was similar in both groups [Ruggenenti et al. 2008]. Several meta-analyses in patients with proteinuric nephropathies concur with the greater efficacy of dual RAS blockade (ACEI + ARB) in decreasing proteinuria [Catapano et al. 2008; Cheng et al. 2012; Jennings et al. 2007; Kunz et al. 2008; MacKinnon et al. 2006]. In a meta-analysis of 4975 patients with CKD [defined as proteinuria or glomerular filtration rate (GFR) < 60 ml/min/1.73 m²], different RAAS combinations (81% of studies corresponded to the combination ACEI + ARB), decreased albuminuria and proteinuria (–90 mg/g creatinine and −291 mg/g, respectively; p <0.001). However, GFR (–1.8 ml/min/1.73 m²; p = 0.005) decreased and there was 3.4% higher rate of hyperkalemia and 4.6% higher rate of hypotension, without benefits in terms of doubling of the serum creatinine level [Susantitaphong et al. 2013]. Based on the remission clinic results, which require confirmation, it is possible that a higher baseline proteinuria (⩾3 g/24 h), therapy individualization and younger age are required for a benefit to be obtained and to minimize adverse effects. It is also possible that absence of diabetes is also required and that has been the interpretation of regulatory authorities. In this regard, ongoing clinical trials in patients with diabetes may provide the answer. These include the VARIETY (A Prospective, Randomized, Probe Trial to Evaluate Whether, at Comparable Blood Pressure Control, Combined Therapy With the ACEI Benazepril and the ARB Valsartan, Reduces the Incidence of Microalbuminuria More Effectively Than BEN or VAL Alone in Hypertensive Patients With Type 2 Diabetes and High-normal Albuminuria) trial on prevention of microalbuminuria in type 2 diabetes [ClinicalTrials.gov identifier: NCT00503152] and the VALID trial (Preventing ESRD in Overt Nephropathy of Type 2 Diabetes) with endpoint progression to ESRD in patients with type 2 diabetes [ClinicalTrials.gov identifier: NCT00494715].

What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents?

Add on of mineralocorticoid receptor antagonists to RAS blockade decreases mortality in chronic heart failure trials such as RALES [Delyani, 2000; Pitt et al. 1999]. In addition to already available spironolactone and eplerenone, MT-3995 and finerenone (BAY 94-8862) are undergoing clinical trials in patients with CKD.

Dual RAAS blockade decreases albuminuria in diabetic and nondiabetic kidney disease, but whether hard endpoints are prevented in the long term is currently unknown. In patients without diabetes with hypertension, albuminuria 30–600 mg/g and estimated GFR (eGFR) at least 50 ml/min/1.73 m² previously treated with ACEIs or ARBs, the EVALUATE trial showed that 50 mg/day eplerenone decreased albuminuria by 17% compared with an increase of 10% for placebo [Ando et al. 2014]. In diabetic nephropathy, dual RAAS blockade with 25 mg spironolactone on top of ACEIs or ARBs decreased albuminuria by 33%. Only one patient discontinued the study due to hyperkalemia [Rossing et al. 2005]. Ongoing trials are testing dual RAAS blockade with MT-3995 or finerenone on top of RAS inhibitors in DKD (eGFR 30–60 ml/min/1.73 m² and albuminuria ⩾ 300 mg/g) [Epstein, 2014; Fernandez-Fernandez et al. 2014]. These are selective, nonsteroidal mineralocorticoid receptor antagonists, with different distribution in organs. In rats, finerenone reduced functional and structural damage with less electrolyte disturbances than eplerenone [Kolkhof et al. 2014]. However, hyperkalemia was not assessed. In the phase II ARTS (Safety and Efficacy of Different Oral Doses of BAY94-8862 in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Nephropathy) trial, in patients with heart failure, decreased left ventricular ejection fraction and CKD, finerenone was as effective as spironolactone in decreasing albuminuria and B-type Natriuretic Peptide (BNP), and there was a smaller increase in serum potassium [Pitt et al. 2013].

The risk of hyperkalemia is dose dependent and higher for patients with diabetes and those with eGFR less than 30 mL/min/1.73 m². The use of mineralocorticoid receptor antagonists is not allowed in patients with advanced CKD (GFR < 30 ml/min/1.73 m²) due to the risk of hyperkalemia. In the EVALUATE trial, serum potassium increased more in the eplerenone than in the placebo group (+0.17 mmol/liter versus +0.02 mmol/liter [Ando et al. 2014; Makani et al. 2013a]. In patients with hypertension and GFR 25–65 mL/min, dual RAAS blockade with 40 mg lisinopril/25 mg spironolactone for 4 weeks increased serum potassium more than placebo (4.87 versus 4.37 mmol/liter). An acute potassium load was predictive of longer term changes in serum potassium and suggested a multifactorial component in hyperkalemia involving reduced renal excretion as well as impaired extrarenal/transcellular potassium disposition [Preston et al. 2009]. Spironolactone raised serum potassium more than losartan when added on top of an ACEI in DKD (5.0 mEq/liter for spironolactone/lisinopril, 4.7 mmol/liter for losartan/lisinopril, and 4.5 mmol/liter for placebo/lisinopril), and this was not accounted for by changes in renal potassium excretion, suggesting again that extrarenal potassium homeostasis contributes to hyperkalemia in these patients [Van Buren et al. 2014].

In summary, dual RAAS blockade with currently available agents appears to be at least as risky for hyperkalemia as dual RAS blockade and from the point of view of nephroprotection, a benefit has not yet been demonstrated for hard outcomes. Future trials on dual RAAS blockade may also benefit from chronic potassium-lowering strategies.

Conclusion and steps forward

Key points are presented in Box 2. We concur with the suggestion that optimal RAS blockade should be defined as the maximal blockade achieved without causing hyperkalemia, hypotension or renal dysfunction [Nussberger and Bohlender, 2013; Makani et al. 2013b]. However, we lack predictive tests that allow definition of patient-specific optimal RAS blockade in advance. Furthermore, it is unclear what degree of RAS blockade is needed for different therapeutic indications and whether this is best achieved by increasing monotherapy dose or by dual blockade. While the theoretical basis for dual RAS blockade or even triple RAAS blockade is appealing, the pro dual RAS blockade camp has failed to date to provide convincing evidence of improved hard outcomes. Reduction of albuminuria should translate into decreased need for dialysis, but it is even unclear whether it is better to achieve optimal albuminuria reduction by supramaximal monotherapy doses or by dual blockade [Schmieder et al. 2005]. Flaws in our understanding of the dose–response curves for RAS blockers contribute to the uncertainty and stem from the fact that most early phase clinical reports include a mix of responders and nonresponders, and this may contribute to apparent flattening of the dose–response curve. For example, intentional ACEI overdose is associated with greater blood pressure lowering response than after therapeutic doses. The long natural history of CKD plays against the dual RAS blockade camp, since the studies needed to clarify the role of dual blockade in CKD in general or specific subpopulations (e.g. proteinuric CKD in younger patients, residual proteinuria > 3 g/day despite monotherapy) require huge resources and only proof of concept preliminary data are available [Ruggenenti et al. 2008]. Early termination of trials on security concerns is not helpful [Fried et al. 2013] and greater flexibility should be incorporated into trials to preserve safety for the wider trial population while optimizing management of safety issues for those most likely to benefit. New safety monitoring tools are required, such as on-the-spot monitoring devices for serum creatinine and potassium, similar to those available for diabetes monitoring, that together with home blood pressure monitoring allow adaptation of RAS blockade (and dual RAS blockade for that matter) to changing individual circumstances (diarrhea, concomitant disease that transiently decreases intake, dietary noncompliance). Novel tools to manage dual blockade safety, such as new oral potassium-lowering agents, may also contribute to improving the safety profile of dual RAS blockade. The new wave of dual RAAS blockade studies will keep the safety of dual blockade at the forefront of cardiovascular and renal medicine for the foreseeable future.

Box 2.

Keypoints.

• Dual renin–angiotensin system (RAS) blockade is now formally contraindicated for most patients

• The risks associated with the combination (hyperkalemia, hypotension, and impaired renal function) contributed to the contraindication

• The safety record of dual RAS blockade can be improved through therapy individualization involving adequate selection of patients, education on sources of potassium and on when to stop the drug when volume depleted, dose individualization and the use of drugs preventing hyperkalemia

• However, further clinical evidence of the benefit of dual RAS blockade is needed and may be provided by ongoing clinical trials. Available yet inconclusive information suggests that younger patients with proteinuria might benefit from dual RAS blockade

• While the therapeutic role of RAAS blockade is still under study, safety issues are expected to be similar to those of RAS blockade, although novel mineralocorticoid receptor antagonists may have a better safety profile