Vol. 13 •Issue 11 • Page 38
Slowing Chronic Renal Disease
Chronic renal disease requires aggressive medical treatment. Is combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers additive?
Eight million people in the United States have physiologic evidence of chronic renal disease (CRD).1 Of those 8 million people, more that 292,000 require life-sustaining dialysis.1 Diabetes mellitus, the leading cause of chronic renal insufficiency, resulted in 119,338 persons requiring dialysis, according to 2003 numbers.1 In 2001, the health care costs for end-stage renal disease (ESRD) patients exceeded $22.8 billion.1
Recent studies show that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), when used as single agents, effectively slow the progression of CRD to ESRD.2 Despite this trend toward kidney protection, treatment with ACEIs or ARBs alone fails to ameliorate ESRD. Current studies theorize that, secondary to differences in mechanism of action, ACEIs and ARBs used together more effectively block the renin-angiotensin system (RAS).3-6 This more complete blockade suggests that combination therapy produces additive effects, thereby offering greater renoprotection.
This review provides a synopsis of ACEIs and ARBs, their mechanisms of action, their indications and their adverse effects, followed by an analysis of five clinical trials examining the idea that additive renoprotective effects exist with combination therapy utilizing ACEIs and ARBs.
Overview of ACEIs
ACEIs are vasodilators, exhibiting vasodilatory properties through two main mechanisms (Figure). The primary mechanism of action is to block the conversion of angiotensin I to angiotensin II in the RAS.7 Studies show that this role in the RAS is vital to kidney protection.2 Angiotensin II, a vasoconstrictor, contributes to increased blood pressure, renal damage and CRD, as well as cardiac muscle hypertrophy and fibrosis.2 Secondarily, ACEIs increase bradykinin production by inhibiting angiotensin-converting enzyme or kininase II, thereby preventing the breakdown of bradykinin, resulting in vasodilation.7
ACEIs exhibit several benefits. ACEIs lower blood pressure by causing vasodilation and decreasing peripheral resistance, slow the progression of chronic renal insufficiency to ESRD, improve morbidity and mortality after myocardial infarction and decrease cardiac remodeling in patients with heart failure.7-9
ACEIs are well tolerated in most patients. The side effect profile of ACEIs includes cough, hypotension, headache, dizziness, angioedema, rash, loss of taste or altered taste, abdominal pain, nausea or vomiting, decreased appetite and increased serum creatinine (Table).7,10 ACEIs are contraindicated in pregnancy and in patients with a glomerular filtration rate less than 20 mL/min. Caution is advised in patients with elevated serum potassium or a GFR less than 30 mL/min.9,10
Overview of ARBs
ARBs, like ACEIs, are vasodilators; ARBs inhibit the RAS by a different mechanism. ARBs block angiotensin II receptors, resulting in decreased vascular resistance and vasodilation. ARBs may also increase production of nitric oxide, resulting in further vasodilation.7
ARBs are effective in decreasing urine protein excretion in diabetic and nondiabetic kidney disease, thereby slowing the progression of chronic renal insufficiency.9 ARBs elicit cardioprotective effects by lowering blood pressure, by reversing myocardial hypertrophy and by reducing morbidity and mortality in patients with congestive heart failure.2,8
The angiotensin II receptor blockers appear to have fewer side effects than the traditional ACEIs, making them an alternative therapy to individuals who cannot tolerate ACEIs.2 The side effects of ARBs include dizziness, hypotension, diarrhea, abdominal pain, upper respiratory infection, cough and nausea. ARBs, like ACEIs, are contraindicated in pregnancy and a GFR less than 20 mL/min and should be used in caution in patients with a GFR less than 30 mL/min.7,10
Clinical evidence proves that monotherapy with ACEIs or ARBs provides renal protection, slowing the progression of CRD to ESRD. However, monotherapy fails to completely halt the advancement to ESRD. ACEIs or ARBs when used alone allow for incomplete blockade of the RAS, permitting production and further renal damaging effects of angiotensin II.2 ACEIs and ARBs exhibit different mechanisms of action, proposing that combination therapy is additive. Thus, providing more complete inhibition of the RAS offers greater renoprotection and prohibits the advancement to ESRD.3-6 The following studies examine the proposed additive effects in diabetic and nondiabetic kidney disease.
Nondiabetic Kidney Disease Studies
Nakao and colleagues conducted a randomized double-blind study of patients with kidney disease of multiple etiologies, excluding diabetic kidney disease.5 The patients were divided into three treatment groups: two groups receiving monotherapy with either an ACEI or ARB, and the last group receiving a combination of the two medications.
From this study, the researchers concluded that combination therapy with both an ACEI and an ARB decreased the number of patients who had progression of their renal insufficiency to end-stage disease and decreased proteinuria (P = 0.01). However, there was no significant further reduction in blood pressure in the combination arm compared with single-drug therapy (P = 0.109).
Kincaid-Smith and colleagues examined the idea that combined angiotensin antagonism with both an ACEI and an ARB is more effective in decreasing blood pressure and urine protein excretion.3 The study population consisted of patients with known chronic renal insufficiency, stable proteinuria and normalized blood pressures managed by ACEI pharmacotherapy.
This study showed that the addition of ARBs was more effective in blood pressure (systolic blood pressure reduction P = 0.001 and diastolic blood pressure P = 0.008) and urine protein excretion (P = 0.04) reduction. It is important to point out that although there was an overall reduction in blood pressure and proteinuria, the study participants with diabetes failed to show this decrease in urine protein excretion. The reason as to why the combination regimen did not produce additive effects in the diabetic participants remains unclear. Potential causative factors include lower than maximum doses of the ACEI as well as higher blood pressure at the onset of the study.3,9
Diabetic Kidney Disease Studies
Eighteen patients with type 2 diabetes mellitus who developed diabetic nephropathy despite treatment with an ACEI participated in a randomized crossover study conducted by Rossing and colleagues.6 This study evaluated the effect of adding an ARB to the current antihypertensive regimen that included an ACEI. The primary endpoints for this study included measurements of systolic blood pressure and urine albumin excretion, as well as parameters of renal function such as GFR.
This study revealed evidence that combination therapy provides more pronounced blockade of the RAS and greater renoprotection without an increase in such adverse effects as hyperkalemia or hypotension over a two-month period. Concomitant administration of an ACEI and an ARB produced greater reductions in systolic blood pressure (P = 0.019) and urine albumin excretion (P = 0.036), suggesting positive renoprotective effects. GFR also decreased in this study (P = 0.045). This decrease, thought to correlate with the reduction in blood pressure, returned to baseline after withdrawal of the ARB.
The researchers concluded that although the study showed statistically significant benefits with combination therapy over the two month period, the long-term renoprotective benefits remain unclear. Therefore, the need for larger studies with more long-term follow-up still exists.6
Agarwal conducted a randomized crossover study of 16 patients with chronic renal insufficiency with proteinuria. Patients received conventional hypertensive therapy that incorporated an ACEI plus placebo or ARB. The primary endpoints studied included urine protein excretion, blood pressure, GFR and cardiac output, as well as plasma renin (PRA) and plasma aldosterone levels. Combination therapy failed to show greater reductions in systolic blood pressure (P = 0.95), diastolic blood pressure (P = 0.59), urine protein excretion (P = 0.89) or cardiac output (P = 0.99). However, GFR (P = 0.017) and plasma renin levels (P = 0.003), in a subset of patients, improved with concomitant ACEI and ARB therapy.
The author concluded that this improvement in GFR (P = 0.017) and fall in PRA (P = 0.003) suggests improved sympathetic nerve activity, improved endothelial function, reduced inflammation or a combination of these factors, suggesting a trend toward renoprotection.10 Again, the results indicating the long-term potentially additive benefits of combination therapy remains a question requiring the evaluation of larger, longer and more extensive clinical trials.
Mogensen and colleagues conducted a double-blind randomized, prospective study of 199 patients with known hypertension and diabetes mellitus with early microvascular changes as noted by elevated microalbumin in the urine.4 Obesity, markedly elevated blood pressures, unstable cardiovascular disease, advanced renal disease, hyperkalemia, pregnancy or lactation prohibited enrollment in the study. During the initial treatment arm of the study participants received either an ACEI or ARB alone. The second-period participants received either an ACEI or ARB alone or in combination. The primary endpoints included blood pressure and urine albumin-to-creatinine ratio. At the conclusion of the trial, combination therapy with both an ACEI and an ARB was more effective in decreasing blood pressure (P = 0.001) and urine albumin excretion (P = 0.001) compared with monotherapy.
The clinical trials discussed provide promising evidence towards greater renoprotection. However, the studies lack strength. The trials enrolled small numbers of participants, often from private practices. The studies also failed to evaluate long-term results. Nevertheless, the outcomes of the trials offer evidence that concomitant therapy with ACEI and ARB is additive, providing greater reductions in blood pressure and proteinuria compared with monotherapy. Thus, the progression of CRD to ESRD reduces significantly.3-6
Combination Therapy Is Promising
Progressive renal disease continues to advance despite monotherapy with ACEIs or ARBs. Recent studies evaluating the renoprotective effects of combining ACEIs and ARBs reveal promising evidence that supports combination therapy. The studies, however, are inconclusive. The studies are small, often from restrictive study populations, resulting in outcomes that may not be able to be generalized.
From these data, we can conclude that larger, more in-depth clinical trails need to be done before health care providers can make definitive treatment guideline changes. ACEI and ARB combination therapy, although an excellent alternative, should be reserved for patients with hypertension and proteinuria who have failed other antihypertensive regimens because of adverse effects or who have failed to reach target goals on monotherapy.
LeAnne Harris Martinelli is a PA in Avondale Estates, Ga.
1. U.S. Renal Data System. USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, Md; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: 2003.
2. Grossman E, Messerli FH, Neutel JM. Angiotensin II receptor blockers: equal or preferred substitutes for ACE inhibitors? Arch Intern Med. 2000;160:1905-1911.
3. Kincaid-Smith P, Fairley K, Packham D. Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrol Dial Transplant. 2002;17:597-601.
4. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321:1440-1444.
5. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361:117-124.
6. Rossing K, Christensen PK, Jensen BR, Parving HH. Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study. Diabetes Care. 2002;25(1):95-100.
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8. Vidt DG. Is there an advantage to combination therapy with ACE inhibitors and angiotensin II-receptor blockers? Cleve Clin J Med. 2000;67:89-91.
9. Thurman JM, Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med. 2003;114:588-598.
10. Agarwal R. Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int. 2001;59:2282-2289.