Combination therapy in the management of hypertension: focus on angiotensin receptor blockers combined with diuretics

There is increasing evidence that combination therapy should be emphasized more than it is at present for the initial treatment of hypertensive patients. Recent guidelines acknowledge the value of combination therapy, although some treatment algorithms fail to echo this message. Observations from major clinical trials in the elderly, diabetics, stroke patients, and African Americans all indicate that combination therapy is necessary to control blood pressure in the majority of these patients. Several combination therapies such as an angiotensin II receptor blocker and a diuretic, an angiotensin-converting enzyme inhibitor with a diuretic, a beta blocker with a diuretic, or an angiotensin-converting enzyme inhibitor with a calcium antagonist have been shown to be effective in patients who do not respond to monotherapy. The current review focuses on the newest such combination; an angiotensin II receptor blocker and a diuretic may have an added advantage of being well tolerated. Recent studies have shown that angiotensin II receptor blockers, given alone or combined with a diuretic, may prevent some cardiovascular outcomes independent of their blood pressure-lowering efficacy.     

Combined Therapy With a Calcium Channel Blocker and an Angiotensin II Type 1 Receptor Blocker

Fixed-dosed combination regimens consisting of a calcium channel blocker and an angiotensin II type 1 receptor blocker represent a new addition to the available antihypertensive treatment options. Clinical trials demonstrate that both the dihydropyridine calcium channel blocker amlodipine and angiotensin II receptor blockers are effective agents for the management of hypertension in individuals with or without cardiovascular disease. When combined, these 2 classes of agents have complementary effects on blood pressure, as each targets separate signaling pathways in the vasculature pivotal to the regulation of vascular function. In clinical trials this combination has demonstrated better efficacy, defined by time to reach blood pressure targets as well as levels of blood pressure achieved, compared with the individual agents. In a comparative trial, a combination of amlodipine plus valsartan (an angiotensin II receptor blocker) also produced greater reductions in blood pressure compared with a combination of lisinopril (an angiotensin-converting enzyme inhibitor) and hydrochlorothiazide. The combination of amlodipine and an angiotensin II receptor blocker is well tolerated, including in patients with stage 2 hypertension and the elderly.     

Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension

Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies, suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive effect on blood pressure with an ACE inhibitor-angiotensin receptor blocker combination, the routine use of this combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed.     

Renal protection by antihypertensive therapy

The attainment of adequate renal protection requires strict blood pressure control and a diminution of proteinuria or microalbuminuria to values as near from normalcy as possible. It has been considered that by getting the first, the second could be attained at the same price. Recent data have confirmed that renal protection in hypertensive patients, diabetics or not, requires combination therapy that has to include an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. A calcium channel blocker can be added to this without renal compromise. A diuretic will also be needed in most cases. Proteinuria will diminish with this combination in particular if up-titration of the drug blocking the effects of angiotensin II is performed. The control of other associated risk factors is also required, in particular smoking and lipids.     

Renal protection by antihypertensive therapy

The attainment of adequate renal protection requires strict blood pressure control and a diminution of proteinuria or microalbuminuria to values as near from normalcy as possible. It has been considered that by getting the first, the second could be attained at the same price. Recent data have confirmed that renal protection in hypertensive patients, diabetics or not, requires combination therapy that has to include an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. A calcium channel blocker can be added to this without renal compromise. A diuretic will also be needed in most cases. Proteinuria will diminish with this combination in particular if up-titration of the drug blocking the effects of angiotensin II is performed. The control of other associated risk factors is also required, in particular smoking and lipids.     

Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy

BACKGROUND: To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker (ARB) on diabetic kidney disease, half doses of each monotherapy were given to type 2 diabetic patients with albuminuria. METHODS: Urinary albumin index (UAI) and blood pressure (BP) were measured in a total of 27 outpatients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg candesartan per day. Either agent was then substituted with a combination of 5 mg imidapril and 4 mg candesartan. After 3 months of combination therapy, UAI and BP were measured. Changes in the parameters were assessed by paired t test. RESULTS: Although BP was not significantly different prior to and at the end of combination therapy, log-transformed UAI was significantly reduced (P = 0.003) from an initial UAI (mean log-transformed UAI +/- SD) of 79.4 (27.4-231)mg/g Cre to 52.5 (17.1-161)mg/g Cre at the end of combination therapy. The reduction was not associated with the initial UAI, initial BP, decrease in BP, pretreatment medication or other concomitant antihypertensive agents. CONCLUSIONS: In patients with type 2 diabetes and nephropathy, dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and, thus, may be renoprotective even when the doses of the agents are reduced by one half.     

Hypertension Control in the Elderly

Hypertension is highly prevalent in older persons and most often presents as isolated systolic hypertension. Systolic blood pressure (BP) is a stronger predictor of risk than diastolic BP in persons older than 50 years. Most of these patients will require multiple drug therapies to achieve the substantial reductions in systolic BP needed to reach target levels. Clinical trials have demonstrated that antihypertensive therapy with β-blockers and diuretics as well as with calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor blockers reduces cardiovascular risk in older patients. Studies examining safety and BP-lowering efficacy have shown that a renin-angiotensin-aldosterone system blocker plus a calcium channel blocker as well as a combination of diuretics and β-blockers or diuretics plus an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker achieves greater BP reductions than monotherapy. Such multiple drug regimens are well tolerated in older patients.     

Combination angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy: its role in clinical practice

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly prescribed for the management of hypertension. In addition, each of these drug classes has been shown to be effective in the treatment of congestive heart failure, proteinuric chronic kidney disease, and most recently the high-cardiac-risk profile patient. The individual success of each of these drug classes has fueled the theory that given together, the overall biologic effect of both would surpass that of either given alone. The foundation of this premise, although biologically plausible, has yet to be proven in a compelling enough fashion to support the everyday use of these two drug classes in combination. Additional clarifying studies are required to establish whether specific patient subsets exist that might benefit from such combination therapy.     

Azilsartan: a newly approved angiotensin II receptor blocker

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality. Blood pressure control is essential to prevent end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Azilsartan is the eighth angiotensin II receptor blocker approved for the management of hypertension, alone or in combination with other agents. At the approved dosage, it reduces systolic blood pressure by 12 to 15 mm Hg and diastolic blood pressure by 7 to 8 mm Hg. A higher dose of azilsartan (80 mg) was superior to valsartan 320 mg or olmesartan 40 mg in lowering systolic blood pressure in short-term studies. Additional blood pressure reduction is expected when azilsartan is used adjunctively with a diuretic. However, the effects of azilsartan on cardiovascular morbidity or mortality are still lacking. Azilsartan is well tolerated; the most common side effects are headache and diarrhea. No cases of hyperkalemia have been reported in 6-week clinical trials. Worsening of renal function and hypotension should be monitored, particularly in those with baseline risk factors. It is unknown whether azilsartan would join angiotensin-converting enzyme inhibitors and other angiotensin receptor blockers as the preferred hypertensive agents for end-organ protection. At this time, azilsartan should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or cannot tolerate other antihypertensive agents, including dry cough induced by angiotensin-converting enzyme inhibitors.     

Renin/prorenin receptor, (P)RR,in end-organ damage: current issues in 2007

We present a critical review on emerging concepts on the role of (pro)renin receptor, (P)RR, in diabetic and hypertensive nephropathy. Discovery of nonproteolytic activation of prorenin by the receptor led to nontoxic peptidic prorenin receptor blocker. The receptor blocker permitted long-term in vivo studies on the role of (P)RR in diabetic and hypertensive end-organ damage. Chronic infusion of receptor blocker prevented streptozotocin diabetic nephropathy and attenuated hypertensive cardiomyopathy and nephropathy. In support of these results, transgenic rats overexpressing the receptor nonselectively developed renal glomerulopathy with aging without elevating blood glucose or blood pressures. It indicated that the receptor overexpression alone is sufficient for end-organ damage, and diabetes mellitus and hypertension induce the end-organ damage by increasing (P)RR expression. We propose that (P)RR is a pivotal link between pathogenesis of diabetes mellitus and end-organ damage. (P)RR seems to activate this mechanism largely by activating receptor signals rather than by local angiotensin II. We realized that (P)RR blocker is a competitive inhibitor against prorenin, and its efficiency depends on ambient concentration of prorenin and renin. Optimization of the condition will be necessary to maximize the inhibitory and therapeutic effects.     

Combination Therapy With Renin‐Angiotensin‐Aldosterone Receptor Blockers for Hypertension: How Far Have We Come?

In a large number of patients with hypertension, > or =2 antihypertensive agents are required to achieve blood pressure (BP) goals. There is good rationale for initial combination therapy based on clinical trials demonstrating that achievement of BP goals within a reasonably short period of time results in fewer cardiovascular events. One approach to attaining BP goals and improving medication adherence is fixed-dose combination therapy, the use of which dates back to the 1960s. Given some of the advantages of renin-angiotensin-aldosterone system (RAAS) blockers in patients with heart disease, kidney disease, and diabetes, many combinations include either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In most studies, however, thiazide diuretics were necessary to achieve goal BP. Calcium channel blockers have also been used in combination with angiotensin-converting enzyme inhibitors to lower BP. Studies are now under way to determine the relative benefits of an RAAS blocker/diuretic compared with an RAAS blocker/calcium channel blocker as initial therapy.     

Dual blockade of the renin angiotensin system in diabetic and nondiabetic kidney disease

Dual blockade of the renin angiotensin system is based on a principle of obtaining the broadest and most efficient blockade of the effects of angiotensin II, by using the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II-receptor blocker (ARB). By combining two, different pharmacologic principles and inhibiting both the ACE and the angiotensin II type 1 receptor, it seems possible to block both the production and the action of angiotensin II, which would serve as efficient antihypertensive therapy. Exploring the beneficial effects of dualblockade therapy is a work in rapid progress, in both diabetic and non-diabetic nephropathy. But evidence is also emerging in cardiovascular medicine, an overview of which is provided in this article.     

Low-Dose Aldosterone Blockade as a New Treatment Paradigm for Controlling Resistant Hypertension

Treatment of resistant hypertension requires confirmation of true resistance, diagnosis and treatment of secondary causes of hypertension, adoption of appropriate lifestyle modifications, and effective use of multidrug antihypertensive regimens. Excessive volume retention often underlies resistant hypertension, so diuretics are generally necessary to achieve blood pressure (BP) goals. Although treatment regimens consisting of 3 or more agents have not been systematically evaluated, the author has found a triple regimen consisting of a thiazide diuretic, a calcium channel blocker, and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to be generally effective and well tolerated. Although hydrochlorothiazide is more widely used, chlorthalidone provides better BP reduction and should be preferentially used in patients with resistant hypertension, particularly if the patient remains uncontrolled on hydrochlorothiazide. Recent studies have demonstrated that low doses of aldosterone antagonists, when added to multi-drug regimens that include a thiazide diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, provide significant additional BP reduction, seemingly exceeding what would be expected with addition of alternative classes of agents. The degree of BP reduction induced by aldosterone blockade has been similar in patients with and without evidence of aldosterone excess. Aldosterone antagonists are generally safe and well tolerated. The most common adverse effect of low-dose spironolactone has been breast tenderness, occurring in about 10% of men. Hyperkalemia is uncommon, but can occur, necessitating biochemical monitoring. Risk of hyperkalemia is increased in patients with chronic kidney disease or diabetes, elderly patients, and patients already receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.     

Optimizing therapeutic strategies to achieve renal and cardiovascular risk reduction in diabetic patients with angiotensin receptor blockers

The major challenge for the treatment of hypertensive patients with type 2 diabetes is to achieve the uniformly recommended blood pressure goal of 130/80 mmHg, and 120/75 mmHg in proteinuric patients. Such low target blood pressure levels require the administration of multiple drugs. Angiotensin receptor blockers and the combination of angiotensin receptor blockers with diuretics fulfil the criteria to lower blood pressure effectively with a placebo-like side-effect profile. Beyond pressure control, clinical prospective trials have documented that it does matter what kind of antihypertensive agent is used to control blood pressure. Large-scale follow-up trials have documented blood pressure independent effects of angiotensin receptor blocker on cardiac [left-ventricular hypertrophy (LVH), congestive heart failure] and renal protection (proteinuria, chronic renal failure). Of note, in these trials, angiotensin receptor blockers have been combined with diuretics, and most of the included patients have been on combination therapy comprising two to four antihypertensive agents. In addition to the combination of an angiotensin receptor blocker with a diuretic, the combination of an angiotensin receptor blocker with an angiotensin-converting enzyme inhibitor appeared to be most effective in reducing proteinuria, attenuating chronic renal failure and treating congestive heart failure.     

The role of angiotensin receptor blockers in heart failure

The effectiveness of ACE inhibitors in reducing morbidity and mortality in patients with heart failure is largely attributable to their suppression of angiotensin II production. Despite chronic therapy with ACE inhibitors, angiotensin II levels may be incompletely suppressed and contribute to the high mortality of patients with heart failure. Recently, angiotensin receptor blockers, which block the effects rather than the production of angiotensin II, have become available. Angiotensin receptor blockers have been evaluated as both monotherapy and in combination with ACE inhibitors. In short term studies, angiotensin receptor blocker monotherapy appears to share many of the hemodynamic and clinical features of ACE inhibitors. In a long-term study, the Losartan Heart Failure Survival Study, angiotensin receptor blockers failed to demonstrate any beneficial effect over that seen with ACE inhibitors. The addition of an angiotensin receptor blocker to an ACE inhibitor appears to exert favorable short term hemodynamic, clinical, and neurohormonal effects. Four ongoing trials, Valsartan Heart Failure Trial, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity, Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan study, and Valsartan In Acute Myocardial Infarction study, are evaluating the role of angiotensin receptor blockers either alone or in combination with ACE inhibitors in the management of left ventricular dysfunction. (c)2000 by CHF, Inc.     

CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.     

Aliskiren: an oral renin inhibitor for the treatment of hypertension

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality worldwide. Blood pressure control is critical in reducing the end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Currently available antihypertensive agents work by different mechanisms to reduce blood pressure. Aliskiren, a novel direct renin inhibitor, lowers blood pressure by decreasing renin activity, and angiotensin I and II levels. At the approved dosage (150-300 mg once daily), it reduces systolic blood pressure by 12-16 mm Hg and diastolic blood pressure by 2-12 mm Hg. In studies its efficacy was comparable to losartan 100 mg, irbesartan 150 mg, and valsartan 80-320 mg. When used adjunctively with ramipril, an angiotensin-converting enzyme (ACE) inhibitor, valsartan, an angiotensin II receptor blocker (ARB), or hydrochlorothiazide, a diuretic, it provides additional blood pressure reduction compared with placebo or monotherapy. Aliskiren is well tolerated, with the most common side effects being gastrointestinal symptoms, fatigue, weakness, and headache. In short-term clinical trials, aliskiren caused fewer disturbances in potassium levels when compared with hydrochlorothiazide, ACE inhibitors and ARBs. Long-term data on morbidity and mortality outcomes are not currently available, thus it is unknown whether aliskiren would join ACE inhibitors and ARBs as the preferred hypertensive agents for end organ protection. At this time, aliskiren should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or intolerability to other antihypertensive agents, including dry cough induced by ACE inhibitors.     

Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers: evidence for and against the combination in the treatment of hypertension and proteinuria

Several treatment guidelines have made strong recommendations to physicians that treatment of nephropathy and hypertension should be based on the use of a long-acting angiotensin converting enzyme (ACE) inhibitor if tolerated. The recently published clinical trials, based on angiotensin II receptor blockers' effects on diabetic nephropathy and essential hypertension, have also shown significant endpoint reduction. Perhaps the time has come to broaden the recommendations to include the use of a renin-angiotensin-aldosterone system altering drug. But what if the treatment goal cannot be reached, and incessant proteinuria and high blood pressure levels persist despite high dosage treatment of either drug? How should this be handled? The dual blockade principle can possibly provide the solution by obtaining the broadest and most efficient blockade of circulating angiotensin II by using the combination of an ACE inhibitor and an angiotensin II receptor blocker. But large clinical trials are yet to come, and at present large endpoint trials have not been published. This article provides an overview of how far we have come with dual blockade treatment in hypertension and nephropathy.     

Combination treatment with a calcium channel blocker and an angiotensin blocker in a rat systolic heart failure model with hypertension.

The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.     

Optimal strategies for preventing progression of renal disease: Should angiotensin converting enzyme inhibitors and angiotensin receptor blockers be used together?

Interruption of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT₁ receptor blockers has been shown to delay progression in a variety of renal diseases, suggesting that the RAS, and its major effector molecule, angiotensin II, are important players in renal pathophysiology. Both antagonists combine inhibition of deleterious effects of angiotensin II with activation of potentially beneficial pathways mediated by nitric oxide and prostaglandins. Some concerns have been raised about the completeness of the RAS blockade achieved by these agents. ACE-independent pathways can generate angiotensin II, whereas increases in angiotensin II levels may compete with the AT₁ receptor blocker at the receptor site. It has been suggested that an ACE inhibitor/AT₁ receptor blocker combination offers a better therapeutic effect than treatment with either agent alone. In this review, we focus on mechanisms of actions of ACE inhibitors and AT₁ receptor blockers, implicate them in the rationale for the use of an ACE inhibitor/AT₁ receptor blocker combination, and discuss evidence evaluating the renal effects of the combination as compared to the effects of a single agent. There is a surprising lack of information about the nephroprotective potential of the combination, allowing no consistent conclusions about the superiority of the combination over the single agent. Several experimental and clinical reports suggest that in some conditions, the combination may be beneficial. Rather than providing unequivocal evidence for the use of combination treatment in the renal disease, these studies should be considered as stimuli for more detailed exploration of this issue.