amlodipine/benazepril: fixed dose combination therapy for hypertension

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Amlodipine/benazepril: fixed dose combination therapy for hypertension Michele A Faulkner & Daniel E Hilleman Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, Nebraska 68178, USA Myocardial infarction, stroke, heart failure and end-stage renal disease have all been linked to inadequate control of blood pressure. Despite overwhelming evidence that uncontrolled hypertension is responsible for a sizeable number of adverse health-related outcomes, control of the disease remains considerably suboptimal. Available data demonstrate that in order to achieve adequate blood pressure control, a large number of patients require therapy with more than one medication. Fixed dose combination antihypertensive therapy has many advantages over other treatment options. Positive effects on blood pressure control, rates of adherence, adverse effects and cost have been identified. Amlodipine/benazepril (Lotrel ® , Novartis) is a fixed dose combination product indicated for the treatment of hypertension. Although not currently recommended as first- line therapy, studies confirm that this combination of a long-acting calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor possesses substantial blood pressure lowering capabilities. Whereas adverse events tend to become more frequent with increasing doses of antihypertensive monotherapy, the rate of adverse events attributed to amlodipine/benazepril in clinical trials often correlates with rates ascribed to placebo. Amlodipine/benazepril is capable of sustaining blood pressure control over a 24 h period and appears to be minimally affected by an occasional dose omission. Unlike the older calcium antagonists, amlodipine is unlikely to cause alterations in myocardial contractility. Additionally, the amlodipine/benazepril combination product costs less than the same therapy administered as the individual components. It is, therefore, reasonable to consider therapy with amlodipine/benazepril in appropriate patients after an adequate trial of antihypertensive monotherapy. Keywords: amlodipine/benazepril, fixed dose combination therapy, hypertension Exp. Opin. Pharmacother. (2001) 2(1):165-178 1. Introduction Myocardial infarction and stroke remain the first and third leading causes of death in the United States respectively. In addition, the incidence of heart failure and end-stage renal disease has risen steadily over the last two decades [1]. Given the association between uncontrolled hypertension and these adverse outcomes, it is alarming to note that hypertension control is substantially inadequate. The most recent National Health and Nutrition Examination Survey (NHANES) III data indicate that only 73% of patients with hypertension are 165 2001 © Ashley Publications Ltd. ISSN 1465-6566 Drug Evaluation 1. Introduction 2. Chemistry and product information 3. Pharmacology and pharmacodynamics 4. Pharmacokinetics 5. Clinical trials in hypertensive patients 6. Safety of amlodipine/benazepril 7. Expert opinion Bibliography http://www.ashley-pub.com Expert Opinion on Pharmacotherapy

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Page 1: Amlodipine/benazepril: fixed dose combination therapy for hypertension

Faulkner & HillemanAmlodipine/benazepril Amlodipine/benazepril: fixed dose

combination therapy for hypertension

Michele A Faulkner & Daniel E Hilleman

Creighton University School of Pharmacy and Allied Health Professions, 2500California Plaza, Omaha, Nebraska 68178, USA

Myocardial infarction, stroke, heart failure and end-stage renal disease haveall been linked to inadequate control of blood pressure. Despiteoverwhelming evidence that uncontrolled hypertension is responsible for asizeable number of adverse health-related outcomes, control of the diseaseremains considerably suboptimal. Available data demonstrate that in orderto achieve adequate blood pressure control, a large number of patientsrequire therapy with more than one medication. Fixed dose combinationantihypertensive therapy has many advantages over other treatmentoptions. Positive effects on blood pressure control, rates of adherence,adverse effects and cost have been identified. Amlodipine/benazepril(Lotrel®, Novartis) is a fixed dose combination product indicated for thetreatment of hypertension. Although not currently recommended as first-line therapy, studies confirm that this combination of a long-acting calciumantagonist and an angiotensin-converting enzyme (ACE) inhibitorpossesses substantial blood pressure lowering capabilities. Whereasadverse events tend to become more frequent with increasing doses ofantihypertensive monotherapy, the rate of adverse events attributed toamlodipine/benazepril in clinical trials often correlates with rates ascribedto placebo. Amlodipine/benazepril is capable of sustaining blood pressurecontrol over a 24 h period and appears to be minimally affected by anoccasional dose omission. Unlike the older calcium antagonists,amlodipine is unlikely to cause alterations in myocardial contractility.Additionally, the amlodipine/benazepril combination product costs lessthan the same therapy administered as the individual components. It is,therefore, reasonable to consider therapy with amlodipine/benazepril inappropriate patients after an adequate trial of antihypertensivemonotherapy.

Keywords: amlodipine/benazepril, fixed dose combination therapy,hypertension

Exp. Opin. Pharmacother. (2001) 2(1):165-178

1. Introduction

Myocardial infarction and stroke remain the first and third leading causes ofdeath in the United States respectively. In addition, the incidence of heartfailure and end-stage renal disease has risen steadily over the last twodecades [1]. Given the association between uncontrolled hypertension andthese adverse outcomes, it is alarming to note that hypertension control issubstantially inadequate.

The most recent National Health and Nutrition Examination Survey(NHANES) III data indicate that only 73% of patients with hypertension are

1652001 © Ashley Publications Ltd. ISSN 1465-6566

Drug Evaluation

1. Introduction

2. Chemistry and productinformation

3. Pharmacology andpharmacodynamics

4. Pharmacokinetics

5. Clinical trials inhypertensive patients

6. Safety ofamlodipine/benazepril

7. Expert opinion

Bibliography

http://www.ashley-pub.com

Expert Opinion on Pharmacotherapy

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aware of their condition, with approximately 50% ofhypertensive patients receiving treatment [2]. Moreimportantly, only 29% of hypertensive patients havetheir blood pressure controlled to less than 140/90mmHg [2]. If the new blood pressure goals from theJoint National Committee on Prevention, Detection,Evaluation and Treatment of High Blood Pressure(JNC VI) for patients with diabetes, heart failure andrenal dysfunction (130/85 mmHg) or for patients with> 1 g of proteinuria per day (125/75 mmHg) wereconsidered, the percentage of patients achievingblood pressure control would be substantially lessthan 30% [3,4].

There are currently more than 70 antihypertensivedrugs available in the United States [5]. These includediuretics, β-blockers, ACE inhibitors, angiotensin IIreceptor blockers, α-blockers, calcium channelblockers and centrally-acting adrenergic inhibitors. Inlight of the availability of this extensive armamen-tarium of drugs to combat hypertension, it isparticularly unsettling that a substantial number ofpatients receiving antihypertensive therapy are notbeing controlled.

A variety of factors influence the ability to effectivelytreat and control hypertension. Some of these factorsinclude compliance, treatment approach, appropriateselection of therapy based on patient characteristicssuch as age, gender and race, the presence of othermedical considerations, failure to recognisesecondary causes of hypertension and cost. Althougha thorough review of these factors is beyond thescope of this paper, issues regarding treatmentapproach and selection of antihypertensive therapyfor individual patients is germane and will bediscussed briefly.

Antihypertensive therapy should be individualised toincrease chances for success. Due to their proveneffects on mortality reduction, diuretics andβ-blockers remain the drugs of choice for initialtherapy in patients with uncomplicated hypertension[3]. The JNC VI guidelines recommend other antihy-pertensive agents for patients with compellingindications for their use, such as ACE inhibitors forpatients with diabetes and renal dysfunction [3].

Materson et al. demonstrated that race and age affectresponses to antihypertensive drug therapy [6]. Inaddition to such demographic information, concomi-tant drug therapy must be considered, because theaddition of an antihypertensive agent may lead to theoccurrence of adverse events, or conversely, to

desirable additive effects. The likelihood that therapywith a particular agent could cause a pre-existingcondition to worsen should also be considered.Finally, the costs of drug therapy, includingmonitoring costs and the ability of a drug to affectquality of life, ought to be evaluated prior to the initia-tion of drug therapy [3].

The rationale for the use of two agents for thetreatment of high blood pressure is that by combiningdrugs with different mechanisms of action, it ispossible to produce additive blood pressurereduction with a tolerability profile equivalent to, orbetter than, the individual components [7]. Comparedwith single-agent therapy, the administration ofmultiple antihypertensive medications results intherapeutic success in 80 - 90% of individuals [8]. Datafrom The Hypertension Optimal Treatment trialdemonstrated that in order to reach a goal bloodpressure of ≤ 130/85 mmHg, a substantial number ofpatients required the addition of either an ACEinhibitor (41%) or a β-blocker (28%) to felodipinetherapy [9]. Preliminary information from theBaragwanath Hypertension APBM multi-arm studyalso demonstrated the need for combination therapyin 57% of subjects evaluated [10]. Single-agent therapyis likely to be inadequate in a considerable number ofpatients as clinicians attempt to achieve the latestblood pressure goals.

Often, monotherapy fails to decrease blood pressureto appropriate levels due to the stimulation ofcompensatory mechanisms [11,12]. Additionally, sideeffects with antihypertensive agents tend to be dose-related [5]. As such, with higher doses of single agentdrug regimens, which are often needed to achieveappropriate blood pressures, intolerable side effectsmay develop. This ultimately may result in a decreasein adherence and subsequent therapeutic failure.Indeed, side effects are the primary cause of the highincidence of non-adherence to antihypertensivetherapy [13]. A single product with two distinctpharmacologic components possessing differingmechanisms of action may provide a means to bypassthe occurrence of some adverse events by allowingfor the use of each agent at a low dose withoutforfeiting blood pressure control [5,11,14].

1.1 Amlodipine/benazepril

The combination product amlodipine/benazepril(Lotrel®) (Figure 1), approved March 3 1995, isdistributed by Novartis Pharmaceuticals Corporation.

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166 Amlodipine/benazepril

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The drug is comprised of a second-generation calciumantagonist (amlodipine) and an ACE inhibitor prodrug(benazepril), each of which is also marketedseparately for the control of blood pressure.Currently, this agent is FDA approved only for thetreatment of hypertension. The drug is not presentlyrecommended as an initial therapeutic option [3].

2. Chemistry and product information

The dihydropyridine calcium antagonist amlodipine(C20H25ClN2O5•C6H6O3S) is present in the combina-tion product as a besylate salt. It is a white crystallinepowder with minimal water and ethanol solubilities.The chemical name of the compound is (R,S) 3-ethyl-5 - m e t h y l - 2 - ( 2 - a m i n o e t h o x y m e t h y l )- 4 - (2 - ch lo ropheny l ) - 1 , 4 -d ihydro -6 -me thy l-3,5-pyridinedicarboxylate benzenesulfonate. Itsmolecular weight is 567.1.

Benazepril hydrochloride (C24H28N2O5•HCl) is aprodrug that is converted to its active form, benaze-prilat, through the hepatic cleavage of an ester group.The compound is a white to off-white crystallinepowder and is soluble in water, ethanol and methanolat > 100 mg/ml. Its chemical name is 3-[[1-(ethoxycar-bonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acidmonohydrochloride. The molecular weight ofbenazepril hydrochloride is 460.96.

Available formulations include capsules containing2.5/10 mg, 5/10 mg or 5/20 mg of amlodipine/benazepril, respectively [15].

3. Pharmacology and pharmacodynamics

3.1 Amlodipine

Controversy has surrounded the older first generationcalcium antagonists because of their association withan increased risk of myocardial infarction anddose-related mortality. This lead to the developmentof second generation calcium channel blockers [16].Amlodipine, a member of this newer drug class, is adihydropyridine calcium antagonist that differs fromthe prototype first generation dihydropyridine,nifedipine, primarily due to the addition of a basicamino side chain attached to the characteristicdihydropyridine ring. It is theorised that this structuralalteration is responsible for the unique properties ofthe drug [17].

Amlodipine is noted to bind to receptors in a fashionunlike other calcium channel blocking agents.Although it is a dihydropyridine calcium antagonist, itdemonstrates interactions with both the phenylal-kylamine and benzothiazepine binding sites [18]. Theslow rate at which amlodipine binds to and dissoci-ates from receptors further demonstrates its uniqueproperties compared to other calcium antagonists.This gradual binding, and the subsequent even onsetof action, result in a comparatively lower incidence ofreflex tachycardia [16,19]. Amlodipine’s extendedhalf-life (≥ 31 h) and prolonged receptor affinitycontribute to its sustained pharmacologic effects,allowing for 24 h blood pressure control and oncedaily dosing [16,19].

Calcium antagonists exert their pharmacologic actionby inhibiting the influx of calcium through voltage-dependent L-channels. This inhibition decreasescontraction in myocardial tissue and vascular smoothmuscle without affecting skeletal muscle [17,19,20].Total coronary blood flow is enhanced by all calcium

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Faulkner & Hilleman 167

NH

OO

O O

Cl

NH2

O

Amlodipine

N

NH

O

O

O

O

OH

Benazepril

Figure 1: Chemical structure of amlodipine and benazepril.

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antagonists due to their ability to decrease vasculartone and resistance in the coronary circulation [19].

The ability of the calcium channel blockers to causevasodilation is substantially greater on the arteriolarside than the venous side. The resultant decrease intotal peripheral resistance is primarily responsible forthe antihypertensive effect of the calcium antagonists[20]. Vascular selectivity varies widely among theseagents. Older calcium antagonists exhibit very lowselectivity for vascular tissue. Often, the higher dosesof first-generation agents that are needed to produceadequate vasodilation to lower blood pressure canadversely affect the contractility of the heart [16].Amlodipine’s affinity for vascular tissue is muchgreater than its affinity for the myocardium.Therefore, at lower doses it maintains its ability tolower blood pressure by decreasing peripheralvascular resistance without reducing the contractilityof myocardial tissue. This makes the drug a moredesirable agent than the first-generation calciumantagonists in patients with heart failure, leftventricular dysfunction or sinus dysfunction, forwhom negative inotropy might be a problem [16,19].

3.2 Benazepril

The ACE inhibitors were developed in an attempt tomodulate the renin-angiotensin system, as it plays asignificant role in the preservation of electrolyte andblood pressure control. ACE inhibitors suppress thevasoconstrictive effect of angiotensin II by blocking itsconversion from angiotensin I. The result is a decreasein both arterial and venous peripheral vascularresistance with a subsequent decrease in bloodpressure and a reduction in preload and afterload(Figure 2) [21]. The decline in angiotensin II levelsresults in an increase in renin and a decrease inaldosterone [22]. Sodium and water reabsorption inthe proximal tubule is lessened with a subsequentreduction in blood volume and blood pressure.Additionally, the ACE inhibitors decrease degradationof the vasodilator bradykinin. This too may play a rolein the regulation of blood pressure [21].

Like the majority of ACE inhibitors, benazepril is aprodrug. Benazepril hydrochloride undergoeshydrolysis after administration to produce benaze-prilat, its biologically active form [22]. The drug iscategorised as a non-sulfhydryl ACE inhibitor. It bindsto ACE at the zinc binding ligand by way of a carboxyl

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Pharmacother. (2001) 2(1)

168 Amlodipine/benazepril

Angiotensinogen

Angiotensin I

Angiotensin II

Vasoconstriction ↑ Aldosterone

↑ Sodium reabsorption

water retention

↑ Blood pressure

↑ Preload

↑ Afterload

Renin

ACE

Figure 2: The renin-angiotensin-aldosterone system.ACE: Angiotensin-converting enzyme.

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group [23]. Compared to other ACE inhibitors, it isamong the most potent when considering inhibitionof ACE in the tissue and is considered a long actingagent [23,24].

4. Pharmacokinetics

The individual pharmacokinetic characteristics ofamlodipine and benazepril are not significantlydifferent than the kinetic properties of eachcomponent when administered as the combinationproduct [25]. Therefore, the profile of each will bediscussed separately.

4.1 Amlodipine

Most calcium antagonists undergo extensive first passmetabolism in the liver with bioavailabilities typically< 50%. Amlodipine, however, has a reported bioavail-ability between 64 and 90% [19,26]. Regardless ofdose, peak plasma concentrations are typicallyachieved within 6 - 9 h of medication administration[26,27]. Faulkner et al. noted that after two weeks ofmedication use, the steady-state drug concentration ofamlodipine was 18.1 ± 7.1 µg/l [26].

In comparison to other calcium antagonists,amlodipine is more hydrophilic due to the existenceof a unique side chain. This chain is positively chargedwhich allows the drug to interact with phospholipidmolecules in such a way that a substantial membraneattraction is produced [17,28]. This phenomenoncontributes to amlodipine’s sizeable volume of distri-bution (21 l/kg), which is substantially larger thanother members of the drug class [17,26]. Like othercalcium antagonists, amlodipine demonstrates signifi-cant protein binding (> 90%) [19].

Though the extent of amlodipine metabolism isconsiderable, it occurs slowly, allowing for anextended duration of action [28]. Metabolites ofamlodipine are pharmacologically inactive. Onlyabout 10% of the parent compound is excretedunchanged in the urine. The half-life (t½) of a singleoral dose of amlodipine is reported to be between 31and 37 h [26,27]. As this is substantially longer than thet½ of benazeprilat, the time to achieve steady-statewith the combination product (approximately 6 - 7days) is determined by the amlodipine component[15,25]. The pharmacokinetics of amlodipine appearto be linear [27]. Its t½ remains relatively constantregardless of the dose given. Total body clearance isapproximately 7 ml/min/kg [26,29].

4.2 Benazepril

Absorption of benazepril is relatively limited at only37% [24]. Mean time to peak concentration is 0.5 h [30].After absorption, the conversion of benazepril tobenazeprilat is rapid. Peak concentrations of themetabolite are achieved at a mean time of 1.5 h (range1 - 6 h) [30]. Benazeprilat is highly bound to plasmaproteins (> 90%), as is its parent compound. Thevolume of distribution of benazeprilat is significantlysmaller than that of amlodipine at approximately 0.7l/kg.

Transformation of benazepril to benazeprilat isrelatively complete with only trace amounts of theparent compound recoverable in the urine. Approxi-mately 20% of benazeprilat is excreted in the urineunchanged [30]. The glucuronide metabolites ofbenazeprilat and benazepril make up 8% and 4% ofthe excreted dose respectively. Elimination of theactive drug component is primarily through the renalroute, although there is evidence that up to 12% ofbenazeprilat is excreted by the biliary system [15].Benazeprilat exhibits biphasic elimination pharma-cokinetics, with an initial t½ of approximately 2.7 hand a terminal t½ of about 23 h [30]. As the accumula-tion t½ (approximately 11 h) is less than the terminalt½ of benazeprilat, it is unlikely that the drug willaccumulate extensively in the body of a normalindividual with regular dosing [24,30]. The renalplasma clearance of benazeprilat is noted to average22.7 ml/min [30].

4.3 Pharmacokinetics in special populations

Kaiser and colleagues studied the effects of renaldysfunction on benazepril pharmacokinetics [31].They noted that patients with a creatinine clearance of< 30 ml/min demonstrated a benazeprilat area underthe concentration-time curve (AUC) more than fourtimes the value for persons with normal renalfunct ion. I t is not recommended thatamlodipine/benazepril be given to individuals with acreatinine clearance below this level. This same groupof investigators noted that although concentrations ofthe prodrug benazepril were found to be doubled inpatients with cirrhosis, benazeprilat concentrationsand bioavailability were not altered leading them toconclude that no dose adjustment is necessary forpatients with cirrhosis who are to receive benazepril[31].

However, hepatic disease may significantly affectamlodipine kinetics. Abernathy noted an elimination

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Faulkner & Hilleman 169

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t½ of amlodipine in patients with cirrhosis that wasnearly two times that of a group of normal volunteers(60 vs. 34 h). The authors concluded that accumula-tion of the drug in patients with significant hepaticdisease is likely [32]. The manufacturer ofamlodipine/benazepril recommends initiatingtherapy with the 2.5/10 mg formulation for patientswith hepatic disease [15].

Abernathy studied the age-related changes in olderpersons taking amlodipine. Patients 65 years of ageand older were compared to patients ≤ 45 years old.Over a 10 week period, doses of amlodipine weretitrated up to a maximum of 10 mg/day until diastolicblood pressures were < 90 mmHg. The washoutelimination t½, though longer in the older group, wasnot significantly different [33].

In older persons, amlodipine/benazepril should bedosed cautiously due to the possibility of increasedsensitivity to the drug and should be adjusted forhepatic and renal dysfunction as discussed above.Initial amlodipine doses of 2.5 mg/day are warranted[15].

4.4 Pharmacokinetic interactions

The safety of benazepril in combination with oralanticoagulants, β-blockers, cimetidine, diuretics,digoxin, hydralazine and naproxen has beendemonstrated. Additionally, amlodipine given withthiazides, β-blockers, nitrates, digoxin, warfarin,non-steroidal anti-inflammatory drugs (NSAIDs), ororal hypoglycaemic agents has not been linked toclinically significant drug interactions to date [15].

Studies in normal volunteers have demonstrated nosignificant drug interactions between benazepril andsalbutamol [34], benazepril and aspirin [35], oramlodipine and grapefruit juice [36]. Several reportshave implicated ACE inhibitors in other potentiallyserious drug interactions, including hyperkalaemiawith potassium supplements or salt substitutes [37-39],and lithium toxicity when given in combination with amember of that drug class [40]. Caution and closemonitoring are warranted when these medications aregiven to individuals taking amlodipine/benazepril.

5. Clinical trials in hypertensive patients

The results of the following trials are summarised inTables 1 and 2.

5.1 Clinical efficacy of amlodipine/benazeprilversus placebo

Fogari and colleagues performed a double-blind,placebo-controlled, randomised study of 24 men withessential hypertension, defined according to WorldHealth Organization criteria as mild-to-moderate [41].Every 3 weeks, 24 h blood pressure monitoring wasperformed. The mean systolic and diastolic bloodpressures of the study participants were 164.6 ± 5.8mmHg and 104.9 ± 3.9 mmHg after a 2 week placebowashout period. At 9 a.m. daily, subjects took eitheramlodipine 10 mg/benazepril 2.5 mg or placebo. After3 weeks, the subjects crossed over to the oppositeregimen. Blood pressures were measured 23.5 - 24.5 hafter the previous dose. A comparison of 24 h bloodpressures revealed a statistically significant (p =0.0001) difference between systolic blood pressure(mean 128.7 ± 7.3 mmHg vs. 145.9 ± 9.1 mmHg) anddiastolic blood pressure (80.7 ± 6.1 mmHg vs. 93.2 ±5.6 mmHg) for the fixed dose combination ofamlodipine/benazepril and placebo, respectively.Individual measurements of daytime and night-timeblood pressures were statistically significant as well[41].

5.2 Clinical efficacy of amlodipine/benazeprilversus other agents

A meta-analysis by Hilleman et al. examined theresults of recent therapeutic trials evaluating theefficacy of nine individual medications, (verapamil,atenolol, enalapril, lisinopril, amlodipine, nifedipine,hydrochlorothiazide, diltiazem and captopril) andone therapeutic combination (amlodipine/benaze-pril) for the treatment of mild to moderatehypertension [42]. In total, 82 studies with 110separate cohorts were included. Supine diastolicblood pressure was the primary determinate ofefficacy, and control of blood pressure wassecondary. Mean differences in blood pressure, whenweighted by the inverse of the variance estimates,were highest with the β-blocker atenolol and thecombination of amlodipine/benazepril, each with anaverage decrease in blood pressure of 11.7 mmHg.The highest number of patients achieving bloodpressure control did so with lisinopril monotherapy(79%) and amlodipine/benazepril (74.3%) [42].

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170 Amlodipine/benazepril

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5.3 Clinical efficacy of amlodipine/benazeprilcombination therapy versus amlodipine and/orbenazepril alone

Fogari and colleagues reported the results of a secondstudy comparing the combination of amlodipine andbenazepril with benazepril monotherapy forhypertension treatment in 448 subjects [43]. For thisrandomised, double-blind, parallel group, multicentrestudy, patients were determined to be eligible if theyhad a diastolic blood pressure between 100 - 120mmHg after a 2 week placebo run-in period. Eachsubject took study medication once daily for a total of8 weeks as benazepril (10 mg)/placebo, amlodipine(2.5 mg)/benazepril (10 mg), or amlodipine (5mg)/benazepril (10 mg). Treatment was consideredsuccessful if diastolic blood pressure (sitting) had

either dropped a minimum of 10 mmHg frompre-study levels, or was < 90 mmHg. At the end of the8-week period, differences in diastolic pressures weresignificantly less in both combination treatmentgroups than in the group receiving benazepril alone.The mean blood pressure in the single-agent groupwas 94.9 ± 10.4 mmHg compared to 90.2 ± 9.3 mmHgin the amlodipine (2.5 mg)/benazepril (10 mg) group(p = 0.0001) and 90.2 ± 9.4 mmHg in the amlodipine (5mg)/benazepril (10 mg) group (p = 0.0006). Differ-ences also reached statistical significance whencomparing standing diastolic blood pressure, as wellas systolic blood pressure (both sitting and standing)[43].

A trial comparing the efficacy of combinationamlodipine/benazepril with each agent individually

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Faulkner & Hilleman 171

Table 1: Mean blood pressure reduction at study end points in clinical trials evaluating efficacy of amlodipine/benazepril in mild tomoderate hypertension.

Doses (mg/day) Absolute reduction in SBP (mmHg) Absolute reduction in DBP (mmHg) Ref.

Placebo vs. A2.5/B10 19.6 (p = 0.0001) 14 (p = 0.0001) [41]

B10 vs. A2.5/B10 7.9 (p = 0.0001) 5.3 (p = 0.0001) [43]

B10 vs. A5/B10 7.9 (p < 0.0001) 4.5 (p = 0.0006)

Placebo vs. A5 16.2 (p < 0.001) 8.8 (p < 0.001) [45]

Placebo vs. B20 12.4 (p < 0.001) 6.7 (p < 0.001)

Placebo vs. A5/B20 24.7 (p < 0.001) 13.2 (p < 0.001)

Baseline vs. B10 18.1 (p < 0.001) 11.9 (p < 0.001) [46]

Baseline vs. A5/B10 24.6 (p < 0.001) 16.6 (p < 0.001)

A: Amlodipine; B: Benazepril; DBP: Diastolic blood pressure; SBP: Systolic blood pressure.

Table 2: Rates of success§ in clinical trials evaluating efficacy of amlodipine/benazepril in mild to moderate hypertension.

Doses (mg/day) Percent response Ref.

B10 40.5% [43]

A2.5/B10 69.2%

A5/B10 65.8%

Placebo 18.3% [44]

B10 37.7%

A2.5 40.5%

A2.5/B10 61.5%

Placebo 15.8% [45]

A5 67.5%

B20 53.3%

A5/B20 87%§Success was defined as diastolic blood pressure below 90 mmHg or a decrease in diastolic blood pressure of ≥ 10 mmHgcompared to baseline.A: Amlodipine; B: Benazepril.

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for the treatment of hypertension was conducted byFrishman and colleagues [43]. A total of 293 patientswith mild to moderate hypertension completed thestudy. After a 2 - 4 week placebo run-in phase wasfinished, patients were randomised to receive eitherplacebo, amlodipine (2.5 mg) alone, benazepril (10mg) alone or a combination of amlodipine (2.5mg)/benazepril (10 mg) daily for a total of 8 weeks.Blood pressures were evaluated between hour 22 and27 after the previous dose at several intervals duringthe study. Criteria for success was defined as a meandiastolic blood pressure of < 90 mmHg, or a 10 mmHgdecrease from pretreatment values. Successfuloutcomes were demonstrated by 18.3% of patientsreceiving placebo, 37.7% of patients receivingbenazepril monotherapy, 40.5% of patients receivingamlodipine monotherapy and 61.5% of patients oncombination therapy. Statistically significant differ-ences were noted when comparing changes in bloodpressure for those receiving amlodipine plus benaze-pril with each of the other three treatment groups (p =< 0.001 for placebo, p = 0.002 for benazepril 10 mgand p = 0.008 for amlodipine 2.5 mg) [44].

Kuschnir et al. described the results of a multicentre,double-blind, randomised, parallel group studycomparing the efficacy of four once-a-day drugregimens for the treatment of essential hypertension[44]:

• amlodipine 5 mg/benazepril 20 mg

• amlodipine 5 mg alone

• benazepril 20 mg alone

• placebo.

A 2 - 4 week placebo run-in period was completed byeligible patients, each of whom demonstrated a sittingdiastolic blood pressure of between 100 - 120 mmHg.Randomisation to one of the four treatment groupswas completed, and therapy continued for a total of 8weeks. Measurements were taken 23 - 26 h after theprevious dose at predetermined points of evaluation.A total of 285 subjects completed the study. Each armreceiving active drug was statistically superior toplacebo for the reduction of both sitting diastolic andsitting systolic blood pressure (p < 0.001). Addition-ally, the combination of amlodipine/benazepril wassignificantly more effective than the amlodipine andbenazepril monotherapy groups (p < 0.001). Thecombination therapy group also demonstrated amaximum hourly mean diastolic blood pressure (by24 h ambulatory monitoring) of 90.2 mmHg compared

to 96 mmHg and 96.4 mmHg for amlodipine andbenazepril, respectively. Of patients receiving theamlodipine/benazepril combination, 87% had adecrease in mean sitting diastolic blood pressure of ≥10 mmHg or more from baseline, or a pressure of < 90mmHg compared with 67.5% with amlodipine, 53.3%with benazepril and 15.8% with placebo (p ≤ 0.005 foreach group) [45].

5.4 Clinical efficacy of amlodipine/benazeprilcombination therapy versus benazepril alone inpatients with Type 2 diabetes andmicroalbuminuria

Fogari and colleagues conducted a study that assessedchanges in urinary albumin excretion in diabeticpatients with hypertension and microalbuminuriawhen a combination of amlodipine/benazepril orbenazepril alone was used [46]. Patients included inthe study all had Type 2 diabetes controlled by oralhypoglycaemics, sitting diastolic blood pressures of96 - 114 mmHg and a urinary albumin excretion (UAE)of ≥ 30 and ≤ 300 mg/day. No patient had beendiagnosed with chronic renal failure. In total, 45patients were randomised to either amlodipine (5mg)/benazepril (10 mg) daily or benazepril (10 mg)daily. Patients were followed for 6 months. Combina-tion therapy resulted in a significantly larger decreasein blood pressure at both 3 and 6 months than didmonotherapy (p = 0.05). Although creatinineclearance decreased slightly in patients treated withbenazepri l a lone, the combinat ion ofamlodipine/benazepril increased values by 7.5% at 3months and 9.8% at 6 months (p < 0.05 and p < 0.02,respectively). UAE was reduced by both therapies at 3and 6 months. The changes at 3 months were notsignificantly different between the two treatmentgroups. However, at 6 months the patients receivingcombination therapy demonstrated a mean decreasein UAE of 24.6% (p < 0.02) compared to a 19.7%decrease with benazepril monotherapy (p < 0.04).The difference, although somewhat better withcombination therapy, was not statistically different.Glycaemic control did not appear to be affected byeither treatment [46].

6. Safety of amlodipine/benazepril

6.1 Adverse effects with amlodipine

As would be expected, the vascular selectivity ofamlodipine and its ability to cause significant arterial

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vasodilation are responsible for several of the mostcommon side effects observed in patients taking thedrug [16]. Side effects associated with this mechanisminclude headache, dizziness and oedema, which werereported to occur at rates of 2.2%, 1.3% and 2.1% inplacebo-controlled studies conducted in the UnitedStates [15]. The oedema associated with the use ofcalcium antagonists is primarily due to the fact that thevasodilation produced with these agents is arterialand unopposed, leading to heightened hydrostaticpressure in the capillaries and subsequent leakage offluid. Therefore, the complement of an agent thatdilates on the venous side, such as an ACE inhibitor,would be expected to offset this effect making thecombination more tolerable than the calcium antago-nist alone [5].

Unlike some of the shorter acting calcium antagonistswhich can stimulate sympathetic responses due totheir abrupt onset, amlodipine does not appear toincrease levels of noradrenaline [47]. This differenceappears to be related to the ability of amlodipine tomaintain consistent blood pressure control over a full24 h period, thus avoiding the fluctuations seen withthe shorter-acting agents.

6.2 Adverse effects with benazepril

The ACE inhibitors are generally considered to have afairly benign side effect profile [48]. One of the mostfrequently observed side effects with this class ofdrugs is a dry, irritating cough which occurs at a rate of1 - 10% [22]. This effect is believed to be related to thedecreased breakdown of substances that maycontribute to cough (primarily bradykinin) secondaryto ACE inhibition. In a review of the controlled trialssubmitted to the FDA for consideration in theapproval of benazepril for the treatment of hyperten-sion, MacNab and Mallows noted headache, dizzinessand fatigue to be the most commonly reportedadverse events. Additionally they found an overallincidence of side effects of 20% in the benazepril-treated patients vs. 18% in the those receiving placebo[48]. There did not appear to be a trend towardsincreased adverse events in older subjects or insubjects being given higher doses of the ACEinhibitor. Patients with high renin often have sympto-matic hypotensive episodes, as do patients who arevolume depleted upon drug initiation [48].

All ACE inhibitors are believed to have the ability toinduce an increase in serum potassium levels due tothe decrease in aldosterone production related to their

use. MacNab and Mallows noted that although mostpatients studied did demonstrate elevated potassium,levels typically remained within the normallyaccepted range. The same investigators noted a 0.2%occurrence of angioedema in study participants, withall episodes categorised as mild [48]. This is consistentwith other members of the drug class, as angioedemais considered rare [23].

ACE inhibitors may cause renal failure in patients whoare predisposed [23]. These patients generally havesome degree of underlying renal dysfunction (usuallyrenal artery stenosis) prior to the initiation of the ACEinhibitor. Transient increases in serum creatinine havebeen noted in some patients as well [48].

Some adverse effects associated with ACE inhibitoruse are generally only observed with agents that havesulfhydryl groups. These include rash, alterations intaste, proteinuria and neutropenia. Benazepril is notlikely to be associated with these effects due to theabsence of a sulfhydryl group in its chemical composi-tion [48].

6.3 Adverse effects in clinical trials withamlodipine/benazepril

Of the 448 patients who took part in the trial describedby Fogari et al. comparing benazepril alone tocombination therapy with amlodipine/benazepril,13% of the patients in the single agent treatment groupreported adverse events [43]. In the combinationtherapy groups, adverse event rates were 15% and12% for amlodipine (2.5 mg)/benazepril (10 mg) andamlodipine (5 mg)/benazepril (10 mg), respectively.The most commonly experienced adverse eventswere cough (16 subjects), leg oedema (nine subjects),headache (seven subjects) and hot flushes (foursubjects) (Table 3). No patient complained ofsymptoms related to orthostatic hypotension,although four subjects (two each in the benazepril (10mg) group and the amlodipine (2.5 mg)/benazepril(10 mg) group) experienced a drop in blood pressureof ≥ 20 mmHg diastolic or ≥ 30 mmHg systolic. Therewere no study withdrawals related to side effects(Table 4) [43].

Frishman and colleagues noted headache to be themost common side effect reported by 329 subjects in astudy comparing amlodipine or benzaepril alone tothe combination or placebo [44]. More patients in theplacebo group (22%) complained of headache than inany of the treatment groups (Table 3). The lowestincidence of headache was noted in the combination

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therapy group (amlodipine (2.5 mg)/benazepril (10mg); 9.6%). There did not appear to be any differencein the number of patients experiencing dizziness inany of the three active treatment arms. The incidenceof cough was higher in the two groups given benaze-pril (3.5% with benazepril alone and 2.4% with thecombination) compared to the placebo group (1.2%)and the amlodipine monotherapy group (0%).Oedema was seen more frequently in the placebogroup and the amlodipine group (4.9% and 3.8%respectively) than in the benazepril monotherapygroup or the combination group (1.2% each).Clinically significant orthostatic blood pressurechanges, defined as a diastolic decrease of > 15 mmHg

or a systolic decrease of > 30 mmHg, were observed infive patients, three of whom were in the placebogroup. No patient in the amlodipine monotherapygroup demonstrated orthostatic changes and nopatient was symptomatic. Potassium increases of >25% were observed in one patient taking placebo, onepatient taking the combination therapy and twopatients in each of the monotherapy groups. Nomedical problems related to the changes wereobserved. A total of 13 subjects withdrew from thestudy due to adverse events (Table 4). The lowestwithdrawal rate occurred in the combination therapygroup with a rate of 1.2%, while the highest rate wasseen in the amlodipine (2.5 mg) group (6.1%). The

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174 Amlodipine/benazepril

Table 3: Adverse event rates in clinical trials evaluating amlodipine/benazepril in mild to moderate hypertension.

Doses (mg/day)

Adverseevent

Placebo A2.5 A5 B10 B20 A2.5/B10 A5/B10 A5/B20 Ref.

Headache

4.2% [41]

1.9% 1.4% 1.4% [43]

22% 11.4% 17.6% 9.6% [44]

Cough

3.1% 2.8% 4.8% [43]

1.2% 0% 3.5% 2.4% [44]

Dizziness

4.2% [41]

0% 5.1% 3.5 4.8% [44]

Oedema

4.2% 8.3% [41]

1.3% 1.4% 3.4% [43]

4.9% 3.8% 1.2% 1.2% [44]

5.2% 16.9% 1.3% 7.8% [45]

A: Amlodipine; B: Benazepril.

Table 4: Rates of withdrawal secondary to adverse events in clinical trials evaluating amlodipine/benazepril in mild-to-moderatehypertension.

Doses (mg/day)

Placebo A2.5 A5 B10 B20 A2.5/B10 A5/B10 A5/B20 Ref.

0% 0% [41]

0% 0% 0% [43]

4.9% 6.1% 3.5% 1.2% [44]

2.6% 5.2% 1.3% 1.3% [45]

A: Amlodipine; B: Benazepril.

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benazepril (10 mg) group and the placebo groupdemonstrated withdrawal rates of 3.5% and 4.9%respectively [44].

A total of 308 patients in a trial described by Kuschniret al. demonstrated adverse event rates of 29.9% and35.1% in patients receiving placebo and amlodipine (5mg) respectively [44]. Fewer adverse events werenoted in patients taking benazepril (20 mg) andamlodipine (5 mg)/benazepril (20 mg) (19.5% each).The difference between the amlodipine group and thecombination therapy group reached statistical signifi-cance (p = 0.032). Of the side effects reported,oedema was the most frequent (Table 3). In theamlodipine group, 16.9% of patients experiencedoedema and four subsequently discontinued therapy.In contrast, 7.8% of patients in the combinationtherapy group were noted to have oedema, one ofwhom withdrew. For the remaining two treatmentgroups, patients that dropped out of the studyincluded one patient receiving benazepril alone andtwo patients in the placebo group (Table 4) [45].

7. Expert opinion

Several factors contribute to the difficulties that maybe encountered when trying to achieve adequateblood pressure control. The willingness of a patient toadhere to a drug therapy regimen is clearly one of themost important variables. Among other things,adherence can be affected by drug cost, side effectsand dosing regimens [49]. Certainly, the once-a-dayformulation of amlodipine/benazepril is likely toimprove the probability that patients will take theirmedication as scheduled. However, drug regimenadherence, even with a once-a-day drug, is notperfect [49].

Despite the occasional missed dose, it has beendemonstrated that blood pressure control in patientsreceiving amlodipine remains adequate due to thedrug’s long duration of action. Even when a dose ofamlodipine is missed, the mean blood pressureresponse is typically at least 50% of the peak effect ofthe drug. This is similar to the response noted attrough levels taken just prior to the next dose in theface of proper adherence [50]. The availability of aonce-a-day combinat ion product such asamlodipine/benazepril should help offset the miscon-ception that single drug therapy is more convenientthan multiple drug therapy [5].

As doses of antihypertensive agents increase, theincidence of side effects, some of which may beintolerable and lead to non-adherence, may alsoincrease [7,8]. As demonstrated by the trialssummarised previously, the incidence of side effectswith the combination of amlodipine/benazepril is nogreater than that noted with either of the two agentsgiven as monotherapy. In fact, rates of adverse eventsoften correlate with, or are less frequent than, thosereported in patients randomised to placebo [43-45,48].One of the benefits of the amlodipine/benazeprilcombination is a decreased incidence of oedema ascompared to amlodipine monotherapy [44,45].Additionally, neither benazepril or amlodipineappears to possess any significant tendency towardscausing adverse metabolic changes [12].

Cost is always a concern when prescribing newmedications. One argument in favour of delayingtreatment with multiple drugs, until an adequate trialwith a single agent has been accomplished, is thatmonotherapy is likely to be less expensive comparedto combination therapy. However, in the event thatmultiple drug therapy is needed, the choice to use twoindividual agents versus a fixed-dose combinationproduct is likely to favour the latter when cost isexamined. Considering that for each separate agentprescribed, there will not only be the cost of the drugitself, but a co-payment and a dispensing fee, acombination product like amlodipine/benazepril willprobably be among the more cost-friendly antihyper-tensive regimens [5]. The decreased frequency ofadverse events compared to high dose monotherapyshould also contribute to keeping expenses down.There is less titration with a fixed dose product, andthe price of the combination drug is substantiallylower than the cost of amlodipine and benazeprilpurchased separately [5]. One potential disadvantage,however, is that fixed-dose combination therapy maylimit the number of dose combinations available.

In order for a combination agent to be approved,several criteria set forth by the FDA must be met.These criteria include evidence that compared to thesum of the individual agents the combination productis more efficacious, evidence that the safety profile ofthe combination is at least equivalent to that observedwith either of the individual agents and evidence thatthe risk/benefit ratio for the combination is less thanthat of either of the agents alone [42]. As demonstratedby the studies summarised here, the combination ofamlodipine/benazepril satisfies these criteria.

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Multiple clinical trials have demonstrated that lowerblood pressures reduce cardiovascular risk. Evensmall differences in the extent of blood pressurereduction can have profound effects on patientoutcomes. The UK Prospective Diabetes Study Groupreported significant differences in rates of fatal andnon-fatal stroke (44%) and diabetes-related mortality(32%) between patients with average blood pressuresof 144/82 mmHg versus 154/87 mmHg [51]. TheHypertension Optimal Treatment trial investigatorsreported similar findings for diabetic subjects withonly a 4 mmHg decrease in blood pressure [9]. Datafrom these two trials clearly support the belief thatpatients achieving the lowest blood pressures alsohave the lowest rates of adverse cardiovascularevents.

There are currently no studies demonstrating thatantihypertensive therapy with a dihydropyridinecalcium channel blocker alone decreases the cardio-vascular event rate. The Fosinopril AmlodipineCardiac Events Trial, a study comparing fosinopril andamlodipine monotherapies with a combination of thetwo, demonstrated no significant reduction in cardio-vascular events when amlodipine was given as asingle agent [52]. The best results for both bloodpressure and cardiovascular events were in factachieved in the combination therapy group.

Optimal blood pressure reduction is essential forpatients with diabetes not only to decrease the risk ofcardiovascular complications, but also to preserverenal function. Although dihydropyridine calciumantagonist monotherapy does not appear to havesignificant effects on the preservation of renalfunction in diabetic patients, both animal and humandata demonstrate that the combination of an ACEinhibitor and a dihydropyridine calcium antagonist iscapable of decreasing proteinuria, which is nowrecognised as an independent risk factor for bothrenal and cardiovascular diseases [53,54]. The Modifi-cation of Diet in Renal Disease study confirmed thatthe extent of proteinuria was significantly reduced insubjects achieving the lowest blood pressures [55].Furthermore, higher blood pressures were associatedwith a more rapid decline in renal function asmeasured by glomerular filtration rate. It thereforestands to reason that in addition to the anticipatedcardiovascular benefits, controlling blood pressurewith an ACE inhibitor/dihydropyridine calciumantagonist combination is likely to result in the preser-vation of renal function in patients with diabetes.

Currently there are limited morbidity and mortalitydata evaluating fixed dose combination therapycompared to that available for the various monothera-pies. Long-term trials assessing cardiovascular andrenal outcomes are eagerly awaited. However,although it makes sense to initiate drug therapy forhypertension with a single agent initially, combina-tion therapy should be considered before extensivedose titration in the interest of preventing theproblems that can lead to non-adherence, and inorder to achieve blood pressure control as rapidly aspossible.

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Michele A Faulkner† & Daniel E Hilleman†Author for correspondenceCreighton University School of Pharmacy and Allied HealthProfessions, 2500 California Plaza, Omaha, Nebraska 68178, USATel.: +1 402 280 4233; Fax: +1 402 280 5219;E-mail: [email protected]

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178 Amlodipine/benazepril