The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension Focus on Recent Studies

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1 REVIEW ARTICLE Am J Cardiovasc Drugs 2010; 10 (5): /10/ /$49.95/0 ª 2010 Adis Data Information BV. All rights reserved. The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension Focus on Recent Studies Steven G. Chrysant Oklahoma Cardiovascular and Hypertension Center, University of Oklahoma School of Medicine, Oklahoma City, Oklahoma, USA Contents Abstract Introduction Rationale for Fixed-Dose Combination Therapy Angiotensin Receptor Blocker/Calcium Channel Blocker Fixed-Dose Combination Therapy: Results from Factorial Design Studies Discussion Abstract Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90 mmhg for uncomplicated and <130/80 mmhg for patients with diabetes mellitus or renal disease. For those with uncontrolled, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of include several major classes of drugs: diuretics, b-adrenoceptor antagonists (b-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [s]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of s in combination with amlodipine for the treatment of, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with s revealed six publications, which are included in this review. 1. Introduction The prevalence of (BP 140/90 mmhg) in the US adult population has increased by 10% from 65 million in 2005 to 72 million in. [1] Despite advances in drug therapy, the percentage of patients with who achieve BP control (BP <140/90 mmhg) remains low, at 36.8%. [2] Uncontrolled is associated with and is a risk factor for chronic kidney disease, diabetes mellitus, stroke, and cardiovascular disease. The relationship between BP and risk of cardiovascular events is continuous, consistent, and independent of other risk factors. [3] Hypertension is a major risk factor for heart failure and atherosclerotic cardiovascular events. [4] In addition, with every 20 mmhg increase in systolic BP or 10 mmhg

2 316 Chrysant increase in diastolic BP, the risk of cardiovascular disease is doubled. [5,6] Because uncontrolled increases the risk of vascular events, it is imperative to increase the percentage of individuals who achieve BP control, and the challenge in achieving this goal is the need for multiple-drug combination therapy in most patients. Fixed-dose drug formulations that contain two classes of agents with complementary mechanisms of action are increasingly available. These drug combinations allow patients to reduce pill burden and potentially reduce the cost of care. In this article, we discuss fixed-dose therapy with the calcium channel blocker (CCB) amlodipine combined with different angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [s]), two drug classes that have been shown to be effective in the treatment of, and are safe and well tolerated. A MEDLINE search from 2006 to 2009 of the English literature revealed six such publications, which are included in this concise review. 2. Rationale for Fixed-Dose Combination Therapy Using two separate drugs with complementary mechanisms of action for the treatment of has long been accepted by physicians. However, the fixed-dose combination of two complementary drugs was slow in gaining acceptance. Because the goal of antihypertensive treatment is to maximize therapeutic efficacy without significant adverse effects, the combination of two low-dose complementary drugs was a reasonable choice. Such low-dose combination therapy has resulted in better BP control, fewer adverse effects, prolonged duration of the antihypertensive effect due to different halflives of component drugs, lower cost of care, and increased patient compliance. [7,8] Because several dose strengths of fixeddose combinations are available, the dosing flexibility is not lost. [8] Concerning the combination of dihydropyridine CCBs with s, their complementary action results from arteriolar dilation and natriuresis by the CCB and counteraction on the effects of stimulated angiotensin II by the s. [9] Another benefit of this combination is the alleviation of pedal edema associated with dihydropyridine CCB monotherapy. [9-12] The pedal edema produced mostly by the dihydropyridine CCBs is due to their preferential arteriolar vasodilation, which creates a pressure gradient between the arteriolar and venular capillaries, leading to fluid exudation in the interstitial tissue. The addition of s, by producing both arteriolar and venular dilation, decreases the pressure gradient and facilitates the absorption of interstitial fluid and the alleviation of pedal edema. [9-12] 3. Angiotensin Receptor Blocker/Calcium Channel Blocker Fixed-Dose Combination Therapy: Results from Factorial Design Studies The fixed-dose combination of an and a CCB offers the additional benefit of reduced incidence of cough and angioedema induced by the ACE inhibitors (ACEIs), [13,14] without compromising their BP-lowering effects. Besides cough reduction, the /CCB combination also reduces CCB-induced peripheral edema and, in addition, imparts a greater BP reduction than monotherapy with amlodipine. [11,15-17] Several recent studies have demonstrated the significant BP reduction and excellent tolerance of these combinations (table I). [11,15-19] The first approved /CCB combination (June ) of valsartan plus amlodipine was supported by a study by Philipp et al. [15] and evaluated the efficacy and safety of different amlodipine (2.5, 5, and 10 mg) and valsartan (40, 80, 160, and 320 mg) dose combinations over an 8-week period in 1911 patients with. The primary efficacy variable, change from baseline in mean sitting diastolic BP (MSDBP), and secondary variable, change from baseline in mean sitting systolic BP (MSSBP) both reported as least square mean (LSM) reduction ranged from reductions of 10.8 to 18.6 mmhg and 15.5 to 28.4 mmhg, respectively, for currently available doses (amlodipine 5 mg/valsartan 160 mg, amlodipine 5 mg/valsartan 320 mg, amlodipine 10/valsartan 160 mg, amlodipine 10 mg/valsartan 320 mg). Response rates as reflected by proportions of responders (MSDBP <90 mmhg or a 10 mmhg reduction from baseline) ranged from 81.1% to 91.3%. [15] In addition, this study found that the incidence of peripheral edema associated with amlodipine monotherapy was reduced by the addition of an (8.7% vs 5.4%, p= 0.014). The next approved /CCB combination (September ), olmesartan medoxomil plus amlodipine, was supported in a study by Chrysant et al. [16] that evaluated the efficacy and safety of different amlodipine (5 and 10 mg) and olmesartan medoxomil (10, 20, and 40 mg) dose combinations over an 8-week period in 1940 patients with. Mean changes (also reported as LSM) from baseline in MSDBP and MSSBP ranged from reductions of 14.3 to 19.4 mmhg and 22.6 to 28.5 mmhg, respectively, across currently available doses (amlodipine 5 mg/olmesartan medoxomil 20 mg, amlodipine 5 mg/olmesartan medoxomil 40 mg, amlodipine 10 mg/olmesartan medoxomil 20 mg, and amlodipine 10 mg/olmesartan medoxomil 40 mg). [16] Response rates, defined as those who achieved a seated diastolic BP <90 mmhg, were as high as 77.6% for patients taking the amlodipine 10 mg/olmesartan medoxomil 40 mg combination. The olmesartan medoxomil/amlodipine

3 Table I. Angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [])/calcium channel blocker (CCB) combination therapy trials Comparison Daily treatments Patient population Study duration (wk) vs vs CCB AML/VAL 10 mg/160 mg, AML 10 mg, or VAL 160 mg treatment for 12 months or for 12 months plus add-on AML 2.5 mg for 12 months, titrated up to 7.5 mg if needed AML/TEL 5 mg/40 mg or AML 5 mg AML 2.5 or 5 mg; VAL mg; AML/VAL in all possible combinations; or PL AML 10 mg; valsartan 160 or 320 mg; AML/VAL 10 mg/160 mg or 10 mg/320 mg; or PL AML 0, 5, 10 mg and/or OLM 0, 10, 20, 40 mg AML 0, 2.5, 5, 10 mg and/or TEL 0, 20, 40, 80 mg Patients with stages 1 2 Patients with already controlled by an Indian patients with stage 2 Patients with mild to moderate Patients with mild to severe Patients with stages 1 2 Variable monitored 10 Two measures of ankle edema 52 PWV and IMT 12 BP reductions 8 Reductions in mean sitting BP 8 Change in seated DBP 8 In-clinic seated trough cuff DBP Results Combination therapy produced a less marked increase in ankle-foot volume (6.8% vs 23.0% for AML; p < 0.01) and in pretibial subcutaneous tissue pressure (23.2% vs 75.5% for AML; p < 0.001) Add-on AML improved PWV from cm/s to cm/s and the IMT from mm to mm independent of its depressor effects 27.4% decrease in SBP with combination therapy vs 16.6% with AML monotherapy (p < 0.05) AML 5 mg, VAL 320 mg and PL were associated with response rates of 71.9%, 73.4% and 40.9%, respectively; the highest response rate in study 1 was associated with the highest dose of combination therapy (AML/VAL 5mg/320 mg: 91.3%) DBP: reductions from 13.8 mmhg with OLM/AML 10 mg/5 mg to 19.0 mmhg with 40 mg/10 mg; SBP: reductions from 23.6 mmhg with OLM/AML 20 mg/5mg to 30.1 mmhg with 40 mg/10 mg (p < 0.001) Consistently greater BP reductions with CCB/ therapy than with either monotherapy. BP control was achieved by 58.9% and 76.5 in the TEL/AML 40 mg/5 mg and 80 mg/10 mg groups, respectively. DBP and SBP responses were achieved by 80.9% and 88.7% (40 mg/5 mg) and by 91.2% and 90.4% (80 mg/10 mg), respectively Study, year Fogari et al., [11] Ichihara et al., [17] Sharma et al., [18] Phillip et al., [15] Chrysant et al., [16] 2008 Littlejohn et al., [19] AML = amlodipine; DBP = diastolic BP; IMT = intima-media thickness; OLM = olmesartan medoxomil; PL = placebo; PWV= pulse wave velocity; SBP = systolic BP; TEL = telmisartan; VAL = valsartan Role of /CCB Combination Therapy 317

4 318 Chrysant combination was generally well tolerated and was not associated with significant adverse effects, with the exception of edema. The incidence of edema was 36.8% with amlodipine 10 mg and decreased to 23.8% with the combination of olmesartan medoxomil 40 mg/amlodipine 10 mg. The third /CCB combination (approved by the US FDA on 16 October 2009), telmisartan plus amlodipine, was investigated in a study by Littlejohn et al. [19] that evaluated the efficacy and safety of different amlodipine (0, 2.5, 5, and 10 mg) and telmisartan (0, 20, 40, and 80 mg) dose combinations over an 8-week period in 1461 patients with (figure 1). Mean changes (also reported as LSM) from baseline in MSDBP and MSSBP ranged from reductions of 16.5 to mmhg and 21.8 to 26.4 mmhg, respectively, across currently available doses (amlodipine 5 mg/telmisartan 40 mg, amlodipine 5 mg/ telmisartan 80 mg, amlodipine 10 mg/telmisartan 40 mg, and amlodipine 10 mg/telmisartan 80 mg) [figure 1]. BP response rates, as reflected by proportions of responders (MSDBP <90 mmhg or a 10 mmhg reduction from baseline; MSSBP Mean reduction in DBP (mmhg) Mean reduction in SBP (mmhg) a b TEL 0 mg TEL 20 mg TEL 40 mg TEL 80 mg * * TEL 0 mg TEL 20 mg TEL 40 mg TEL 80 mg AML 0 mg AML 2.5 mg AML 5 mg AML 10 mg Fig. 1. Effect of 8 weeks of treatment with telmisartan (TEL) 0, 20, 40, and 80 mg plus amlodipine (AML) 0, 2.5, 5, and 10 mg on the change from baseline in in-clinic seated trough (a) diastolic (DBP) or (b) systolic (SBP) BP. Data are mean (SE) values adjusted for dosage, country/region and baseline BP (reprinted with permission from Littlejohn et al. [19] ). * p < 0.05 vs TEL monotherapy, - p < 0.05 vs AML monotherapy. <140 mmhg or a 10 mmhg reduction from baseline), ranged from 80.9% to 91.9% and from 87.4% to 96.7%, respectively. [20] Amlodipine/telmisartan combinations were also consistently better at lowering 24-hour BP than were the corresponding monotherapies. [21] The addition of telmisartan to amlodipine allows this combination of antihypertensive therapy to provide effective 24-hour BP control and will allow protection from the early morning period that is associated with a high incidence of myocardial infarction, sudden cardiac death, and stroke. [22] The most common adverse events were headache and peripheral edema. Peripheral edema was highest in the amlodipine 10 mg group (17.8%); however, the rate was markedly reduced to 8.9% in the combination with telmisartan mg. Furthermore, telmisartan mg in combination with amlodipine 5 mg was at least as effective as amlodipine 10 mg with a rate of peripheral edema of 1.7%. [20] 4. Discussion In this concise review, evidence was presented that the prevalence of continues to rise [1] and, at present, affects 30% of the US population. [2] Since monotherapy will likely result in controlling less than 50% of subjects, combination therapy will be required in the majority of subjects with. Blood pressure control is very important, as a large meta-analysis of one million hypertensive patients showed that a 2 mmhg reduction in systolic BP is associated with 7% and 10% reductions in the risk for cardiovascular and stroke deaths, respectively. [6] Therapeutic options include several different classes of antihypertensive drugs, such as diuretics, b-blockers, ACEIs, s, direct renin inhibitors, CCBs, and central sympatholytics, alone or in combination. In addition to treating, concomitant risk factors should also be considered because certain drugs (diuretics, b-blockers) have the potential to aggravate coexisting diabetes, induce insulin resistance and cause new-onset diabetes. [23] Recently, several drug combinations with neutral or complementary metabolic effects have been developed and are approved by the FDA for the treatment of. These drug combinations include the combinations of s with CCBs, among others, and have been shown to be very effective and safe in the treatment of, as is presented in this review. Although the BP effects of /CCB combinations are similar to those of ACEI/CCB combinations, the former are safer than the latter with respect to cough, angioedema and patient tolerance, which also results in better treatment adherence. The pedal edema that is produced with amlodipine

5 Role of /CCB Combination Therapy 319 monotherapy is significantly reduced when amlodipine is combined with an. Monotherapy with amlodipine causes selective arteriolar vasodilation, which produces a pressure gradient between the arteriolar and venular capillaries, leading to fluid exudation into the interstitial tissue, which is enhanced with orthostatic gravity. The addition of an that causes both arteriolar and venular capillary dilatation decreases the pressure gradient and leads to interstitial fluid absorption and alleviation of the edema. [15,16,19] With respect to telmisartan, an additional benefit is its 24-hour BP control when added to amlodipine, as has been demonstrated by a 24-hour ambulatory BP measurement, [21] which is important in protecting the patient from the early morning vulnerable period associated with a high incidence of heart attacks, sudden cardiac death and strokes. [22] In addition, telmisartan has been shown to reduce cardiovascular complications, similar to ramipril, in a large clinical outcomes study, and was recently approved by the FDA for the treatment of cardiovascular risk reduction in patients unable to take ACEIs. [24] In other studies, [17] the addition of low-dose amlodipine to an for 12 months in well controlled hypertensive patients decreased pulse wave velocity and carotid intima-media thickness. These changes indicate a reduction in central aortic pressure and reversal of vascular remodeling, and could result in the long-term decrease in cardiovascular morbidity and mortality as shown by the CAFE (Conduit Artery Function Evaluation) study. [25] Although there are no cost analysis studies available, it could be speculated that the beneficial cardiovascular effects exerted by these drugs will be cost effective long term. In summary, although the BP effects of /CCB combinations are similar to those of ACEI/CCB combinations, they may be a better choice for the treatment of based on their efficacy and safety profiles. In particular, the combination of telmisartan with amlodipine, two proven, long-acting drugs, will provide sustained 24-hour BP control. Acknowledgments This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Writing and editorial assistance was provided by Michelle S. Olsher, PhD, of Publication CONNEXION (Newtown, PA, USA), which was contracted by BIPI for these services. The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors, was fully responsible for all content and editorial decisions, and was involved at all stages of manuscript development. The author has received research grants and serves as a consultant to BIPI, Daiichi-Sankyo Pharma and Novartis Pharmaceuticals. References 1. 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6 320 Chrysant analysis of a randomized, placebo-controlled, parallel-group, 4 4 factorial study. Postgrad Med 2009; 121: Littlejohn III T, Majul CR, Oigman W, et al. Combination therapies of telmisartan and amlodipine are effective at lowering 24 hour BP: findings on an ABPM substudy in hypertensive patients [abstract P-50]. J Clin Hypertens (Greenwich) 2008; 10 Suppl. A: A Chrysant SG, Chrysant GS, Desai A. Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan. J Hum Hypertens 2005; 19: Bakris G, Molitch M, Hewkin A, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care 2006; 29: ONTARGET Investigators. Telmisartan, ramipril or both in patients at high risk for vascular events. N Engl J Med 2008; 358: Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE ) Study. Circulation 2006; 113: Correspondence: Dr Steven G. Chrysant, MD, PhD, 5850 West Wilshire Boulevard, Oklahoma City, OK , USA. schrysant@yahoo.com