The Role of Olmesartan Medoxomil-Based Combination Therapy in the Management of Hypertension: A Review for Nurse Practitioners
M Roberts
Keywords
angiotensin ii receptor blockers, blood pressure control, hypertension, nurse practitioners, olmesartan medoxomil
Citation
M Roberts. The Role of Olmesartan Medoxomil-Based Combination Therapy in the Management of Hypertension: A Review for Nurse Practitioners. The Internet Journal of Advanced Nursing Practice. 2012 Volume 11 Number 2.
Abstract
Introduction
According to data from the 1999–2008 National Health and Nutrition Examination Survey (NHANES), an estimated 29% of Americans aged ≥18 years are presently living with hypertension,1 with another 28% of American adults classified as being at risk of developing the disease.2 Stage 1 hypertension, defined as a systolic blood pressure (SBP) of 140–159 mm Hg or a diastolic blood pressure (DBP) of 90–99 mm Hg, affects an estimated 25 million adults in the United States.3 Stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) is more common in the elderly and in Blacks. Poorly controlled hypertension is associated with many adverse cardiovascular and cerebrovascular outcomes and contributes a substantial financial burden to the healthcare system.4 Nurse practitioners have a unique opportunity to positively impact the national standard of care for patients with hypertension. These opportunities arise from their ability to effectively communicate complex medical information to patients, especially the risks associated with medical non-compliance.
Clinical Consequences of Uncontrolled Hypertension
The major long-term concern of uncontrolled hypertension is damage to organs such as the heart, brain, and kidneys, which may increase patient morbidity and mortality (see Figure 1). The risk of death due to stroke or ischemic heart disease (angina, myocardial infarction [MI], and heart failure) is estimated to double with every 20-mm Hg increase in SBP >115 mm Hg and with every 10-mm Hg increase in DBP >75 mm Hg.5 Hypertension causes higher after-load pressures in the arterial vasculature that blood must be pumped against. Myocardial hypertrophy may lead to heart failure resulting in reduced ejection fraction and decreased end-organ perfusion. Manifestations of left-sided heart failure include pulmonary congestion, orthopnea, exercise intolerance, and dyspnea at rest. Angina is also likely, with myocardial thickening due to an imbalance between myocardial oxygen demand and blood supply.
Figure 1
Uncontrolled hypertension greatly increases the risk of embolic and hemorrhagic stroke. In an Australian study evaluating major risk factors of intracerebral hemorrhage, patients with hypertension were 2.5 times more likely to experience stroke than patients who were not hypertensive.6 Sustained elevated blood pressures (BPs) are also associated with renal complications and elevated serum creatinine levels.7,8 Sustained elevated BP is of particular concern to patients who have diabetes mellitus, where the risk of end-stage renal disease is estimated to be five to six times higher than patients who have diabetes without hypertension.9
The Nurse Practitioner’s Role in Patient Management
Nurse practitioners and other clinicians in a variety of practice settings have the opportunity to identify patients who are at risk of developing hypertension and to ensure that patients with hypertension are not left untreated or undertreated.10 A common barrier to effective hypertension management is the lack of patient adherence to treatment regimens. As many as 40%–50% of patients with cardiovascular disease (CVD) and hypertension do not follow their prescribed regimens.11,12 Furthermore, an increased duration of therapy for chronic conditions has been correlated with decreased adherence.13,14 Simplifying hypertension treatment through the use of fixed-dose combination therapy has helped to increase BP control in patients.15 Nurse practitioners who counsel patients on lifestyle modifications and good health practices, as well as prescribe medication regimens that take into account issues of adherence, can bring the best of evidence-based medical care of hypertension to their patients.
Management of Hypertension
Lifestyle Modifications
The management of hypertension usually begins with lifestyle modifications.4 A 10-pound reduction of body weight may reduce BP or prevent hypertension altogether.4 In a randomized controlled trial (RCT) of 181 patients, the mean SBP reduction associated with weight loss over an 18-month period was 6.9–13.3 mm Hg.16 Patients can be counseled that proper weight reduction is achieved by eating a healthy diet and by increasing daily physical activity. The Dietary Approaches to Stop Hypertension (DASH) eating plan is recognized by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines as a diet that can help lower BP. DASH consists of a diet high in fruits, vegetables, and low-fat dairy products, while avoiding or minimizing foods that are high in saturated fat or cholesterol (red meat, fried foods, etc.). Dietary sodium reduction complements the DASH diet. A sodium intake of less than (<) 2.4 grams/day in combination with the DASH diet has been shown to reduce SBP by 11 mm Hg in one clinical trial.17 Alcohol reduction is also advised to improve hypertension. In a meta-analysis of 15 RCTs, moderation of alcohol intake resulted in a 2–4-mm Hg SBP reduction.18
Regular exercise and smoking cessation are also recommended lifestyle modifications for hypertensive patients. Patients, who are physically capable, should exercise for 30 minutes per day most days of the week.4 In two separate meta-analyses of RCTs, patients who engaged in either aerobic exercise or resistance training programs were found to have BP reductions ranging from 4–9 mm Hg.4,19 Finally, smoking cessation should be encouraged to patients as smoking is a known cardiovascular risk factor.4
Pharmacotherapy of Stage 1 and 2 Hypertension
The pharmacologic management of hypertension is based on severity and the presence of compelling indications (diabetes, chronic kidney disease, heart failure, post-MI, high coronary disease risk, and recurrent stroke prevention).4 For most patients, a target BP goal is ≤140/90 mm Hg. For patients who have diabetes or chronic kidney disease, the BP goal is ≤130/80 mm Hg. Monotherapy is recommended initially for patients with stage 1 hypertension.
Figure 2
*Heart failure = diuretic, -blocker, ACE inhibitor, ARB, aldosterone antagonist; post-myocardial infarction = -blocker, ACE inhibitor, and aldosterone antagonist; high coronary disease risk = diuretic, -blocker, ACE inhibitor, CCB; diabetes = diuretic, -blocker, ACE inhibitor, ARB, CCB; chronic kidney disease = ACE inhibitor, ARB; recurrent stroke prevention = diuretic, ACE inhibitor.
Available at http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BP, blood pressure; CCB, calcium channel blocker.
In the JNC 7 treatment algorithm for patients without compelling indications, the treatment of choice is a thiazide-type diuretic (hydrochlorothiazide [HCTZ] or chlorthalidone)4 (see Figure 2). If BP goals are not reached with thiazide-type diuretics alone, then thiazides may be given in combination with other antihypertensive medications including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta (β)-blockers, and aldosterone antagonists. Other classes of medications apart from thiazide diuretics are not recommended by JNC 7 as initial monotherapy in patients without compelling indications, although studies have shown that ACE inhibitors, ARBs, CCBs,
β-blockers,20 and aldosterone antagonists21 are also effective choices as initial monotherapy. The data supporting the use of other classes of medications as initial monotherapy are also confirmed by the 2009 reappraisal of the European Society of Hypertension/European Society of Cardiology (ESH/ESC) 2007 guidelines, which recommend the use of thiazide diuretics, ACE inhibitors, ARBs, CCBs, and β-blockers as first-line therapy.22 Updated guidelines from the American Diabetes Association (ADA) recommend ARBs or ACE inhibitors as monotherapy for initial antihypertensive therapy in patients with diabetes.23 For patients with stage 2 hypertension or those who are high risk and require more rapid BP lowering, initiating treatment with a thiazide-type diuretic plus a second agent is recommended.4 Drugs should be initiated at lower doses and titrated carefully to avoid hypotension and other adverse effects. More recently, fixed-dose combinations of ARBs and CCBs have been approved as first-line antihypertensive medications in patients who are unlikely to achieve their BP goals with monotherapy.
Blood Pressure Measurement
Traditionally, BP is assessed with seated cuff measurements. Ideally, a seated cuff BP (SeBP) measurement is performed after the patient has been at rest for 3–5 minutes.24 Appropriately sized BP cuffs should be used for both obese and pediatric patients, and care must be taken to assure that the patient’s rolled-up sleeve is not acting as a tourniquet. Two BP measurements taken 1 minute apart, with the average of the two values recorded as the patient’s final BP, is recommended. If a difference of >5 mm Hg exists between both measurements, then an additional one or two measurements should be taken with the average of all measurements used as the final result.24
Ambulatory BP monitoring (ABPM) has several advantages over SeBP monitoring. BP values fluctuate naturally according to a circadian profile,25 and ABPM allows the clinician to obtain the average of multiple BP measurements rather than the average of 2–3 readings obtained in one clinical appointment. Secondly, ABPM measurements have been shown to have a closer association with target organ damage than SeBP measurements.26 Patients who do not have a decrease in BP during the sleeping hours are more likely to experience cardiovascular events. Similarly, most patients are at a higher risk during the morning hours when BP surges are common. ABPM can help to identify the magnitude of these nighttime and morning BP fluctuations. At present, the JNC 7 guidelines recommend that ABPM be used for suspected white-coat hypertension, apparent drug resistance, hypotensive symptoms while on medication, and for episodic hypertension and autonomic dysfunction.4
The use of ABPM and home BP monitoring (HBPM) has been elevated more recently into the role of helping to confirm a diagnosis of hypertension. The National Institute for Health and Clinical Excellence (NICE) released new hypertension guidelines for 2011 that state that ABPM and HBPM average daily values of ≥135/85 mm Hg are confirmatory of a clinical diagnosis of hypertension.27 The American Heart Association (AHA), American Society of Hypertension, and Preventive Cardiovascular Nurses Association, in a joint statement, recommended that HBPM become part of the routine BP measurement regimen in patients with known or suspected hypertension.28 HBPM can help solidify a diagnosis, monitor response to treatment, and may help improve adherence to therapy.
Disease Management in Populations with Difficult-to-Treat Hypertension
Common subgroups of patients with difficult-to-treat hypertension include the elderly, obese, diabetics, Blacks, and patients with metabolic syndrome. Patients from these subgroups and those with multiple comorbidities are often difficult to treat.4,29-31
The Elderly
The incidence of hypertension has been shown to increase in both males and females as patients age.32 Effective and focused treatment of hypertension in the elderly is associated with reduced primary outcomes such as stroke, MI, or non-MI cardiac death.33,34 One challenge in treating the elderly is BP variability. During morning hours, the elderly are likely to have BP surges that place them at increased risk for cardiovascular and cerebrovascular events.25,35 Adequate BP control regimens must take BP variability and the morning BP surge into account. Elderly patients are also prone to sudden drops in BP with changes in position. Medications whose effects are sustained throughout the day can help to minimize this orthostasis. Finally, the elderly are very likely to require multiple agents to reach BP goals, which add to increased pill burden for other conditions treated concomitantly. Fixed-dose combination products can be very helpful in minimizing pill burden in the elderly, provided that patients can tolerate multiple antihypertensives. The 2011 Expert Consensus Document on Hypertension in the Elderly encourages that medication therapy be initiated at the lowest possible dose and then gradually titrated upwards.36 A BP target of <140/90 mm Hg is recommended, provided that the doses and medications required to reach this BP target are tolerated by the patients. In patients who are aged ≥80 years, an SBP of 140–145 mm Hg should be regarded as acceptable. However, a BP of <130/65 mm Hg should generally be avoided in patients ≥80 years of age due to concerns about inadequate organ perfusion.36
Patients with Diabetes
Hypertension occurs in patients with type 2 diabetes at an estimated rate of 77%.37 Patients with diabetes are at risk for both microvascular and macrovascular complications, outcomes that are highly dependent on adequate BP control. In at least one study evaluating data from NHANES, only 35.3% of patients with diabetes who were treated for hypertension were found to be at BP goal.37 The ADA and JNC 7 guidelines point out that achieving BP goals may be difficult in this population and that patients may require two to three antihypertensive agents.4,23 Both sets of guidelines recommend the use of an ACE inhibitor or ARB in a combination treatment regimen due to their demonstrated ability to reduce the incidence of albuminuria and the progression of nephropathy.38 Along with the elderly, pill burden and poor adherence to medical therapy are barriers to treatment for this subgroup, as patients with diabetes may also be treated concomitantly for dyslipidemia, poor glucose control, and many other conditions.
More recently, some debate has occurred about the appropriateness of the JNC 7-recommended BP goal of <130/80 mm Hg in patients with type 2 diabetes. The 2009 reappraisal of the 2007 ESH/ESC guidelines examined clinical trials that showed a positive benefit on primary endpoints with BP lowering.22 In patients with type 2 diabetes, the mean SBP achieved in trials with positive primary outcomes ranged from 134–153 mm Hg, above the JNC 7-recommended SBP target of <130 mm Hg. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP study and a
Blacks
Blacks have been shown to have higher rates of hypertension including hypertension that is considered severe (≥180/110 mm Hg).42 In addition, Blacks have been shown to have less nighttime decreases in BP compared with Caucasians.4 Normally, nighttime BPs drop by 10%–20% from 12 p.m.–6 a.m. ABPM measurements have shown that Blacks often experience nighttime BP reductions of <10%.42 In Blacks, it is common to see stage 2 hypertension, increasing the risk for target organ damage occurring earlier in life. Data from the National Center for Health Statistics have shown higher incidences of CVD, renal disease, and all-cause mortality in Blacks relative to Caucasians.43 A 2010 update of the International Society on Hypertension in Blacks (ISHIB) Consensus Statement affirms the need to reverse the accelerating prevalence of hypertension in this population.42
ISHIB classifies patients with hypertension by two risk categories: primary prevention and secondary prevention.42 Primary prevention groups are patients with high BP with no evidence of end-organ damage, preclinical or current CVD, and who have a goal BP of <135/85 mm Hg. Secondary prevention groups are patients who have high BP with target organ damage, preclinical CVD, or a history of CVD. The same six compelling indications in JNC 7 guidelines define secondary prevention groups in the ISHIB 2010 guidelines with the exception of the addition of coronary heart disease or angina as a seventh compelling indication. Patients in the secondary prevention risk category have a goal BP of <130/80 mm Hg.
In the primary prevention group, treatment with a diuretic or CCB is recommended as initial therapy when lifestyle modifications do not achieve desired goals.42 In primary prevention patients whose SBP is >15 mm Hg and/or DBP >10 mm Hg above goal, two-drug therapy with a CCB plus a renin–angiotensin system (RAS) blocker or a thiazide and RAS blocker combination should be considered. In the secondary prevention group, initial monotherapy in patients who are <15/10 mm Hg above the goal BP of <130/80 mm Hg should include an agent that is appropriate to treat the compelling indication. In secondary prevention patients whose BP is >15/10 mm Hg over the goal BP of <130/80 mm Hg, combination therapy including an agent appropriate for the compelling indication is preferred.
Patients with Metabolic Syndrome
The most recent AHA/National Heart, Lung, and Blood Institute guidelines describe metabolic syndrome as a combination of metabolic risk factors that predispose a patient to atherosclerotic CVD.44 Metabolic risk factors include hypertension, dyslipidemia, and elevated blood sugar. Underlying risk factors further contributing to metabolic syndrome include aging, abdominal obesity, physical inactivity, and hormonal imbalance. Patients with elevated BP and metabolic syndrome are recommended to initiate lifestyle modifications once BP is ≥120/80 mm Hg.44 Healthy lifestyle modifications are similar to recommendations in the JNC 7 treatment guidelines—DASH diet, sodium restriction, moderation of alcohol consumption, weight control, and increased exercise.4 Pharmacological treatment is initiated once BP is ≥130/80 mm Hg in patients with chronic kidney disease or diabetes, and once BP is ≥140/90 mm Hg for all others. Treatments using ACE inhibitors or ARBs are appropriate choices in patients with metabolic syndrome due to their renoprotective and cardioprotective effects.45 A meta-analysis of 12 RCTs showed that ACE inhibitors and ARBs reduced the progression of study subjects to type 2 diabetes by 25% (95% confidence interval, 0.69–0.82).46 Patients included in this analysis had hypertension, metabolic syndrome, or at least one cardiovascular risk factor at baseline.
The Need for Combination Therapy
Most clinical trials investigating the efficacy of antihypertensive therapy on endpoints such as stroke or cardiovascular events have generally allowed for a combination of agents to be used in order to bring study subjects to BP goals. BP control rates in study populations are as low as 27%–37% at baseline on monotherapy and as high as 53%–75% at study conclusion when multiple agents are used and/or optimized.47-49 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), patients were randomized to monotherapy utilizing chlorthalidone, amlodipine (AML), or lisinopril. At study close, 67% of patients achieved an SBP of <140 mm Hg, and 63% of those study subjects required two or more medications to reach their goal.47 Nurse practitioners must be cognizant that, for most patients, monotherapy will be a stepping stone to combination therapy in order to achieve BP goals.
Fixed-Dose Combination Therapy
Fixed-dose combination therapy can be regarded as taking combination therapy to a new level. Advantages of improved efficacy over monotherapy are offered while providing the added benefit of simplification of the BP control regimen using a single pill. Many fixed-dose combinations build upon a single agent by adding on one or two additional classes of antihypertensives. As fixed-dose combinations are available that contain different doses of the individual component agents, different dose combinations can be selected while retaining the convenience of a single pill. Fixed-dose combination treatment has been shown to increase persistence and adherence.22 In addition, fixed-dose combination therapy demonstrates similar or even improved tolerance, as one component may sometimes offset the deleterious effects of another.22 Nurse practitioners may consider fixed-dose combination therapy as the first option for patients to improve adherence with medical therapy.
Olmesartan Medoxomil
Olmesartan medoxomil (OM) is an ARB approved by the US Food and Drug Administration (FDA) in April 2002 for the management of hypertension in adults when used as monotherapy or in combination with other antihypertensive agents.50 Olmesartan, the active metabolite, has a half-life of approximately 13 hours50 compared with the shorter half-lives of other commonly prescribed ARBs such as valsartan (6 hours)51 and losartan (2 hours) [active metabolite EXP-3174 6–9 hours].52 In February 2010, the FDA revised labeling to include the indication of the management of hypertension in pediatric patients aged 6–16 years. Olmesartan is available as monotherapy (Benicar®), in dual fixed-dose combinations with HCTZ (Benicar HCT®) or AML (Azor®), and as a triple single-pill combination with all three agents (Tribenzor™). The dosing of OM-based combination therapy and other ARB-based fixed-dose combination therapies are presented below.
Figure 3
Olmesartan Mechanism of Action
BP control in the body is regulated by the renin–angiotensin–aldosterone system (RAAS). Renin is released by the kidneys due to BP decreases, decreased sodium chloride levels in the renal filtrate, and from increased sympathetic nervous system activity.67 Renin converts angiotensinogen, which is produced in the liver, to its active form angiotensin I (see Figure 3). Angiotensin I is then converted to angiotensin II by ACE in the lungs. Angiotensin II is a potent vasoconstrictor, which upon binding to the angiotensin I (AT1) receptor, causes arterial constriction and an increase in BP. Effects of the receptor binding are not limited directly to the blood vessel. Angiotensin II also causes an increase in the synthesis and release of aldosterone from the kidneys, which increases sodium and water retention in the blood. BP rises due to the increased blood volume.
Figure 4
Reprinted with permission from Mire DE, et al.
ARBs such as OM are classified alongside ACE inhibitors as RAS inhibitors; however, both classes of medications act by differing mechanisms. ACE inhibitors block the conversion of angiotensin I to angiotensin II, while ARBs block the binding of angiotensin II at its AT1 receptor site. Other differences in the mechanisms of action include interaction with the bradykinin and substance P degradation pathways. ACE inhibitors are believed to impede the degradation of bradykinins and substance P in the lungs, while the receptor-blocking mechanism of ARBs does not interfere with the degradation of these substances. Because of these differences, an estimated 5%–35% of patients are unable to tolerate ACE inhibitors due to a chronic, nagging dry cough.68 Common adverse events shared by both ACE inhibitors and ARBs include hypotension, dizziness, headache, and fatigue.50,69 Mild and transient hyperkalemia is possible, though often resolves with continued therapy, and can be minimized by avoidance of concomitant use of potassium-sparing diuretics or potassium supplements.50,69 Rare and potentially life-threatening adverse events associated with ACE inhibitors and ARBs include angioedema and acute renal failure in patients with renal insufficiency.50,69
Efficacy and Safety of Olmesartan Medoxomil/HCTZ
Thiazide diuretics add additional BP-lowering effects to OM by reducing blood volume through the excretion of sodium and chloride ions into the renal filtrate.58 The combination of OM and HCTZ has been evaluated in a variety of clinical trials, and key trial data are summarized in Table 2.
Figure 5
The pivotal US study for approval of OM/HCTZ combination therapy was a randomized, double-blind factorial study in 502 patients.70 Following a 4-week placebo run-in period, patients were randomized to one of 12 possible treatment groups for a period of 8 weeks. Treatment groups consisted of OM monotherapy (10, 20, or 40 mg/day), HCTZ monotherapy (12.5 or 25 mg/day), any combination of the OM and HCTZ monotherapy doses, or placebo. Mean trough SeBP was reduced by –3.3/–2.8 mm Hg, –20.1/–16.4 mm Hg, and –26.8/–21.9 mm Hg for placebo, OM/HCTZ 20/12.5 mg, and OM/HCTZ 40/25 mg, respectively. Combination therapy provided greater BP reductions compared with OM and HCTZ given as monotherapy. In addition, OM/HCTZ was found to be well tolerated with an overall discontinuation rate due to adverse effects of 2%. The efficacy of OM/HCTZ in subpopulations of interest is discussed below.
The BeniSILVER (Benicar Efficacy: New Investigation Shows Olmesartan Medoxomil Treatment Increasingly Leads Various Elderly Populations to Safe BP Reductions) study demonstrated efficacy of OM/HCTZ treatment in a difficult-to-treat population.71 Following a placebo run-in period, 178 elderly patients were treated with OM monotherapy before being up-titrated every 3 weeks to a maximum dose of OM/HCTZ 40/25 mg if SeBP was ≥120/70 mm Hg. In total, 159 patients required titration to combination therapy, and the mean ambulatory BP decreased from 148.8/80.9 mm Hg to 123.1/68.6 mm Hg by study end. Reductions from baseline were found to be statistically significant throughout the 24-hour dosing interval (
The BENIFICIARY (Benicar Safety and Efficacy Evaluation: an Open-label Single-arm, Titration Study in Patients with Hypertension and Type 2 Diabetes) study investigated the efficacy and safety of OM/HCTZ in patients with diabetes and hypertension with a real-world dose-titration, open-label study design.72 By study end, 24-hour ambulatory SBP decreased from 146.4 mm Hg to 126.0 mm Hg, a statistically significant decrease of –20.4 mm Hg from baseline (
Figure 4. Hourly mean systolic BP (SBP) and diastolic BP (DBP) at baseline and following 12 weeks of treatment with olmesartan medoxomil ± hydrochlorothiazide in patients with diabetes and hypertension in the BENIFICIARY study. Blood pressure (BP) changes during the 24-hour dosing interval and treatment reduced BP throughout the dosing interval including the morning BP surge. End-of-study mean 24-hour ambulatory BP was 126.0/72.2 mm Hg compared with 146.4/83.3 mm Hg at baseline.72
The BENIFORCE (Benicar Efficacy: New Investigative Findings Show Olmesartan Medoxomil Safely and Effectively Reduces Blood Pressure Compared With Placebo in a Clinical Evaluation of Patients With Stage 1 or Stage 2 Hypertension) trial was a placebo-controlled, dose-titration study of 12 weeks’ duration.73 A total of 276 patients were randomized to active treatment or placebo. Active treatment started with daily dosing of OM 20 mg. If SeBP was ≥120/80 mm Hg, doses were titrated at 3-week intervals up to a maximum dose of OM/HCTZ 40/25 mg. Statistically significant reductions in mean seated SBP/DBP of –22.3/–12.1 mm Hg from baseline were observed with OM/HCTZ 40/25 mg versus placebo at –0.1/+0.8 mm Hg (
Efficacy and Safety of Amlodipine/Olmesartan Medoxomil
Amlodipine adds additional BP-lowering ability to olmesartan through the blockade of L-type calcium (Ca2+) channels resulting in vasodilation of blood vessels (see Figure 5).74 The COACH (Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure) study was a randomized, double-blind, placebo-controlled, factorial study of 8 weeks’ duration where 1940 patients were randomized into OM monotherapy, AML monotherapy, AML/OM combination therapy, or placebo. Statistically significant reductions in SeBP were observed at all combinations of AML/OM versus placebo (
Figure 6
Reprinted from
Figure 7
After 8 weeks of treatment, 53.2% of patients in the COACH study achieved a goal BP of <140/90 mm Hg (<130/80 mm Hg for patients with diabetes) with combination therapy compared with 32.5% with AML monotherapy and 36.3% with OM monotherapy. Edema, which is a commonly observed adverse effect with AML monotherapy, occurred at a rate of 36.8% in patients treated with AML 10 mg. Combination therapy with AML/OM at a dose of 10/40 mg significantly reduced the incidence of edema to 23.5% (
The AZTEC (AZOR Trial Evaluating Blood Pressure Reductions and Control) study assessed reductions in BP with AML/OM combination therapy as determined by ABPM in 185 patients.76 If SeBP was ≥120/80 mm Hg, AML 5 mg daily was titrated upward every 3 weeks to AML/OM 5/20 mg, AML/OM 5/40 mg, and AML/OM 10/40 mg daily. The primary endpoint in AZTEC was the change from baseline in mean 24-hour ambulatory SBP at week 12. Baseline mean 24-hour ambulatory BP was 144.8/85.7 mm Hg, and a reduction in ambulatory BP of –21.4/–12.7 mm Hg was attained at week 12 (
Efficacy and Safety of Olmesartan Medoxomil/Amlodipine/HCTZ
In a 44-week open-label extension of the COACH study, 1684 patients not on combination therapy were started on AML/OM 5/40 mg and then uptitrated to AML/OM 10/40 mg.78 HCTZ was added on to the maximally titrated AML/OM 10/40 mg dose in increments of 12.5 mg, up to a maximum of HCTZ 25 mg until patients achieved BP goals. At the conclusion of the extension study (week 52), 66.7% of patients achieved goal BP, including patients with diabetes. At the combination dose of OM/AML/HCTZ 40/10/25 mg, a mean change in BP from baseline of –36.1/–19.8 mm Hg was observed compared with a reduction of –29.8/–18.7 mm Hg with the combination dose of OM/AML 40/10 mg. The extension of the COACH study provided more insight into long-term side effects associated with combination therapy. Overall, OM/AML/HCTZ combination therapy was well tolerated. Edema occurred in 10.7% of patients treated with OM/AML/HCTZ 40/10/25 mg compared with 11.1% and 7.0% incidence in patients taking AML/OM 10/40 mg daily and AML/OM 5/40 mg daily, respectively.78
TRINITY (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study) lends some insight into the potent BP reductions afforded by triple combination therapy.79 TRINITY, a phase III, multicenter, parallel-group study of 12 weeks’ duration in 2492 patients, compared the efficacy and tolerability of OM/AML/HCTZ 40/10/25 mg with corresponding doses of AML/OM, OM/HCTZ, and AML/HCTZ combination therapy. The least-squares mean reduction in BP was –37.1/–21.8 mm Hg for the OM/AML/HCTZ group compared with –27.5 to –30.0/–15.1 to –18.0 mm Hg for the other three treatment groups, a statistically significant reduction relative to the other treatment groups (
Figure 8
The BP-CRUSH (Blood Pressure Control in All Subgroups with Hypertension) study investigated the efficacy of AML/OM combination therapy in patients with hypertension uncontrolled on monotherapy to reach JNC 7 BP goals.80 A total of 999 patients were switched from previously failed monotherapy to a fixed-dose combination of AML/OM 5/20 mg. At 4-week intervals, therapy was up-titrated to AML/OM 5/40 mg and AML/OM 10/40 mg if mean SBP was ≥120 mm Hg or if mean DBP was ≥70 mm Hg. Patients were up-titrated to AML/OM 10/40 mg + HCTZ 12.5 mg and AML/OM 10/40 mg + HCTZ 25 mg if mean SBP was ≥125 mm Hg or if mean DBP was ≥75 mm Hg. By week 12, 77.1% of patients achieved a cumulative SeBP goal of <140/90 mm Hg (<130/80 mm Hg for patients with type 2 diabetes), with the proportion increasing to 90.3% at week 20 at the maximally titrated dose of AML/OM 10/40 mg + HCTZ 25 mg. The mean end-of-study SeBP at week 20 was 129.6/79.7 mm Hg, a decrease of –25.1/–13.7 mm Hg from a baseline mean SeBP of 154.7/93.4 mm Hg. BP reductions across all titration steps were statistically significant versus baseline (
Beyond Blood Pressure Effects of Olmesartan Medoxomil
Recent evidence suggests the benefits of olmesartan are not limited to its antihypertensive mechanism of action. The OLAS (Olmesartan/Amlodipine vs Olmesartan/Hydrochlorothiazide in Metabolic Syndrome) study was conducted to investigate the effects of OM-based combination therapy on inflammatory and metabolic parameters in 120 non-diabetic patients with metabolic syndrome.81 Following a placebo washout period, patients were randomized to either OM/AML or OM/HCTZ with doses titrated upwards every 13 weeks to maximal combination doses. Once at maximized combination therapy (week 26), doxazosin was added-on, starting at 4 mg and up-titrated to 8 mg at week 39, so long as SBP was ≥140 mm Hg. After 78 weeks of treatment, both treatment arms demonstrated similar significant reductions in albuminuria from baseline (
Apart from inflammatory mediators and metabolic indicators, great interest and research is focused on the effects of olmesartan on biomarkers that are indicative of cardiovascular health. The OLIVUS (Impact of Olmesartan on Progression of Coronary Atherosclerosis: Evaluation by Intravascular Ultrasound) trial looked at the effects of olmesartan on the progression of atherosclerosis as evaluated by intravascular ultrasound (IVUS) in patients with stable angina pectoris.82 In total, 247 patients were enrolled and randomized to OM treatment or control groups. Following percutaneous coronary intervention, IVUS was performed in nonculprit vessels to obtain baseline atheroma volume. Following 12–16 months of treatment, IVUS was performed again to detect changes in atheroma volume. At the end of the study, total atheroma volume increased by 5.4% in the control group compared with a significantly lower increase of 0.6% for OM (
The EUTOPIA study investigated the anti-inflammatory effects of OM alone and in combination with the HMG-CoA reductase inhibitor pravastatin in patients with hypertension and microinflammation.83 Patients were treated for 12 weeks with OM (n = 100) or placebo (n = 99), and pravastatin was added at week 6 for all patients. HCTZ was added, as necessary, to control BP. In the OM group, high-sensitivity CRP (–15.1%;
Conclusions
Hypertension is a prevalent condition that requires attentive and comprehensive management of patients to reduce cardiovascular morbidity and mortality. Nurse practitioners can positively impact patient outcomes by educating patients, encouraging positive lifestyle changes, and incorporating combination drug therapy in the treatment of hypertension where appropriate. Olmesartan medoxomil and its family of fixed-dose combination therapies treat a wide variety of patient populations who cannot obtain BP control on monotherapy. Fixed-dose combination therapies can increase adherence and minimize side effects experienced from taking multiple antihypertensive agents versus taking them as high-dose monotherapy. A large body of evidence suggests fixed-dose combination therapy allows for safe achievement of BP control in difficult-to-treat populations.
Acknowledgements
Robert Schupp, PharmD, and Christopher J. Jones, PhD, of
Funding Source: The preparation of this manuscript was supported by Daiichi Sankyo, Inc.
