Rationale for Combination Therapy as Initial Treatment for Hypertension

Abstract

Recent hypertension guidelines recommend initiating antihypertensive therapy with a combination of two or more agents in patients whose blood pressure exceeds their appropriate blood pressure goal by 20/10 mm Hg. This recommendation is based on the knowledge that the majority of patients with blood pressures of this magnitude will not achieve sufficient blood pressure reduction with monotherapy. Further, compared with high‐dose monotherapy, combination therapy is often associated with fewer adverse effects and, for this reason, may improve patient adherence. Bringing patients to blood pressure goal quickly is likely to improve clinical outcomes. This article discusses the rationale for using combination antihypertensive therapy as initial therapy for high blood pressure in selected patients and reviews data from a study of 364 high‐risk patients with Stage 2 hypertension in which a fixed‐dose combination product (amlodipine besylate/benazepril HCl) proved more successful as initial therapy than high‐dose monotherapy (amlodipine besylate) in reducing blood pressure.

Epidemiologic survey data indicate that the prevalence of blood pressure control among adults with hypertension in the United States has improved over the past decade. Nonetheless, two thirds of patients with hypertension still do not have their blood pressure controlled to a level of <140/90 mm Hg (Figure 1). ¹ Importantly, blood pressure control to this level (<140/90 mm Hg) is inadequate for many high‐risk patients—such as those with diabetes and renal disease—for whom a lower blood pressure goal (<130/80 mm Hg) is recommended. ¹ , ² , ³ , ⁴

Figure 1.

Hypertension awareness, treatment, and control in the United States from 1976–2000. ¹ NHANES=National Health and Nutrition Examination Survey

The importance of tight blood pressure control is well supported. A recent meta‐analysis ⁵ based on data from 61 prospective studies and comprising nearly 1 million persons aged 40–69 years without cardiovascular disease (CVD) at the time of enrollment estimated each person's usual blood pressure at an average of 5 years before death. The study's methodology, which corrected for time‐dependent regression dilution bias, revealed that each increase of 20 mm Hg in usual systolic blood pressure (SBP) (or a 10 mm Hg increase in usual diastolic blood pressure [DBP]) was associated with a doubling of the absolute risk of death due to CVD causes. This steep increase in CVD death with increasing blood pressure was continuous for all blood pressure levels 115/75 mm Hg.

As a result of such analyses, an important change was made in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹ from prior JNC reports: the creation of a new diagnostic category. Blood pressure levels <120/80 mm Hg are considered to be normal, whereas levels >120/80 mm Hg and <140/90 mm Hg are classified as prehypertension. This publication also stresses that patients' motivation to adhere to the antihypertensive regimen is optimized when they have positive experiences and trust their clinicians. Good patient‐clinician communication can improve both adherence and clinical outcomes. ⁶ The Table outlines the significant changes that appear in JNC 7.

Despite the benefits of aggressive blood pressure management and the availability of numerous effective antihypertensive therapies, poor blood pressure control persists. Below, the rationale for using combination antihypertensive therapy as initial therapy for high blood pressure in selected patients is discussed as a strategy for improving control rates, as well as offering other therapeutic advantages. Data from a study of 364 high‐risk patients with Stage 2 hypertension ⁷ in which a fixed‐dose combination product (amlodipine besylate/benazepril HCl) proved significantly more successful as initial therapy than high‐dose monotherapy (amlodipine besylate) in reducing blood pressure are presented to illustrate this approach. Compared with monotherapy, combination therapy demonstrated a lower rate of peripheral edema—an adverse event commonly associated with dihydropyridine calcium channel blocker (CCB) therapy.

FROM STEPPED‐CARE TO JNC 7

Combination therapies for hypertension have been utilized since the 1950s, ⁸ yet have only recently been advocated as first‐line therapy. The threshold for diagnosing and treating high blood pressure has lowered progressively since the publication of the first report of the JNC in 1977 ⁹ through the recent publication of JNC 7 in May of 2003. ¹

For the past 25 years, guidelines for the treatment of high blood pressure have recommended a stepped‐care approach to antihypertensive treatment, involving titration of initial monotherapy and addition of agents with different, complementary mechanisms of action until goal blood pressure is achieved. ⁹ , ¹⁰ During this same time period, the definition of when to lower blood pressure changed. There were no recommendations in either JNC I ⁹ or JNC II ¹¹ regarding the definition or treatment of high SBP. In 1984 and again in 1988, JNC III ¹² and JNC IV ¹³ defined the value for high SBP as >160 mm Hg. The JNC V ¹⁴ and JNC VI ¹⁵ guidelines lowered the SBP goal to <140 mm Hg, and with JNC 7, ¹ SBP >120 mm Hg and <140 mm Hg is currently defined as prehypertension. ¹ , ⁹ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ During this period, similar drastic changes for DBP have been enacted. ¹ , ⁹ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵

In tandem with lower blood pressure goals, data from several randomized clinical trials during the past decade have indicated that two or more antihypertensive agents are required to achieve set blood pressure targets (Figure 2). ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² Many hypertension experts now acknowledge that for a large number of patients there is a role for combination therapy at the initiation of antihypertension treatment. This strategy of initiating therapy with two drugs (either as separate agents or in fixed‐dose combinations) for patients with an SBP >20 mm Hg over goal or a DBP >10 mm Hg over goal is endorsed by JNC 7, noting that initial combination therapy may increase the likelihood of achieving blood pressure goals more rapidly. However, caution is advised for employing this practice in persons who may be at risk for orthostatic hypotension. ¹

Figure 2.

This graph displays the mean number of antihypertensive agents needed in various clinical trials to achieve the specified level of blood pressure control. 16, 17, 18, 19, 20, 21, 22, 30

BP=blood pressure; DBP=diastolic blood pressure; MAP=mean arterial pressure; SBP=systolic blood pressure; UKPDS=United Kingdom Prospective Diabetes Study; ABCD=Appropriate Blood Pressure Control in Diabetes; MDRD'=Modification of Diet in Renal Disease; HOT=Hypertension Optimal Treatment; AASK=African American Study of Kidney Disease and Hypertension; IDNT=Irbesartan Diabetic Nephropathy Trial; ALLHAT=Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial

CAUSES OF POOR BLOOD PRESSURE CONTROL

Clinical inertia is cited by JNC 7 as one of the many reasons why a more aggressive approach to controlling blood pressure has been underused. ¹ Other reasons include the interrelated pathologies that result in high blood pressure, the need for multiple drug therapies to control blood pressure in most instances, the adverse event profile of high‐dose monotherapy, patient adherence issues, and confusion regarding the best strategies for controlling blood pressure.

Interrelated Pathologies Produce Hypertension

Although often asymptomatic, chronic high blood pressure damages the target organs; that is, the kidneys, brain, heart, blood vessels, and eyes. Hypertension is a complex disorder involving multiple, interrelated pathophysiologic pathways, including increased blood volume and vasoconstriction, and often overactivity of the sympathetic nervous system and renin‐angiotensin‐aldosterone system (RAAS). ²³ These individual causes are known to interactively exacerbate one another. The ultimate goal of decreasing blood pressure is to prevent target‐organ damage and subsequent CVD events. The antihypertensive regimen should be selected with the goal of using agents that offer the greatest degree of protection against these adverse outcomes by their mechanism of action, and by targeting more than a single pathophysiologic pathway while minimizing adverse effects. ¹ , ²⁴

Combination antihypertensive therapy, consisting of agents from two or more antihypertensive drug classes, increases the likelihood of achieving the blood pressure goal by targeting more than a single pathologic mechanism and achieving additive or even synergistic blood pressure‐lowering effects. ²⁵ Compared with monotherapy, combination therapy also offers the potential for greater protection against target‐organ damage. It is theoretically designed for each component agent to potentiate and maximize the effects of the other, and, in some cases, to mutually counteract adverse effects. ¹ For example, peripheral edema occurs less frequently when a CCB, which causes precapillary vasodilation, is administered with an angiotensin‐converting enzyme (ACE) inhibitor, which lowers post‐capillary resistance. ²⁶ , ²⁷

Need for Multiple Medications

Because of the complex nature of vascular disease, it is not surprising that single agents do not normalize blood pressure for the majority of patients with hypertension. In responders, the typical blood pressure reduction associated with a single antihypertensive agent varies from 7–12 mm Hg for DBP ²⁸ and 13–18 mm Hg for SBP. ²⁹ These reductions will prove inadequate for a large proportion of hypertensive patients to achieve blood pressure control.

Major clinical outcome trials (Figure 2), including the Hypertension Optimal Treatment (HOT) study, ¹⁶ the United Kingdom Prospective Diabetes Study (UKPDS), ¹⁷ and the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ¹⁸ have shown that 40%–50% of patients require multiple antihypertensive drugs to achieve blood pressure control. Clinical trial data also show that patients with diabetes or renal disease will require an average of 2.6–4.3 different antihypertensive medications to achieve a blood pressure goal of <130/80 mm Hg. Similarly, in the African American Study of Kidney Disease and Hypertension (AASK), ¹⁹ two to three drugs were needed, on average, to reduce mean arterial blood pressure to <92–107 mm Hg in African Americans with hypertension and mild‐to‐moderate renal dysfunction. The need for multidrug therapy was evident in the Modification of Diet in Renal Disease (MDRD) study, ²⁰ , ³⁰ where the average number of medications needed was 3.6 in the group assigned to a mean arterial pressure of <92 mm Hg.

Criteria for selecting the class of antihypertensive agents for the initiation of treatment of high blood pressure has been the object of considerable research ¹⁵ , ¹⁶ , ¹⁹ , ²⁰ and controversy. There are substantial data showing that lowering blood pressure with ACE inhibitors, angiotensin II receptor blockers (ARBs), β blockers, CCBs, or thiazide diuretics significantly reduces cardiovascular events. ¹ The long‐anticipated results of ALLHAT ¹⁸ confirm that diuretics are clinically effective antihypertensive drugs, and JNC 7 ¹ suggests that they should be used in the regimen of most hypertensive patients. However, this should not be perceived as a mandate to use diuretics in the initial therapy selection in every patient, as certain limitations to ALLHAT—and to diuretic therapy—should be noted. Thiazide diuretics, such as hydrochlorothiazide and chlorthalidone, are commonly prescribed antihypertensive agents because of their known efficacy and proven clinical benefits, particularly in elderly hypertensive patients. However, higher doses of thiazide diuretics (e.g., >25 mg hydrochlorothiazide) may result in secondary activation of the sympathetic nervous system and the RAAS, resulting in the potential for hypokalemia, hypomagnesemia, and increased serum glucose concentrations. ³¹ Additionally, higher doses of diuretics may cause or exacerbate erectile dysfunction or cause other adverse effects in some patients. ³² Therefore, low doses of thiazide diuretics are most appropriate in combination therapy.

Problems Associated With High‐Dose Monotherapy

Over 25 years of use, the stepped‐care approach recommended by the JNC reports resulted in a clinical preference for titration of initial monotherapy to achieve blood pressure control in patients not responsive to the starting dose. Unfortunately, increasing doses of most classes of antihypertensive agents are often positively correlated with a higher rate of adverse effects, as already noted with the thiazide diuretics. ACE inhibitors and ARBs are a prominent exception to this rule, with excellent tolerability and little evidence of dose‐related increases in adverse effects. ³³ Adverse effects are perhaps one of the most common reasons for patient nonadherence to an antihypertensive regimen. A more rational pharmacologic approach to controlling blood pressure without causing adverse effects is the use of combination therapy with two or more antihypertensive medications, strategically chosen for their complementary ability to address the patient's specific risk factors. This rationale is fully endorsed by JNC 7. ¹

Some combinations are more effective at lowering blood pressure than others. ²⁷ For example, there are additive effects when a low‐dose diuretic is prescribed in combination with an ACE inhibitor, an ARB, and/or a β blocker. A combination of a CCB and an ACE inhibitor or ARB is also very effective. Interestingly, the blood pressure‐lowering effect of CCBs is less dependent upon dietary sodium restriction than that of other classes of agents, including ACE inhibitors, ³⁴ but a CCB/diuretic combination has been shown to be more effective than a CCB or diuretic as monotherapy. This may be of particular relevance in African‐American patients. ³⁵

Resistant Hypertension

Patients whose blood pressures remain above target level despite full doses of an appropriate three‐drug regimen that includes a diuretic are considered to be resistant to drug treatment ¹ ; this may occur in up to 20% of patients with hypertension. In these patients adherence should be carefully assessed, and any secondary cause of hypertension must be ruled out. Some patients may be using prescribed drugs, over‐the‐counter drugs, illicit drugs, or herbal remedies that can affect blood pressure—notably, nonsteroidal anti‐inflammatory agents, Cox‐2 inhibitors, decongestants, cocaine, and licorice. Additional measures to assist patients in their efforts to adhere to therapeutic lifestyle changes, such as weight loss, sodium restriction, and moderation of alcohol intake, should be employed. Importantly, the drug regimen should be re‐evaluated because, as previously noted, some combinations of medications may be less efficacious than others. The complexity of the drug regimen may be a factor in poor adherence.

Compelling Indications

Data from controlled clinical trials conducted over the past decade have demonstrated that greater benefits are seen with specific classes of agents when used in certain types of high‐risk patients. Current JNC 7 recommendations ¹ (Figure 3) find that there are compelling indications for selected classes of agents in the treatment of post‐myocardial infarction patients (ACE inhibitors or β blockers); patients with heart failure (ACE inhibitors, ARBs, β blockers, or diuretics); those at risk for coronary heart disease (ACE inhibitors, β blockers, CCBs, or diuretics); diabetes (ACE inhibitors, β blockers, ARBs, CCBs, or diuretics); renal disease (ACE inhibitors or ARBs); or for secondary prevention of stroke (ACE inhibitors or diuretics). Aldosterone antagonists, while not considered first‐line agents for hypertension, can be considered beneficial in the regimen of patients with congestive heart failure or those who are post‐myocardial infarction. Thiazide diuretics are ineffective in the presence of renal insufficiency; in these cases a loop diuretic should be employed.

Figure 3.

Compelling indications for prescribing specific classes of antihypertensive agents by disease. ¹

βB=β blocker; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; AA‐aldosterone antagonist; MI=myocardial infarction; CAD=coronary artery disease

INITIATING TREATMENT OF HYPERTENSION WITH COMBINATION THERAPY

The case for utilizing combination therapy in patients with hypertension is strong. A careful evaluation of the patient's usual blood pressure (taken with appropriate technique on two or more occasions) can assist the clinician in predicting who will ultimately require more than a single agent for blood pressure control. There now exist relevant guidelines for deciding which patients should start therapy with more than one antihypertensive agent at their initial diagnosis of high blood pressure (Table). ¹ , ³

Table.

Key Messages From the JNC 7 Report ¹

Most patients with hypertension will require two or more antihypertensive medications to achieve blood pressure goal (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease)

If blood pressure is >20/10 mm Hg above goal, consideration should be given to initiating therapy with two agents, with caution to avoid hypotension

Blood pressure levels from 120/80 mm Hg to 139/89 mm Hg should be classified as prehypertension

In persons aged >50 years, systolic blood pressure is a much more important cardiovascular disease risk factor than diastolic blood pressure

Thiazide diuretics should be used in drug treatment for most patients with hypertension, either alone or in combination with other drugs

Motivation to adhere to the antihypertensive regimen improves when patients have positive experiences with and trust their physicians

JNC 7=the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

To avoid “overstepping the mark” and producing hypotension, particularly in elderly patients, appropriate caution in these patients is warranted. Blood pressures should be recorded sitting and standing. A timely response to the initial medication regimen is helpful for better patient adherence, as is simplifying multiple‐drug medication regimens. ³⁶ , ³⁷ Further, an initial regimen of combination therapy may obviate the need for repeated office visits to augment the initial regimen—which often undermines patient and clinician confidence in their mutual ability to achieve an appropriate blood pressure goal.

As noted, JNC 7 recommends that patients with blood pressure levels that are >20/10 mm Hg above goal should be initiated on combination therapy, ¹ whereas other experts suggest initiation of combination therapy for patients whose blood pressures are >15/10 mm Hg above goal. ³ Combination antihypertensive therapy is therefore an option for first‐line therapy for all patients with Stage 2 hypertension (defined as blood pressure 160/100 mm Hg) because these patients' blood pressure measurements are >20/10 mm Hg above goal. ²² , ³⁸ This strategy is particularly relevant for patients at higher risk, for whom the target blood pressure goal is <130/80 mm Hg, such as those with diabetes or chronic kidney disease. ¹ , ² , ³

As noted, several classes of medications have compelling indications for specific groups of patients, and therefore should be included in the initial therapy (Figure 3). In clinically controlled trials, in particular, ACE inhibitors have been shown to confer targetorgan protection. Thus, use of a combination medication that includes an ACE inhibitor may be appropriate as initial therapy in patients at high CVD risk, such as those with diabetes, CVD, renal insufficiency, or any combination of these risk factors. In these patients, combination therapy allows the clinician to include a RAAS‐blocking agent at the onset of treatment. Unfortunately, many clinicians do not initiate treatment for high blood pressure with ACE inhibitors simply because it is predictable that this class will not reduce blood pressure sufficiently. Thus, initiating treatment with combination therapy would provide a greater degree of blood pressure control and protection from target‐organ damage as early as possible in the treatment process. The CCBs reduce blood pressure by causing arterial vasodilation in vascular smooth muscle. Although very potent at reducing blood pressure, higher doses of CCBs often result in peripheral (ankle) edema. When used in combination with a CCB, ACE inhibitors have been shown to ameliorate dose‐related edema associated with CCB monotherapy, due to their ability to lower postcapillary resistance. ²⁶ , ³⁵

Patients with inadequate blood pressure control who experience adverse effects with high‐dose monotherapy may benefit by switching to a low‐dose combination therapy regimen. Successful treatment should be defined as a blood pressure regimen that achieves the patient's blood pressure goal in a reasonable time frame without causing unacceptable adverse effects. To determine if combination therapy met these qualifications for successful initial therapy, a 12‐week, multicenter, randomized, double‐blind study ⁷ compared a fixed‐dose combination product with monotherapy as the initial therapy for patients with JNC 7‐defined Stage 2 hypertension (blood pressure 160/100 mm Hg). The fixed‐dose combination product contained a dihydropyridine CCB (5 mg amlodipine besylate titrated to 10 mg) and an ACE inhibitor (20 mg benazepril HCl titrated to 40 mg), and the single‐agent therapy regimen was initiated with 5 mg amlodipine besylate titrated to 10 mg.

More than 90% of patients in each group were titrated to the highest drug doses. After 12 weeks, combination therapy was significantly better than monotherapy at achieving both SBP goals (74% vs. 54%; p<0.0001) and DBP goals (67% vs. 48%; p<0.0003). Reductions with combination therapy were particularly impressive in the group of patients with high SBP (180 mm Hg) at baseline. Among these patients, amlodipine besylate/benazepril HCl combination therapy resulted in significantly greater reductions in SBP compared with the highest recommended dose of amlodipine besylate monotherapy (−42.3 mm Hg vs. −30.4 mm Hg, respectively, p=0.0001) (Figure 4). Importantly, a significantly smaller percentage of patients receiving amlodipine besylate/benazepril HCl experienced peripheral edema compared with patients receiving monotherapy with amlodipine besylate (12.6% vs. 23.0%; p=.01), despite 90% of patients receiving the same dose of amlodipine besylate.

Figure 4.

Results for systolic blood pressure (SBP) reduction in subjects with high baseline SBP ( 180 mm Hg) in a 12‐week study of 364 subjects with JNC 7‐defined Stage 2 Hypertension. ⁷

CONCLUSIONS

Routinely prescribing monotherapy for the treatment of hypertension ended with the publication of JNC 7. Lower thresholds for the diagnosis and treatment of high blood pressure mean that increasing numbers of patients will require a combination of antihypertensive agents to achieve their appropriate level of blood pressure control. Initiating combination therapy may be indicated in patients with Stage 2 hypertension, patients with isolated systolic hypertension, high‐risk patients with lower blood pressure goals (e.g., <130/80 mm Hg), and in patients who have compelling indications for agents that may not sufficiently lower their blood pressure unless used in combination with an additional agent.