Creating a Combination Antihypertensive Regimen: What Does the Research Show?

Abstract

Major randomized clinical trials have demonstrated unquestionable clinical benefits of lowering blood pressure without establishing superiority of any specific antihypertensive medication. Most notably, these trials have indicated that a majority of patients with hypertension will require more than one drug to control blood pressure. The recognition that many patients with hypertension should receive a combination of two agents as initial therapy is reflected in current hypertension guidelines, including the recently published consensus statement by the Hypertension in African Americans Working Group (HAAWG) and the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). In addition, there are some data that suggest that combination therapy may afford greater cardioprotection compared to monotherapy. For example, findings from A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy (ALERT) indicated that low‐dose combined angiotensin‐converting enzyme inhibitor and calcium channel blocker antihypertensive treatment improved measures of cardiovascular structure and function compared with high‐dose monotherapy with either component. Intuitive clinical wisdom suggests that some combinations of antihypertensive agents may provide enhanced clinical benefits; however, clinical trial data have not established optimal combination regimens. Thus, a challenging task for investigators is to determine which combination therapy regimens will provide the greatest cardiovascular benefits for patients with hypertension. A trial that is now in progress, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), directly compares cardiovascular mortality and morbidity rates for two preselected, fixed‐dose combination therapies.

Combination therapy with drugs from two different classes of antihypertensive agents targets more than a single mechanism to correct the multiple pathophysiologic factors that play a role in blood pressure elevation. By this means, combination antihypertensive therapy offers the potential for greater reductions in blood pressure and a lowered risk for target‐organ damage than is achieved with monotherapy. Data from decades of large, randomized clinical trials (RCTs) have failed to establish superiority of any specific antihypertensive class; however, data from seven more recent, large RCTs have provided compelling evidence that more than a single antihypertensive agent is required to control blood pressure in patients with hypertension (Figure 1). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ In the Hypertension Optimal Treatment (HOT) study, ⁴ for example, 68% of subjects required more than one agent. In the United Kingdom Prospective Diabetes Study (UKPDS), ¹ 29% of subjects required three or more agents to achieve a blood pressure of <150/85 mm Hg at 9 years after randomization. In the recently completed Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ⁷ patients received an average of two agents to achieve blood pressure levels <140/90 mm Hg.

Figure 1.

The mean number of antihypertensive agents needed in various clinical trials to achieve the specified level of blood pressure control. 1, 2, 3, 4, 5, 6, 7 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.

Based on this evidence, current clinical guidelines, including the recently published consensus statement by the Hypertension in African Americans Working Group (HAAWG) ⁸ and the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ⁹ endorse combination therapy as the initial therapy in selected patients. Importantly, numerous RCTs have provided evidence for compelling indications for the use of specific classes of antihypertensive agents in selected patient groups; this understanding is also reflected in current clinical guidelines. ⁸ , ⁹ , ¹⁰ , ¹¹

The JNC 7 ⁹ guidelines recommend that thiazide‐type diuretics should be used as drug treatment for most patients with hypertension, either alone or in combination with drugs from other classes. They further provide indications for selected classes of agents for patients with diabetes, renal disease, or heart failure; for patients who are at high risk for coronary artery disease or are post‐myocardial infarction; and for the prevention of secondary stroke. However, the JNC 7 algorithm for agent selection is very broad; for example, an agent from any of five classes could be selected as the initial agent of choice for a patient with diabetes. The HAAWG consensus statement ⁸ does not recommend thiazide‐type diuretics as the basis for initiating antihypertensive therapy; rather, it recommends selecting an agent from any of the five major classes of antihypertensive agents: angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers (CCBs), or thiazide‐type diuretics. When combination therapy from two major drug classes is required to achieve target blood pressure goals, the following combinations may be considered effective: β blocker/diuretic, ACE inhibitor/diuretic, ACE inhibitor/CCB, or ARB/diuretic. For patients with diabetes or kidney disease, the HAAWG ⁸ recommends that combination therapy should always include a renin‐angiotensin system blocking agent, either an ACE inhibitor or an ARB. Current clinical guidelines agree that blood pressure levels should be <130/80 mm Hg in these two high‐risk patient groups. ⁸ , ⁹ , ¹¹

Currently, creating optimal combination therapy regimens for patients with hypertension is based upon clinical judgment, because data from RCTs regarding this critical question are lacking. Most recent RCTs have compared classes of antihypertensive agents for their efficacy, tolerability, and ability to reduce cardiovascular morbidity and mortality by initiating blinded therapy with agents from different classes and then adding on agents to create a combination therapy regimen for the majority of study participants. These trial designs have certain inherent problems in elucidating the question of optimal combination therapy. In general, add‐on therapy disallows any crossover of agents from the classes under investigation between or among the groups being studied, thus limiting the types of combination regimens under investigation. Additionally, add‐on therapy relies on the judgment of individual investigators to design combination regimens for study participants. Further, equivalent blood pressure levels are rarely achieved by all groups under investigation, leading to the inability to answer the question of whether the clinical benefits observed in the trial occurred due to blood pressure reduction alone. This article describes the considerations for prescribing combination therapy as the initial treatment for patients with hypertension, based on currently available clinical trial data, and suggests directions for future clinical trials of combination therapy regimens.

INVESTIGATIONS OF ANTIHYPERTENSIVE REGIMENS

The recent Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ⁷ shows how difficult it is to apply trial data to real clinical practice. The objective of ALLHAT, a large multicenter RCT, was to establish an optimal first step for antihypertensive therapy by comparing amlodipine besylate, lisinopril, or doxazosin (agents from newer classes) with chlorthalidone (an agent from an older class) for the primary outcome of combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction. (Another arm of the study investigated the effects of lipid‐lowering agents on the same outcomes; these data will not be discussed here.) The participants (N=42,400) were North American men and women aged 55 years who had systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg (or were taking medication for hypertension) and had at least one additional risk factor for CHD. Secondary outcomes were all‐cause mortality, stroke, combined CHD events, and combined cardiovascular events.

In January 2000, after an interim analysis, the doxazosin treatment arm was discontinued due to a higher risk of stroke, combined cardiovascular disease (CVD) events, and heart failure compared with patients in the chlorthalidone arm. ¹² Baseline characteristics for the remaining participants (n=33,357) were similar among the three groups; overall, the mean age was 67 years, 47% were women, 35% were African American, 19% were Hispanic, and 36% had diabetes. The mean follow‐up time was 4.9 years, and there were no differences among treatment groups for the primary outcome (Figure 2) or for all‐cause mortality.

Figure 2.

In the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ⁷ the cumulative event rate for the primary outcome (fatal coronary heart disease or nonfatal myocardial infarction), showed no significant differences among the three treatment groups.

There were significant differences in blood pressure and other secondary outcomes, and these differences among the three treatments have generated considerable debate. This controversy is based on the still unresolved question of whether some classes of agents offer additional beneficial effects on cardiovascular and renal events that go beyond their ability to lower blood pressure. Identical reduction in blood pressure for all study groups would be necessary to answer this question; however, this critical outcome was not achieved in ALLHAT nor has it been achieved in most other similarly designed, large RCTs. Most of the significant findings of ALLHAT were in line with results from previous large RCTs that have shown the benefits of diuretics, the lack of superiority of various antihypertensive classes, and the need for combination therapy.

Although the blood pressure differences among the groups in ALLHAT were small, they were statistically significant. These small differences in both systolic blood pressure and diastolic blood pressure have been shown in other studies to make a significant difference in CVD outcomes. ¹³ , ¹⁴ A recent meta‐analysis ¹⁵ of the relationship between blood pressure and clinical events, based on observations of usual blood pressure in 1 million persons enrolled in prospective epidemiologic studies, indicated that blood pressure differences similar to those observed in ALLHAT could account for powerful effects on stroke and CHD mortality rates.

Thus, in ALLHAT it is impossible to assess any of the study drugs as initial monotherapy and difficult to find superiority in clinical outcomes for the three study drugs beyond what is attributable to their ability to lower blood pressure. Equal blood pressure reductions are needed to definitively compare benefits in clinical outcomes for each antihypertensive class. As noted elsewhere, the discrepancy in blood pressure across the treatment groups was predictable from the advent of the study, when the organizers chose to attempt multiple comparisons in a single trial rather than the more direct approach of separate, head‐to‐head comparisons. ⁷

Based on the data, ALLHAT investigators recommend chlorthalidone (and thiazide‐type diuretics by proxy) as the initial agent of choice for treating a wide range of high‐risk patients with hypertension, including diabetic patients with and without nephropathy. To a large degree, this sweeping recommendation stands in opposition to considerable data that demonstrate compelling reasons to use other antihypertensive classes, either as initial therapy or in combination with other agents. ⁸ , ⁹ , ¹⁰ , ¹¹ Substantial data from well‐designed clinical trials support the use of an ACE inhibitor as initial therapy in patients with diabetes (with or without nephropathy) as well as in patients with nondiabetic renal disease, patients who are postmyocardial infarction, and patients with congestive heart failure. ⁵ , ⁸ , ⁹ , ¹¹ Data now clearly support the use of ARBs in patients with renal disease, and there is also a strong rationale for their use in preventing stroke, in patients with left ventricular hypertrophy, in the presence or absence of diabetes, and in diabetic nephropathy. ⁷ , ¹⁶ , ¹⁷ , ¹⁸ It should be recognized, however, that in most of the hypertensive‐diabetic trials an ACE or an ARB was given with a diuretic in a high percentage of cases. There are also compelling indications to use β blockers as initial therapy in patients with ischemic heart disease and stable angina pectoris. ⁹ These data cannot be ignored, particularly when making clinical recommendations for the highest of high‐risk patients: those with diabetes, renal insufficiency, or both. Further, these patients should be brought to a lower blood pressure goal than was set or achieved in ALLHAT, so the benefits of treating to a more appropriate goal (e.g., <130/80 mm Hg), or the best regimens for these patients, could not be appreciated in ALLHAT.

Overall, attempts to claim superiority for any single drug class have been repeatedly thwarted by inconsistencies among the data. In contradistinction to the ALLHAT findings, the Second Australian National Blood Pressure Study (ANBP‐2) ¹⁹ found that older, male hypertensive patients (aged 65–84 years) had better CVD outcomes with ACE inhibitors than with diuretic agents, despite similar blood pressure reductions.

To compare the effects of diuretics, ACE inhibitors, CCBs, and β blockers on mortality and major CVD events among diverse populations, Neal and colleagues ²⁰ performed separate analyses of randomized, controlled clinical trials comparing active treatment regimens with placebo and trials comparing treatment regimens based on different drug classes. These investigators found strong evidence of benefits of ACE inhibitors and CCBs in placebo‐controlled trials and weaker evidence of differences based on different drug classes. Trials showed virtually no difference between ACE inhibitors and diuretics or β blockers for outcomes of stroke, CHD, congestive heart failure, major CVD events, CVD deaths, or all deaths. When they looked at trials that compared CCBs with diuretics or β blockers, CCBs reduced stroke by about 13% more than did the other two classes, and all other outcomes were equivalent. When ACE inhibitors were compared with CCBs, ACE inhibitors reduced CHD events and congestive heart failure about 20% more than did CCBs, with other events being equivalent (3, 4, 5).

Figure 3.

Blood Pressure Lowering Treatment Trialists' Collaboration findings for the relative risk of cardiovascular (CV) events and mortality: angiotensin‐converting enzyme (ACE) inhibitors vs. diuretics or β blockers (βBs). Studies included are Swedish Trial in Old Patients with Hypertension‐2 (STOP‐Hypertension 2), United Kingdom Prospective Diabetes Study (UKPDS), and Captopril Prevention Project (CAPPP). Diamonds represent the 95% confidence intervals (CIs) for pooled estimates of effect and are centered on pooled relative risk. ²⁰ CHD=coronary heart disease

Figure 4.

Blood Pressure Lowering Treatment Trialists' Collaboration findings for the relative risk of cardiovascular disease (CVD) events and mortality: calcium channel blockers (CCBs) vs. diuretics or β blockers (βBs). Studies included are International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment (INSIGHT), National Intervention Cooperative Study in Elderly Hypertensives study (NICS‐EH), Swedish Trial in Old Patients with Hypertension 2 (STOP‐Hypertension 2), Nordic Diltiazem study (NORDIL), and Verapamil in Hypertension and Atherosclerosis Study (VHAS). Diamonds represent the 95% confidence intervals (CIs) for pooled estimates of effect and are centered on pooled relative risk. ²⁰ CHD=coronary heart disease

Figure 5.

Blood Pressure Lowering Treatment Trialists' Collaboration findings for the relative risk of cardiovascular disease (CVD) events and mortality: angiotensin‐converting enzyme (ACE) inhibitors vs. calcium channel mockers (CCBs). Studies included are Appropriate Blood Pressure Control in Diabetes (ABCD) and Swedish Trial in Old Patients with Hypertension 2 (STOP‐Hypertension 2). Diamonds represent the 95% confidence intervals (CIs) for pooled estimates of effect and are centered on pooled relative risk. ²⁰ CHD=coronary heart disease

Other trials have been equally unconvincing of any superiority claim for a particular class of antihypertensive agents. The Metoprolol Atherosclerosis Prevention in Hypertension (MAPHY) trial, ²¹ but not the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, ²² demonstrated a greater mortality benefit with β blockers than with hydrochlorothiazide. The International Prospective Primary Prevention Study in Hypertension (IPPPSH) ²³ and the Medical Research Council Working Party study ²⁴ found β blockers and diuretics to be equivalent with respect to morbidity and mortality, although diuretics held a slight advantage for elderly patients. No major or consistent differences were observed among five different agents (acebutolol, amlodipine besylate, enalapril, chlorthalidone, and doxazosin) in the Treatment of Mild Hypertension Study. ²⁵

Further, the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents reported no significant differences among monotherapies, ²⁶ , ²⁷ and general equivalence between old and new antihypertensive drugs was shown in the Swedish Trial in Old Patients with Hypertension 2 (STOP‐Hypertension 2) study ²⁸ —with the caveat that rates of myocardial infarction and congestive heart failure were lower in patients treated with ACE inhibitors than in patients treated with CCBs.

SELECTION OF PHARMACOLOGIC TREATMENTS FOR HYPERTENSION

The value of pharmacologic antihypertensive therapy was not clear until the publication in the 1970s of the Veterans Administration Study, ²⁹ the first prospective, randomized, double‐blind study demonstrating that drug treatment for mild hypertension decreased morbidity and mortality. In the past three decades, new pharmacologic agents have been developed based on increased knowledge of the pathophysiology of hypertension, including such contributory variables as genetic, environmental, and metabolic factors; vascular responses; activity of the renin‐angiotensin system and the sympathetic nervous system; sodium sensitivity; and endothelial functions.

The failure of monotherapy to control blood pressure and the recognition that blood pressure goals needed to be lowered led to the increased use of combination therapy. In IPPPSH, ²³ for example, two thirds of the patients randomized to receive a β blocker were also given a diuretic, and one third of these patients were given a third drug. The result was satisfactory blood pressure control in 80% of patients in this study. Up to 76% of patients in the HOT study ⁴ required more than one antihypertensive drug at the 36‐month follow‐up. The UKPDS 38 ¹ also supported the need for combination therapy; during its 9‐year follow‐up, 60% of patients required two or three drugs to maintain tight blood pressure control. The African American Study of Kidney Disease and Hypertension (AASK) also confirmed the need for two or more agents to reach blood pressure goals. ⁵

Emergence of Combination Therapy for the Initial Treatment of Hypertension

Combination therapies have been well studied for efficacy and safety, and numerous fixed‐dose combination therapies are available (Table). A large number of patients would appear to benefit from initial therapy with one of these combination products in the interest of achieving blood pressure control and providing agents from classes for which the patient has specific indications.

Table.

Antihypertensive Therapy Combinations and Available Fixed‐Dose Combinations

Combination	Fixed‐Dose Combinationsace
ACE inhibitors and CCBs	Amlodipine besylate/benazepril HCl Enalapril maleate/felodipine Trandolapril/verapamil	(Lotrel®) (Lexxel®) (Tarka®)
ACE inhibitors and diuretics	Benazepril/HCTZ Captopril/HCTZ Enalapril maleate/HCTZ Lisinopril/HCTZ Moexipril HCl/HCTZ Quinapril HCl/HCTZ	(Lotensin HCT®) (Capozide®) (Vaseretic®) (Prinzide®) (Uniretic®) (Accuretic®)
ARBs and diuretics	Candesartan cilexetil/HCTZ Eprosartan mesylate/HCTZ Irbesartan/HCTZ Losartan potassium/HCTZ Telmisartan/HCTZ Valsartan/HCTZ	(Atacand HCT®) (Teveten HCT®) (Avalide®) (Hyzaar®) (Micardis HCT®) (Diovan‐HCT®)
Beta blockers and diuretics	Atenolol/chlorthalidone Bisoprolol fumarate/HCTZ Propranolol LA/HCTZ Metoprolol tartrate/HCTZ Nadolol/bendroflumethiazide Timolol maleate/HCTZ	(Tenoretic®) (Ziac®) (Inderide®) (Lopressor®) (Corzide®) (Timolide®)
Diuretic and diuretic	Amiloride HCl/HCTZ Spironolactone/HCTZ Triamterene/HCTZ	(Moduretic®) (Aldactone®) (Dyazide, Maxzide®)
ACE=angiotensin‐converting enzyme; CCB=calcium channel blocker; HCTZ=hydrochlorothiazide; ARB=angiotensin II receptor blocker; LA=long acting

Combination therapy with an ACE inhibitor and a CCB is of particular interest, as this combination offers the protection of renin‐angiotensin system blockade with the potent vasodilatory effects of a CCB. ³⁰ Along with diuretics, ACE inhibitors and CCBs are among the most effective and widely used antihypertensive agents available. Emerging evidence suggests the optimal use of these agents may be as fixed, low‐dose combination therapy rather than as monotherapies. Further, this combination reduces the incidence of ankle edema, which is commonly found with CCB therapy. ³¹

Blood Pressure Reduction Plus Target‐Organ Protection

Although blood pressure reduction and tolerability are very important, reduction in cardiovascular events must also be shown for combination therapies, and not just for monotherapies with add‐on agents. In addition to blood pressure lowering, a combination should also prove the additive benefits in clinical outcomes beyond those found with the components as monotherapy.

A prospective, randomized study examined whether combined therapy has greater arterial and cardiac effects than doubled doses of the individual drugs. A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy (ALERT) ³² compared the effects of amlodipine besylate/benazepril HCl combination therapy with those of monotherapy with the component drugs on arterial distensibility and left ventricular mass. The study enrolled 106 patients aged 18 years with mild‐to‐moderate hypertension. Patients were randomized to amlodipine besylate 5 mg or benazepril HCl 20 mg for 2 weeks; then, depending on randomization assignment, they were forcetitrated to amlodipine besylate 10 mg or benazepril HCl 40 mg monotherapy, or to combination amlodipine besylate/benazepril HCl (5/20 mg) treatment for 22 weeks. Arterial distensibility was assessed using the DynaPulse ambulatory system (Pulse Metric, San Diego, CA), and left ventricular mass was assessed by echocardiography.

At the end of the study period, significant decreases in mean 24‐hour blood pressure were seen in all three arms of the study; combination therapy produced blood pressure reductions comparable to those seen in the high‐dose amlodipine besylate group and significantly greater than those observed in the benazepril HCl group. The increase from baseline in arterial distensibility was significantly greater with low‐dose amlodipine besylate/benazepril HCl combination therapy (0.71 mL/mm Hg) compared with monotherapy with either high‐dose amlodipine besylate (0.28 mL/mm Hg) or high‐dose benazepril HCl (0.39 mL/mm Hg; p=0.008 vs. amlodipine besylate monotherapy and p=0.03 vs. benazepril HCl monotherapy) (Figure 6). Similarly, reduction in left ventricular mass was also greater with combination treatment (65 g) than with amlodipine besylate monotherapy (28 g) and benazepril HCl monotherapy (42 g; p<0.02 vs. amlodipine besylate monotherapy). Reductions in left ventricular mass index were also superior with combination treatment compared with monotherapy (Figure 7). The results of ALERT demonstrate that low‐dose combination ACE inhibitor and CCB treatment significantly improves measures of cardiovascular structure and function compared with high‐dose monotherapy with either component. These findings indicate that appropriately selected combinations of antihypertensive drugs might have enhanced cardioprotective effects.

Figure 6.

Changes in arterial distensibility showing superiority for amlodipine besylate/benazepril HCl compared with amlodipine besylate or benazepril HCl monotherapies in A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy (ALERT). ³² Distensibility measured with DynaPulse DP5000A ambulatory system (Pulse Metric, San Diego, CA). *p<0.01 vs. baseline; ^†p<0.05 vs. amlodipine besylate; ^‡p<0.03 vs. benazepril HCl

Figure 7.

Changes in left ventricular mass index (LVMI) showing superiority for amlodipine besylate/benazepril HCl compared with amlodipine besylate monotherapy in A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy (ALERT). ³² LVMI is calculated based on echocardiographic measurement of left ventricular mass. *p<0.01 vs. baseline; ^†p<0.01 vs. amlodipine besylate

FUTURE DIRECTIONS FOR HYPERTENSION CLINICAL TRIALS

In the future, clinical trials must be designed that allow for head‐to‐head comparisons of combination therapy regimens. Only long‐term clinical trials comparing combination therapies will determine if indeed there are superior morbidity and mortality outcomes with specific combinations of antihypertensive agents. A trial that is now in progress, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is described elsewhere in this monograph. The design for this trial will allow investigators to provide antihypertensive regimens that are realistic, practical, and commonly used in clinical practice. Data from this trial should begin to answer the question of which combination regimens are optimal.

SUMMARY

We are currently at a crossroads in the evolution of antihypertensive treatment trials; to progress, we need to study combinations of antihypertensive drugs rather than regimens based on initial monotherapy. Many patients with hypertension should receive a combination of agents as initial therapy, and future clinical trials are needed to compare various combination therapies. The combination of a CCB and an ACE inhibitor, amlodipine besylate/benazepril HCl, may be a promising combination for efficacy and target organ protection.