Dispelling the Myth of “Aggressive” Antihypertensive Therapy

Abstract

Data from well designed randomized trials have proven the effectiveness of an intensive approach to hypertension management in reducing morbidity and mortality. Based on these data, guidelines recommend a blood pressure goal of <140/90 mm Hg in the general population, with lower goals for high‐risk patients. Clinical trials also show that most patients will require at least two antihypertensive agents to reach goal. Despite this evidence base, only about one third of individuals with hypertension receive sufficient therapy to attain a blood pressure of <140/90 mm Hg. Physicians may be reluctant to use multiple antihypertensive agents to achieve this goal because they may consider it to be “aggressive” and not always in the best interests of the patient, especially in those deemed at low risk. Such perceptions may be founded on several myths: 1) the approach demands a complex, time‐consuming titration‐to‐response strategy, during which the patient may be lost to follow‐up; 2) it increases the pill burden, which will decrease patient compliance; 3) it increases treatment‐related side effects; and 4) it is not cost‐effective. The availability of fixed‐dose combinations containing two antihypertensive agents should help to dispel these myths. Careful selection of efficacious, well tolerated, once‐daily, fixed‐dose combinations allows goal blood pressure to be achieved quickly in a broad range of patients and encourages patient concordance with therapy. Such formulations are also cost‐effective. Thus, reducing blood pressure using multiple drugs as fixed‐dose combinations is a strategy that recognizes the multiple pathophysiologic changes that lead to hypertension.

The purpose of early and so‐called “aggressive” antihypertensive treatment is to delay, prevent, or reverse blood pressure (BP)‐related target organ vascular damage to protect against future morbidity and mortality. The most serious manifestations of hypertensive organ damage are sudden cardiac death, stroke, myocardial infarction, left ventricular hypertrophy, congestive heart failure, angina pectoris, peripheral vascular disease, and renal failure.

The chronic pathophysiologic consequences of hypertension are usually subclinical in their early phases, such that a high proportion of cardiovascular (CV) events, which are frequently fatal, occur in previously asymptomatic individuals. This implies that preventive strategies (including BP control) should be initiated in apparently healthy people at high risk of future CV events before complications develop, as well as in patients with existing atherosclerotic disease.

A continuous and graded relationship exists between BP and CV risk. Even mild elevations in BP heighten this risk, as shown in a study investigating the correlation between baseline BP status and the incidence of CV disease on follow‐up among Framingham Heart Study participants. ¹ Compared with optimal BP (systolic BP [SBP] <120 mm Hg and diastolic BP [DBP] <80 mm Hg), high‐normal BP (SBP 130–139 mm Hg and/or DBP 85–89 mm Hg) was associated with a risk‐factor‐adjusted hazard ratio for CV disease of 2.5 (95% confidence interval [CI], 1.6–4.1) among women and 1.6 (95% CI, 1.1–2.2) among men.

Increasingly challenging treatment goals are being recommended in hypertension management guidelines (Table I). ² , ³ , ⁴ , ⁵ , ⁶ These new guidelines advocate a goal of <140/90 mm Hg in the general population with uncomplicated hypertension. Lower goals are set for higher‐risk patients, such as those with diabetes and/or renal disease (<130/80 mm Hg). These recommendations are based on evidence accumulated from long‐term trials indicating that lower Bps are associated with better outcomes in a broad range of patients. ⁷ , ⁸ The most prominent of these trials are the Hypertension Optimal Treatment (HOT) study, ⁹ the Perindopril Protection against Recurrent Stroke Study (PROGRESS), ¹⁰ the UK Prospective Diabetes Study (UKPDS), ¹¹ the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ¹² and the Heart Outcomes Prevention Evaluation (HOPE). ¹³ Such clinical trials also showed that most patients will require at least two antihypertensive medications to achieve BP control. ⁹ , ¹¹ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰

Table I.

Summary of Blood Pressure (BP) Goals (mm Hg) Recommended in Current Management Guidelines

	Patient Population
Guideline	General	Diabetes	Renal Disease	Statement Regarding Combination Treatment
ADA (2005) 3	—	<130/80	—	Many patients with diabetes will require three or more drugs
ESH‐ESC (2003) 4	<140/90	<130/80	<125/75 (proteinuria >1 g/d)	Suggests initiating treatment with a low‐dose combination, according to baseline BP and the presence or absence of complications, as an alternative to low‐dose monotherapy
ISHIB (2003) 5	<140/90; <130/80 should be considered for at‐risk patients	<130/80	<130/80 (proteinuria >1 g/d)	If BP ≥15/10 above goal, start with a combination of two drugs; use an ACEI or ARB as part of combination in patients with diabetes or renal disease
JNC 7 (2003) 2	<140/90	<130/80	<130/80	If BP >20/10 above goal, start with a combination of two drugs (one should be a diuretic); initiation of therapy with more than one drug increases the likelihood of achieving BP goal in a more timely fashion
WHO/ISH (2003) 6	<140/90 (for patients at low [15%] or medium [15%–20%] CV risk)	<130/80 (patients at high CV risk [>20%])	<130/80 (patients at high CV risk [>20%])	Where more than two drugs are needed to control BP, one should be a diuretic
ADA=American Diabetes Association; ESH/ESC=European Society of Hypertension‐European Society of Cardiology; ISHIB=International Society on Hypertension in Blacks; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin receptor blocker; JNC 7=seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; WHO/ISH=World Health Organization/International Society of Hypertension; CV=cardiovascular

Despite wide dissemination of well defined practice guidelines on hypertension management, the availability of effective and well tolerated antihypertensive therapies, and the demonstration in trials that BP goals are attainable, a significant gap remains between desired control and that achieved in clinical practice. One reason for the failure to consistently achieve goal BP is that physicians perceive it as an “aggressive” approach, involving the need for two or even more drugs. This may give them several concerns. First, there may be uncertainty as to the correct prescribing strategy to adopt to achieve BP control when more than one antihypertensive agent is required. Second, physicians may fear that complex dosing regimens for multiple agents will jeopardize patient compliance, leading to poorer BP control. Third, they may believe that intensive antihypertensive therapy will introduce safety and tolerability issues. Fourth, they may consider that using multiple agents is not cost‐effective. For these reasons, many physicians may accept moderate BP reduction instead of titrating treatment to achieve goal and risking the patient's discontinuing treatment completely due to problems of medication adherence and tolerability.

This review explores how, with the availability of efficacious, well tolerated, fixed‐dose combinations, these concerns are largely myths—and that using two or more antihypertensive agents should be perceived as intuitive rather than aggressive.

THE PROBLEM OF POOR BP CONTROL

Population data published in 1970 revealed that only half of all individuals with hypertension were identified, half of those identified were treated, and half of those treated were controlled (the so‐called “rule of halves”). ²¹ Underperformance in hypertension management remains today, as evidenced by data from the most recent United States National Health and Nutrition Examination Survey (NHANES) ²² (1999–2000). Of all adults with high BP (≥140/90 mm Hg or on antihypertensive medication), 68.9% were aware they were hypertensive. Of the 58.4% who were treated, BP was controlled to <140/90 mm Hg in 53.1%, representing 31.0% of all participants with hypertension. BP control was particularly poor in patients with diabetes: nearly 75% did not have their BP controlled to <130/85 mm Hg (the Joint National Committee recommendation at that time). ²³

Various explanations have been put forward to account for the undertreatment of hypertension. One factor is a poor working knowledge among physicians of the BP goals specified in guidelines ²⁴ , ²⁵ and insufficient education and training focusing on how these goals can be achieved in clinical practice. ²⁶ Levels of awareness of the lower goals for at‐risk populations (such as patients with diabetes or renal disease) are especially poor. ²⁷ Undertreatment of hypertension may also be attributed to overestimation by practitioners of the level of care they provide. ²⁸

MYTH: ACHIEVING BP CONTROL WITH MULTIPLE ANTIHYPERTENSIVE AGENTS IS COMPLICATED AND INCONVENIENT

Few linear opportunities exist in formalized medical training programs for physicians to learn how to intensify therapy to meet standard‐of‐care goals. While they may be aware of new guidelines, physicians may be unsure of their application in clinical practice. Achieving BP control pharmacologically—after lifestyle measures have failed—with several drugs sequentially may be seen as a complicated, time‐consuming process, requiring numerous clinic visits to monitor the response.

Hypertension is a multifactorial disease caused by many environmental factors and genetic abnormalities. The number of hypertensive phenotypes resulting from different environmental‐genetic interactions may explain the heterogeneity in treatment response and why only 40%–50% of patients respond to any single antihypertensive agent targeting one mechanism. ²⁹ , ³⁰ Because of this unpredictable response to monotherapy, even optimizing initial therapy in individual patients can be challenging and may require switching between drugs. If goal BP is not attained on monotherapy, a second or even third drug may be required. In such cases, the entire process of goal attainment, involving multiple class switches and dose titrations, is likely to reduce patient confidence, resulting in poor compliance and an increased probability that the patient will abandon treatment due to a feeling of failure and the inconvenience of frequent clinic visits. Consequently, physicians may settle for suboptimal BP control rather than attempt to titrate to goal and risk losing the patient altogether.

Dispelling the Myth

Clinical trials have shown that BP goal attainment does not have to be a protracted process, but can be achieved quickly and conveniently by following clear treatment algorithms. Guidelines also recognize that the overwhelming majority of patients will require more than one antihypertensive agent to achieve goal BP and have revised their recommendations accordingly (Table I). ² , ³ , ⁴ , ⁵ , ⁶ Some guidelines now advocate starting treatment in certain patient groups with two drugs (one of which should be a diuretic ¹² , ³¹ ), either as separate prescriptions or in fixed‐dose combination (Table I). The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) incorporates a simple algorithm for hypertension management, providing clear advice on the appropriate use of combination therapy (Figure 1). ² Follow‐up visits to assess the therapeutic response should be monthly for most patients, but more often for those with stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) or comorbid conditions. After stabilizing BP at goal, follow‐up visits can be at 3‐ to 6‐month intervals.

Figure 1.

Clinical algorithm for achieving target blood pressure, included in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. SBP=systolic blood pressure; DBP=diastolic blood pressure; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB=β blocker; CCB=calcium channel blocker. Adapted with permission from JAMA. 2003;289:2560–2572. ²

Two drugs from different classes with complementary mechanisms of action have additive BP‐lowering effects. ³² For example, volume contraction induced by diuretics activates the renin‐angiotensin‐aldosterone axis producing a compensatory increase in BP; this counter‐regulatory mechanism can be blunted by coadministration of an angiotensin‐converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). Such additive effects mean that combination treatment can achieve response rates exceeding 80% in patients with mild‐to‐moderate hypertension. ³³ , ³⁴ Administration of two agents also eliminates some uncertainty about the predicted response to treatment, since a higher percentage of patients will respond to combination therapy than to higher‐dose monotherapy. Combinations of a diuretic plus an ACE inhibitor or an ARB are especially useful in African Americans. ³⁵ , ³⁶ , ³⁷

Initiating treatment with two agents having complementary mechanisms of action and additive antihypertensive effects should not only simplify the process of goal attainment, but should also shorten the time to achieve that goal. ³³ , ³⁸ Achieving BP normalization quickly after the initiation of therapy can be expected to promote long‐term compliance—and thus BP control—since the patient will have more confidence in the efficacy of the treatment regimen and that it is of benefit. ³³ Thus, achieving goal BP should not be considered aggressive from the standpoint of requiring a complex and drawn‐out titration strategy. Appropriate use of combination therapy should simplify and expedite goal attainment, such that it is achieved in the majority of patients in just one or two steps.

MYTH: USE OF MULTIPLE AGENTS WILL REQUIRE COMPLEX DOSING REGIMENS WHICH WILL JEOPARDIZE PATIENT COMPLIANCE

Patient adherence to lifestyle changes and antihypertensive therapy is possibly the most important determinant influencing long‐term rates of BP control. Studies consistently show that compliance with antihypertensive therapy is poor ³⁹ , ⁴⁰ , ⁴¹ , ⁴² and that poor compliance is associated with higher health care costs. ⁴³ Although more efficacious than monotherapy, combination treatment with two or more drugs will increase the complexity of the dosing regimen if multiple pills are prescribed. Every additional medication will have its own dosing instructions, increasing the potential for patient error and the risk of noncompliance due to loss of motivation. Pill burden is likely to compromise compliance further in patients on medications for comorbid conditions. Means to increase compliance with antihypertensive drug therapy are needed to improve patient outcomes and reduce health care costs.

Dispelling the Myth

It seems intuitive that a medication that combines two or more components of a treatment regimen in a single pill would improve adherence to therapy. ⁴⁴ In the setting of hypertension, if more than one drug is needed to control BP, the regimen can be simplified by prescribing single‐pill, fixed‐dose combinations that are administered once daily. Compliance with antihypertensive therapy improves dramatically as the prescribed dose frequency decreases, ⁴⁵ which should translate into improved patient outcomes over the long term. Psychologically, patients feel better taking just one or two pills per day than taking three or four, which they may perceive as a sign of poor health.

Minimizing the total number of daily doses needed for BP control represents a major advantage of fixed‐dose combinations. This is supported by a number of clinical studies. For example, Dezii ⁴⁶ showed that 1 year after starting antihypertensive treatment, more patients persisted with a fixed‐dose combination of enalapril/hydrochlorothiazide than with separate pills of enalapril and a diuretic (70.0% vs. 57.5%; p<0.05) (Figure 2). Similarly, more patients persisted with a fixed‐dose combination of lisinopril/hydrochlorothiazide than with separate pills of lisinopril and a diuretic (68.7% vs. 57.8%; p<0.05). In another study, patients receiving a fixed‐dose amlodipine/benazepril combination had greater adherence over a period of at least 1 year than patients receiving a calcium channel blocker plus an ACE inhibitor as separate pills (80.8% vs. 73.8%; p<0.001). ⁴⁷ This translated to an additional 26 days of compliance in any given year among subjects receiving the amlodipine/benazepril fixed‐dose combination.

Figure 2.

Persistence rates for a single‐pill combination of enalapril/hydrochlorothiazide (HCTZ) vs. separate pills of enalapril maleate and a diuretic. Statistical significance (p<0.05) demonstrated at Months 6 and 12. Reproduced with permission from Manag Care. 2000;9(suppl):2–6. ⁴⁶

The availability of fixed‐dose combinations at different strengths will enable a large proportion of patients to achieve their BP goal from a single, once‐daily pill. It is, therefore, unjustified to consider treatment schedules involving the administration of more than one drug as aggressive on the basis that they demand patient adherence to a prohibitively complex dosing regimen.

MYTH: TREATING TO GOAL WILL INTRODUCE SAFETY AND TOLERABILITY ISSUES

Hypertension is commonly asymptomatic until target organ damage is manifested, hence the term “the silent killer.” The subclinical nature of hypertension poses several management challenges, especially if more than one antihypertensive agent is needed to achieve goal BP.

Patient management typically focuses on symptom resolution. Thus, elevated BP may be regarded as unimportant, or physicians may be less motivated to intervene than in patients with symptomatic disease. There is also, understandably, a reluctance to prescribe drugs to a patient who feels well because of the potential emergence of drug‐related side effects and a reduction in the patient's quality of life. Patients themselves are also likely to resist taking drugs if they believe themselves to be healthy and feel well. A preventive philosophy focusing on maintaining health needs to be adopted, both among physicians and their patients.

Finally, clinicians may believe that intensive BP reduction will cause orthostatic hypotension (with an attendant risk of falls) or an increase in overall CV risk (the J‐shaped curve).

Dispelling the Myth

Emerging evidence from clinical trials using ARBs suggests that hypertension is not truly asymptomatic. For example, irbesartan significantly reduced the incidence of headache vs. placebo among patients with hypertension, ⁴⁸ and a recent survey showed that lowering BP with telmisartan actually improved patients' perceptions of well‐being. ⁴⁹ Thus, associating antihypertensive therapy with a deterioration in quality of life seems to be unsubstantiated if well tolerated drugs such as ARBs (which, as a class, have placebo‐like side‐effect profiles) are used.

Treatment with two or more antihypertensive drugs can also be well tolerated if the drugs and doses are selected carefully. Fixed‐dose combination products exploit the dissociation between the dose‐response and dose‐adverse effects curves: the greatest BP reduction for the smallest dose increment typically occurs on the logarithmic portion of the therapeutic response curve, which falls at the low end of the dose‐adverse effect curve (Figure 3). ³³ When two antihypertensive agents are administered together, efficacy is additive if not synergistic. Consequently, effective BP reduction can be achieved with lower doses of two drugs, which minimizes drug‐related, dose‐dependent side effects.

Figure 3.

Idealized dose‐therapeutic and dose‐adverse response relationships. Fixed‐dose combination therapy, wherein low doses of two drugs are given, generally provides low but effective doses without the risk of concentration‐dependent adverse effects. Reproduced with permission from Drugs. 2002;62:443–462. ³³

Another advantage of combination therapy is that one of the drugs may prevent or attenuate some of the adverse effects associated with the other. For example, diuretic‐induced potassium depletion can be offset by the concomitant administration of an ACE inhibitor ⁵⁰ or ARB, ⁵¹ , ⁵² and calcium channel blocker‐related peripheral edema can be ameliorated by coadministration of an ACE inhibitor. ⁵³ , ⁵⁴

Patient resistance to polypharmacy can be overcome by appropriate education. Patients should be reassured that being on two antihypertensive medications is normal and that drugs work better when combined; it does not mean they are treatment failures. Awareness should also be improved among asymptomatic individuals of the long‐term vascular repercussions of inadequate treatment.

The J‐curve debate is ongoing. Data from HOT indicate that for nonischemic hypertensive subjects, lowering DBP to 82.6 mm Hg is optimal, although it is safe (but unproductive) to go lower. ⁹ For subjects with coronary artery disease (limited coronary flow reserve), however, a J‐curve does appear to exist between treated DBP and myocardial infarction, indicating that it would be prudent to avoid reducing DBP to below the low 80s mm Hg in patients at high risk of myocardial infarction. ⁵⁵ The Systolic Hypertension in the Elderly Program (SHEP) also suggested that excessive DBP lowering in elderly patients with isolated systolic hypertension increases the risk of stroke, myocardial infarction, and CV disease. ⁵⁶

In conclusion, a patient should not be denied effective antihypertensive therapy with multiple drugs on the grounds that it is aggressive and increases adverse effects. Tolerability should not present an obstacle to goal attainment if low‐dose combinations of antihypertensive agents are used. Combinations of an ARB plus a thiazide diuretic appear particularly attractive in this regard.

MYTH: USING MULTIPLE AGENTS IS NOT COST‐EFFECTIVE

Hypertension undertreatment may be partially attributed to concerns over the cost of lifelong therapy with several different drugs. This is compounded by the asymptomatic nature of hypertension, as physicians may be more mindful of the cost of medication to keep a seemingly healthy person well vs. that for a patient who expects symptom relief. Prescription costs may also deter patients from obtaining refills, especially if several different drugs are prescribed.

Dispelling the Myth

It is clear that treating hypertension with two drugs combined in a single formulation at doses that are well tolerated is cost‐effective. ³³ , ⁵⁷ , ⁵⁸ , ⁵⁹ Acquisition costs and pharmacy reimbursement for a single combination tablet may be lower than high‐dose monotherapy requiring multiple doses, or the two drugs administered as separate tablets. For example, the cost of a fixed‐dose combination of a diuretic with a β blocker, ACE inhibitor, or ARB is typically no higher than that of the nondiuretic component alone.

Fixed‐dose combination therapy with good efficacy and tolerability profiles should also incur fewer costly office visits for dose titration, treatment‐related side effects, or laboratory tests. Taylor and Shoheiber ⁴⁷ reported that a fixed‐dose amlodipine/benazepril combination is associated with an overall lower cost of care vs. a regimen comprising a calcium channel blocker plus an ACE inhibitor as separate tablets (Table II).

Table II.

Average Annual Cost ($) per Patient on Amlodipine/Benazepril Fixed‐Dose Combination Therapy (Group 1) vs. Those on Separate Pills of Calcium Channel Blocker and Angiotensin‐Converting Enzyme Inhibitor (Group 2)

Medication or Service	Group 1 (n=2754)	Group 2 (n=2978)	p Value
Amlodipine besylate/benazepril HCl therapy	427	572	<0.001
Other antihypertensive medications	46	92	<0.001
All other medications	796	1007	<0.001
Physician visit (cardiovascular‐related care)	90	88	0.898
Inpatient care (cardiovascular‐related)	164	848	<0.001
Total care (cardiovascular‐related)	726	1600	<0.001
Adapted with permission of Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with fixed‐dose amlodipine besylate/benazepril HCl versus comparable component‐based therapy. Congest Heart Fail. 2003;9:324–332. 47 Copyright 2003 by CHF, Inc.

Improved rates of BP control with well tolerated, fixed‐dose combinations, resulting from greater efficacy and a positive effect on compliance, should reduce the incidence of complications arising from hypertensive target organ damage. If hypertension were left untreated or inadequately treated, the cost of managing such complications, which may include hospitalization and lost productivity, would far exceed that of lifelong antihypertensive therapy. Additional savings may accrue from any nonhemodynamic benefits of the component drugs, such as renoprotection with ACE inhibitors and ARBs.

Treatment with two or more drugs to achieve goal BP should therefore not be withheld from patients with hypertension because of cost factors, especially if fixed‐dose combinations are prescribed.

CONCLUSIONS

A major obstacle to achieving BP control in the general hypertensive population is the reluctance of physicians to treat high BP early, intensively, and persistently.

Providing patients with a positive experience with their initial therapy, whereby goal BP is achieved early with minimal side effects, may serve to improve long‐term compliance, translating into better outcomes. Patients are also likely to value and trust their physician more if they feel that they are treatment successes, making them more receptive to advice and education on the benefits of multiple drug therapy and the importance of staying on treatment. The physician‐patient relationship could be enhanced further by engaging the patient in the treatment decision‐making process.

The management of hypertension is undergoing several paradigm shifts. Current guidelines reflect a move toward achieving and maintaining increasingly stringent BP goals as quickly as possible, especially among patients at high risk. In most long‐term hypertension trials that have goal attainment as the objective, patients were initiated on monotherapy, with the addition of further antihypertensive agents as necessary. In many cases, two or three drugs were needed. Therefore, it would seem logical that some patients might benefit from initial treatment with a fixed‐dose combination. Contemporary management guidelines support this view and encourage greater use of multidrug therapy, given either as separate components or as a fixed‐dose combination, to achieve BP goals. There is also greater realization that caring for patients is more than just symptom relief, as many individuals with hypertension will have subclinical disease.

With the availability of efficacious, well tolerated, easy‐to‐use, fixed‐dose combination products, there can be no grounds for interpreting intensive BP lowering to the goals recommended in treatment guidelines as aggressive. In contrast, based on the available evidence, the decision to treat to goal should be more accurately interpreted as “intuitive.”

Disclosure: Editorial assistance for the development of this manuscript was provided by Elaine Griffin, PhD, Envision Pharma, with the financial support of the Bristol‐Myers Squibb/Sanofi‐Synthelabo Partnership. Elizabeth O. Ofili, MD, MPH is supported by NIH grants No. 5P20RR11104 (Research Centers in Minority Institutions) and No. 5U54RR14758 (Center of Clinical Research Excellence), and a grant from Medtronic Foundation. Dr. Ofili has served as a consultant for Bristol‐Myers Squibb Co., Novartis, and Sanofi‐Aventis.