Use of Fixed Dose Combination Antihypertensives for Uncontrolled Hypertension Patients Currently on Monotherapy

• Introduction
  
  
• Impact of HTN in High-Risk Populations
  
  
• Achieving BP Goals with Combination Therapy
  
  
• Improved Adherence
  
  
• ACEIs and Diuretics
  
  
• ARBs and Diuretics
  
  
• Beta-blockers and Diuretics
  
  
• CCBs and ACEIs
  
  
• Conclusion
  
  
• Figures
  
  
• References
  
  

Introduction

Nearly one in three Americans has hypertension (HTN), a condition that is often of unknown etiology. Although the condition is easily detected and usually controllable, an estimated 30% of people with HTN are unaware of having it, and only 34% have their blood pressure (BP) adequately controlled.^1,7
Among those at greatest risk for HTN and its complications are people with multiple risk factors, such as smoking, obesity, and concomitant diseases such as diabetes and the metabolic syndrome.^3,8 Certain demographic and ethnic groups are also at increased risk, including women, the elderly, African Americans, and Mexican Americans.^1,3 The overall prevalence and mortality rates for HTN are higher in women, at 33% and 59%, respectively, as compared with men.¹ Elderly Americans (aged 55 and older) also have higher prevalence and mortality rates than younger populations. A recent prospective study of 1,298 participants from the Framingham Heart Study found that adults aged 55 to 65 years had a 90% residual lifetime risk of developing HTN.⁹ The prevalence of HTN among blacks in the United States, estimated at 42% to 45%, is among the highest in the world. And, although the number of cases of HTN among Mexican Americans approximates the number of cases among whites, rates of BP control in Mexicans are significantly lower (18%) than those of either whites (33%) or non-Hispanic blacks (28%).¹

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Impact of HTN in High-Risk Populations

HTN causes substantial morbidity and mortality, increasing the risk of strokes, heart attacks, heart failure, kidney disease, atherosclerosis, and death. In 2002, HTN caused or contributed to 261,000 deaths.⁷ The impact of this condition on high-risk populations is of particular concern. HTN compounds the risk of developing cardiovascular sequelae in adults with diabetes, who already have a two to four fold increase in the risk of stroke and heart disease mortality as compared with adults without diabetes, as well as in adults with the metabolic syndrome, who have a three fold increased risk of heart disease and stroke.^8,10 African Americans, who tend to develop HTN earlier in life and have a higher average BP than whites, experience the following¹:

• 1.3 times greater rate of nonfatal stroke
• 1.8 times greater rate of fatal stroke
• 1.5 times greater rate of heart disease death
• 4.2 times greater rate of end-stage kidney disease

Likewise, women, the elderly, and Mexican Americans have a high risk of poor outcomes because of the high prevalence of HTN combined with trends toward less aggressive treatment in these subpopulations.^1,11-13

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Achieving BP Goals with Combination Therapy

• Improved efficacy
• Additive or synergistic effects
• Complementary mechanisms of action
• Enhanced response rate
• Fewer adverse events because of lower dose of each agent
• Improved adherence
• Less expensive regimens (less co-pays)
  

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Improved Adherence

Fixed-dose combination therapies may provide additional benefits by improving patients’ adherence, convenience, and, in some cases, cost effectiveness (eg, lower co-pay with one versus two products). One possible drawback, however, is the loss of dosing flexibility.^18-21
Numerous pharmacologic agents are currently available for the chronic treatment of HTN. All agents belong to one of six drug classes based on mechanism of action, as listed in Table 1.^3,22 Excellent clinical trial data have proven a reduction in complications of HTN with several classes of drugs, including ACEIs, ARBs, beta-blockers, CCBs, and thiazide-type diuretics^.3,14,23-29 Drug combinations of two or more agents from the different classes include diuretic combinations, diuretics + ACEIs, diuretics + ARBs, diuretics + beta-blockers, ACEIs + CCBs, and other miscellaneous combinations (see Table 1).^3,18,22 Studies have shown that various combination therapies, including fixed-dose combinations, can decrease BP and reduce complications among various patient populations more effectively than monotherapy.^19-21,30-33
The most commonly used medications in combination therapies are diuretics. Diuretics produce a dose-dependent reduction in BP that levels off with higher doses, and these agents enhance the effects of other antihypertensive drugs.^34-36 Given at low doses (eg, 6.25 or 12.5 mg of hydrochlorothiazide), diuretics provide nearly unsurpassed BP control while minimizing metabolic adverse effects, such as hypokalemia, increased lipid levels, insulin resistance, and increased uric acid levels.^37-39 For these reasons, JNC-7 recommends a thiazide-type diuretic alone or in combination with another antihypertensive agent as first-line therapy for HTN.³

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ACEIs and Diuretics

Thiazide diuretics cause volume and sodium depletion, which stimulates the production of renin and angiotensin. The latter effect leads to a relative increase in BP and sodium retention, which counteracts some of the other antihypertensive effects of thiazide diuretics. By interfering with the conversion of angiotensin I to angiotensin II, ACEIs decrease angiotensin II levels, thereby decreasing sodium retention and enhancing the antihypertensive effect. Clinical trials show that when combined, the synergism between ACEIs and diuretics controls BP in approximately 80% of patients.^40-43
In a multicenter study, 505 patients were randomized to receive placebo, lisinopril, hydrochlorothiazide, or the combination of lisinopril and hydrochlorothiazide.⁴¹ All drug therapies were more effective than placebo in lowering BP. However, the combination of antihypertensive therapies produced the greatest effect (Figure 3). The lower dose of hydrochlorothiazide (12.5 mg) produced fewer adverse metabolic effects than the higher dose (25 mg). Cough was more prevalent among patients who received combination therapy than among those who received placebo.⁴¹
In addition to their effects on BP, ACEIs have favorable effects among patients with diabetic nephropathy and albuminuria, as demonstrated in other studies.^44,45 These advantages make ACEI + diuretic combination therapies preferable for people with diabetes or renal disease. Deterrents to ACEI + diuretic combination therapies include cough, a common adverse effect, and angioedema, a rare effect overall but one that is more common in blacks than in other groups.²³

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ARBs and Diuretics

ARBs work by blocking specific angiotensin II subtype I, thereby selectively inhibiting the vasoactive properties of angiotensin II. Like ACEIs, these agents work synergistically with diuretics to significantly decrease BP, and they have beneficial effects on diabetic nephropathy and albuminuria.^30,33,45,46 In head-to-head comparisons, ARBs and ACEIs have shown comparable efficacy.⁴⁷ However, ARB + diuretic combinations may be preferable to ACEI + diuretic combinations for patients who cannot tolerate ACEIs because of cough or those who may be at risk for angioedema. Interestingly, although ARBs and ACEIs have different mechanisms of action, relatively few data exist on the effects of combination therapy with ARBs + ACEIs.⁴⁸
The recent Irbesartan/Hydrochlorothiazide Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial33 nicely demonstrated the role of a fixed-dose ARB + diuretic combination in effectively controlling BP. 1,005 patients
with HTN poorly controlled on monotherapy were enrolled in the study, including 30% with type 2 diabetes and 46% with the metabolic syndrome. By week 18, 77% of INCLUSIVE patients had achieved target SBP goals, 83% had achieved target DBP goals, and 69% had achieved combined BP goals.³³ Results for various study subgroups are illustrated in
Figure 4.^33,49-52

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Beta-blockers and Diuretics

Beta-blockers and diuretics are an effective combination because beta-blockers blunt the increase in the plasma renin level that is induced by diuretics, whereas diuretics decrease the sodium and water retention that is caused by beta-blockers.³⁵ In a comparison of the safety and efficacy of the cardioselective beta-blocker bisoprolol alone or in combination with low doses of hydrochlorothiazide, monotherapy with either agent was more effective than placebo, but combination therapy provided additive beneficial effects compared with either agent used alone (Figure 5).¹⁹ A favorable safety profile was reported in the study with the lower doses of hydrochlorothiazide (6.25 mg vs 25 mg) and bisoprolol (2.5 mg vs 10 mg and 40 mg).¹⁹ Decreases in coronary events with beta-blockers demonstrated in other studies also suggest that beta-blockers may be particularly useful in patients with HTN and stable angina or acute coronary syndromes.^{23-25,28,53,54}
However, beta-blocker + diuretic combination therapies are not suitable for all patients. These agents may be less effective (especially monotherapy) than other combination therapies for the treatment of HTN in African Americans and in patients with diabetic nephropathy and renal disease.^3,4 Usual contraindications to beta-blockers include asthma and moderate to severe chronic obstructive pulmonary disease (COPD).

Relative contraindications include the following:

• Diabetes
• Metabolic syndrome
• COPD
• Peripheral vascular disease
• Edema
• Cognitive disorders
• Depression

In addition, some patients are unable to tolerate beta-blockers because of fatigue, sexual dysfunction, or sleep disturbance.

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CCBs and ACEIs

The potential drawbacks of beta-blocker + diuretic combination therapies as well as the limited long-term data on the benefits of beta-blockers in patients with HTN and coronary artery disease provided the rationale for studies that compared the efficacy of the older combination of a beta-blocker + diuretic to the newer combination of a CCB + ACEI.^55,56 CCBs exert much of their antihypertensive effect through a vasodilatory action and have diuretic and natriuretic properties, whereas ACEIs blunt the stimulation of the renin-angiotensin-aldosterone axis that may result from this diuretic effect. ACEIs also inhibit the central sympathetic stimulation that may result from CCB-associated vasodilatation, although both classes of drugs are potent vasodilators.^18,57,58
The International Verapamil-Trandolapril (INVEST) Study compared outcomes among 22,576 patients with HTN and coronary artery disease treated with a CCB + ACEI combination versus a beta-blocker + diuretic combination.⁵⁶ Overall, this study showed that verapamil + trandolapril was just as clinically effective as atenolol + hydrochlorothiazide. Equivalent efficacy was also seen in a subset analysis of clinical outcomes in the cohort of patients with diabetes and coronary artery disease.⁵⁹ In a separate study, verapamil-based combination therapy reduced the risk of new-onset diabetes.⁶⁰
In contrast to INVEST, a separate comparative study demonstrated superior efficacy of a CCB + ACEI combination versus a beta-blocker + diuretic combination. The Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) study randomized 19,275 patients with HTN and multiple cardiovascular risk factors to atenolol + bendroflumethiazide or amlodipine + perindopril treatment.^25,61 After a median of 5.5 years of follow-up, the amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen (Figure 6). Some of the beneficial effects were believed to be independent of the BP-lowering effects of the CCB + ACEI combination. The efficacy and safety of CCB + ACEI combinations, demonstrated in studies such as INVEST and ASCOT-BPLA, make them particularly useful for patients with diabetes and renal disease.^3,6,62

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Conclusion

Combination antihypertensive therapies, including fixed-dose combinations, can substantially improve BP control and reduce cardiovascular complications.^19-21,30-33 Whereas monotherapy helps patients attain BP goals in only 50% of cases, combination therapy increases this proportion to as high as 80%.^33,56 Different combinations of drug classes may have particular advantages in specific patient populations. For instance, ACEI- or ARB-based treatments reduce the progression of diabetic nephropathy and albuminuria,^3,44,45 and ARBs reduce the progression to macroalbuminuria.^3,45,46 Although all antihypertensive agents decrease BP in African Americans, CCBs and diuretics produce somewhat better BP responses than ACEIs, ARBs, and beta-blockers. The addition of a diuretic to the latter agents is believed to eliminate the difference in responses. Regardless of the group in question, aggressive management with combination therapy can control HTN in high-risk populations.

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