Antihypertensive Combination Drugs: Effectiveness, Adherence, and Pleiotropic Effects

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Hypertension is a chronic, asymptomatic, progressive disease that remains one of the most important public health problems today, affecting more than one quarter of the population and responsible for 50% to 60% of cerebrovascular events and myocardial infarctions. The decreasing age of onset of hypertension in the general population paired with increasing life expectancy has resulted in an increased incidence of this disorder, which will likely culminate in higher rates of morbidity and mortality in the future.

The causes of hypertension are multifactorial and still a matter of active research. Although somewhat of an oversimplification, currently 3 factors are known to produce hypertension: (1) contractility (as it relates to cardiac output); (2) volume status; and (3) vascular tone. Over activity in 1 or more of these hemodynamic factors may cause blood pressure to go up. Several medication classes have demonstrated benefits in treating hypertension, such as thiazide diuretics, beta blockers, alpha blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and dihydropyrodine calcium channel blockers. All of these medications are directed to affect volume, contractility, vascular tone, or some combination of these to achieve a controlled and sustained reduction in blood pressure.

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Thiazide diuretics remain first-line agents for hypertension because they are clinically effective and affordable. Additional medications may be added initially or serially as hypertensive control wanes over time. Comorbidities, such as diabetes mellitus, atrial fibrillation, coronary artery disease, or renal dysfunction, may influence the decision regarding the choice of which initial or additional medications to use for blood pressure control. It is important to accept that most patients will need several medications to control their blood pressure, and, owing to the progressive nature of the disease, they will likely require additional medications over time to achieve recommended blood pressure levels. This necessary polypharmacy is further complicated by the presence of comorbidities, which require additional medications. Approximately 25% of patients over the age of 65 years will be taking 5 or more medications daily, significantly increasing the risk of medication interactions, side effects, errors, and noncompliance. Because much of the polypharmacy today is associated with hypertension treatment, convenient combinations of well-established antihypertensive medications have been developed. These combination pills promote adherence by simplifying the medication list, reduce the risk of medication errors by simplifying delivery, and, in many cases, decrease the cost of acquiring the medications.

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In addition to the health risk posed by hypertension, patients with this disorder are at increased risk for developing cardiovascular comorbidities, which interact and worsen prognosis. Specifically, patients with hypertension have a 42% higher incidence of atrial fibrillation and are at risk of developing diabetes, likely related to metabolic dysfunction. ACE inhibitors and ARBs have both shown promise in reducing the risk of atrial fibrillation and diabetes in patients with hypertension. We examine ACE inhibitors and ARBs in the treatment of hypertension, as well as their use in combination with calcium channel blockers. We also review some of the newer antihypertensive combination pills, such as Exforge (amlodipine and valsartan), which may help prevent cardiovascular morbidity and promote medical compliance.

Renin-angiotensin-aldosterone system

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The renin-angiotensin-aldosterone system (RAAS) has been a target for developing pharmacologic agents since the discovery of ACE in 1957.10 Agents capable of interfering with multiple steps within the RAAS have been developed. The widespread use of ACE inhibitors, ARBs, and aldosterone antagonists has resulted in significant reductions in cardiovascular morbidity and mortality. Experimental and clinical evidence is overwhelming that RAAS manipulation with these agents improves blood pressure, reduces myocardial fibrosis, and slows the progression of chronic renal insufficiency in diabetic and nondiabetic chronic renal disease.

ACE inhibitors and aldosterone antagonists have become an integral component of the treatment strategy in chronic congestive heart failure, postmyocardial infarction, left ventricular systolic dysfunction, and nonischemic cardiomyopathies; however, a significant minority cannot tolerate this class of drugs because of their side effects. The most common side effect is an ACE inhibitor-induced cough, which occurs in up to 20% of patients started on this therapy. The cough is typically dry, persistent, nonproductive, and often necessitates discontinuation of the medication. It is thought to be related to accumulation of bradykinin, and possibly other metabolites, as a consequence of the action of the ACE inhibitors. In practice, patients are often warned of the potential side effect of cough by their health care practitioner or pharmacist; however, this hypervigilance comes at the risk of attributing any cough, including those that result from periodic upper respiratory tract infections, to ACE inhibitors.

Angioedema, also related to the accumulation of kinins, is an especially worrisome potential side effect because it can be life threatening. Inpatient observation is warranted for those who develop this complication to avoid airway compromise until the condition resolves. This is because this form of angioedema is usually not responsive to antihistamines or steroids.

ARBs are a safe alternative for patients who developed side effects or were otherwise intolerant to ACE inhibitors. Rather than blocking the conversion to angiotensin I to angiotensin II, these medications selectively block the angiotensin receptor and competitively inhibit the activity of angiotensin. Although there have been case reports of cough and angioedema resulting from ARBs, the frequency is significantly lower than with ACE inhibitors, and these agents appear to be quite safe in patients who have had adverse reactions to ACE inhibitors.

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In addition to their blood pressure effects, ACE inhibitors and ARBs have been noted to reduce the risk of developing atrial fibrillation and diabetes in patients with hypertension and heart failure. This effect has been noted in numerous studies with multiple ACE inhibitors and ARBs. Although the long-term benefits of delaying or preventing atrial fibrillation and diabetes with these treatments is not yet known, much of the morbidity and mortality associated with these comorbid illnesses would presumably be reduced. Studies are currently underway to evaluate the added value of this unique ARB characteristic.

Calcium channel blockade

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Dihydropyridine calcium channel blockers have become a mainstay of hypertension treatment. They cause direct vasodilatation by blocking smooth muscle calcium channels. As a class, these medications provide simple, effective blood pressure control by decreasing peripheral resistance. They are very well tolerated, with few side effects and drug-drug interactions being extremely rare. Consequently, they are an ideal medication to add when patients are not well controlled on 1 or more medications. Because of the low frequency of drug-drug interactions, dihydropyridine calcium channel blockers are ideal for use in patients who require additional antihypertensive medication and are already on polypharmacy regimens. They also can be initiated in new patients who present with severe hypertension and for whom few laboratory data are available, such as serum creatinine or potassium levels. The most common side effect of the dihydropyridine calcium channel blockers is peripheral edema. Although the edema is usually mild, it can be extremely bothersome, especially during the hot and humid summer months. This complication can be especially troublesome for elderly patients, and symptoms may be minimized by the addition of an ACE inhibitor or a diuretic. In the ACCOMPLISH (Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ) trial, the benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events.

Combination therapy

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Polypharmacy regimens are often required to achieve blood pressure control; thus, many combination pills have been developed to provide 2 medications in 1 pill. Various combinations of a thiazide diuretic with ACE inhibitors, ARBs, or beta blockers have been developed. Combinations of dihydropyridine with ACE inhibitors, ARBs, or beta blockers also have been marketed. The use of fixed-dose combination pills has been shown to be effective in the treatment of hypertension and to significantly increases medication adherence.

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The presence of comorbid conditions may provide help in choosing which medications to use initially or as secondary agents (Table). In general, most patients will be treated initially with a thiazide diuretic. The next line (or even first-line) agent for patients with diabetes or renal dysfunction is often an ACE inhibitor or ARB because of the renoprotective effects. Additional data demonstrating reduction in the development of atrial fibrillation and diabetes suggest these agents are reasonable for most patients.Beta blockers are clearly recommended in patients with a history or strong risk factors for coronary ischemic disease. While beta blockers are effective in the treatment of hypertension, there may be a trend towards worsened glycemic control in diabetic patients.

(Click table to view as a larger image)

Diabetes and renal dysfunction are common; thus, secondary therapy with ACE inhibitors is frequently used. ACE inhibitors have a long history of consistent efficacy and positive outcome results. These agents are also generally less expensive because several generic versions are now available. If blood pressure is well controlled, there are several combinations of diuretic and ACE inhibitors that could be considered to decrease pill burden. Patients intolerant of ACE inhibitors can be transitioned to ARB therapy, and a diuretic and ARB combination is also available.

Calcium channel blockers are a reasonable third-line agent for treating hypertension, and, in some cases, they may even be an appropriate first- or second-line therapy. Patients requiring 2 or more agents often need just a bit more afterload reduction to achieve blood pressure control. Calcium channel blockers are extremely effective, and because of the low rate of interactions with other medications, they are generally very well tolerated. The calcium channel blockers are also available in combination with ACE inhibitors, which can facilitate transition to a different medication without the addition of another pill.

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Until recently, no combinations of calcium channel blockers with ARBs were available; however, a combination of amlodipine and valsartan (Exforge) was approved by the US Food and Drug Administration in 2007 for the treatment of hypertension. The combination of amlodipine and olmesartan (Azor) is also available. In addition to the efficacy of amlodipine and valsartan to control hypertension, these combinations were shown to reduce the rate of recurrent atrial fibrillation compared with an atenolol and amlodipine combination. The EX-FAST (Efficacy of the Combination of Amlodipine and Valsartan in Patients With Hypertension Uncontrolled With Previous Monotherapy: The Exforge in Failure After Single Therapy) study provided additional support for the blood pressure lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy. In another study, hypertensive patients not controlled at 5 weeks by ramipril 5 mg and felodipine 5 mg experienced significant additional blood pressure reductions after 5 weeks on amlodipine 10 mg and valsartan 160 mg. This dosage of the amlodipine and valsartan combination was well tolerated.

Conclusions

Hypertension is a chronic progressive illness, and multiple medications are often needed to attain and maintain control. In the setting of comorbid illness, it behooves health care providers to consider the pleiotropic effects from currently available therapies. One such consideration in patients with hypertension is the significant risk and morbidity associated with the development of diabetes mellitus and atrial fibrillation. ACE inhibitors and ARBs are effective antihypertensives that have been shown to reduce the incidence of atrial fibrillation and diabetes. Combination therapy with ARBs and a calcium channel blocker (valsartan/amlodipine [Exforge] or olmesartan/amlodipine [Azor]) is now available and provides an opportunity to treat hypertension, prevent comorbidities, and increase medication compliance.