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Combination Therapy in the Practical Management of Hypertension

Practice-Based Strategies Utilizing Combination Therapy for Optimal Hypertensive Control

“Currently, only one third of patients with hypertension in the United States is achieving adequate blood pressure control,” said Addison A. Taylor, MD, PhD, Professor, Department of Medicine, Pharmacology, Molecular Physiology and Biophysics; and Chief, Section of Hypertension and Clinical Pharmacology, Baylor College of Medicine and Affiliated Hospitals, Houston. In 2003, the Joint National Committee on Detection, Evaluation and Treatment of Hypertension (JNC 7) issued new guidelines, noting new blood pressure goals: < 140/90 mmHg for those with uncomplicated hypertension and < 130/80 mmHg for those with diabetes or chronic kidney disease (Chobanian et al. JAMA. 2003;289:2560). According to Dr. Taylor, “In the vast majority of patients with hypertension, multiple drugs are required to achieve target blood pressure goals and significantly reduce cardiovascular risk.”

According to Dr. Taylor, “A patient who is hypertensive on a single drug and is not achieving his or her target blood pressure should be considered for combination antihypertensive therapy. In addition, patients who present with comorbidity—such as diabetes, renal disease, or proteinuria—should be considered for first-line combination antihypertensive therapy,” Dr. Taylor explained. He cautioned that even persons who respond well to antihypertensive monotherapy initially may ultimately require two or three agents to maintain this effect.

Focusing on Systolic Blood Pressure
Recent study data have emphasized not only the importance of diastolic blood pressure, but also the role of systolic blood pressure in cardiovascular risk. In one meta-analysis of 15,000 people, a reduction in systolic blood pressure was associated with a significant reduction in fatal or nonfatal stroke, fatal or nonfatal coronary events, and
cardiovascularmortality (Staessen et al. Lancet. 2000;355:865). “Indeed, in persons older than age 55, systolic blood pressure itself has been shown to be the major risk factor for cardiovascular events,” Dr. Taylor noted. In the STOP-Hypertension-2 trial, aggressive antihypertensive treatment to reduce diastolic blood pressure did not result in the achievement of systolic blood pressure goals, regardless of the therapy used. “In contrast, if systolic blood pressure is adequately controlled, diastolic blood pressure is also achieved,” Dr. Taylor pointed out (Hansson et al. Lancet. 1999;354:1751).

This dynamic was demonstrated in the SOLACE trial, which compared an amlodipine/benazepril combination therapy (dihydropyridine calcium channel blocker and ACE inhibitor) with higher-dose amlodipine alone in persons with hypertension. Over 12 weeks, the combination therapy was consistently associated with significantly better achievement of systolic blood pressure goals. In both treatment groups, the addition of hydrochlorothiazide resulted in an improved response (Neutel et al. Am J Hypertens. 2003;16(pt 2):196A).

Minimizing Side Effects
With combination therapy, the goal is not only to enhance treatment efficacy, but also to minimize treatment side effects. “For example, the combination of a potassium-sparing agent and a potassium-depleting agent allows a second drug to offset an adverse effect of the first,” Dr. Taylor said. In the case of calcium channel blocking agents, peripheral edema is a major side effect of treatment. Indeed, these agents cause arterial dilation, which leads to an increase in capillary pressure and peripheral edema. The addition of an ACE inhibitor promotes efferent postcapillary vasodilation, providing a balance of pressure along the capillaries and a reduction in peripheral edema.

In the SOLACE trial, hypertensive patients taking a calcium channel blocker/ACE inhibitor combination experienced half as much peripheral edema as those receiving higher-dose calcium channel blocker alone (Neutel et al. Am J Hypertens. 2003;16(pt 2): 196A).

In the SELECT trial, hypertensive patients received higher-dose amlodipine alone, higher-dose benazepril alone, or amlodipine/benazepril combined. “The combination approach demonstrated an additive effect, with significantly greater reductions in systolic and diastolic blood pressures compared with either agent alone. In addition, peripheral edema was significantly reduced compared with either monotherapy (Neutel et al. Am J Hypertens. 2004; 17(5): 183A).

Reducing Cardiovascular Risk
A number of factors act to increase a patient’s risk for cardiovascular morbidity and mortality. These include insulin resistance, diabetes, dyslipidemia, and hypertension. “Hypertension itself is associated with independent progression of coronary and peripheral arterial disease, leading to atherosclerosis,” Dr. Taylor explained. Left ventricular hypertrophy can lead to cardiac insult, coronary artery disease with myocardial ischemia or infarction, resulting in arrhythmia, loss of muscle function, and heart failure (Dzau et al. Am Heart J. 1991;121:1244). “For this reason, our goal is to reduce blood pressure before target organ damage occurs—or to detect this process early when it is potentially reversible,” Dr. Taylor said.

In the ALERT study, persons with hypertension received either amlodipine/ benazepril or higher-dose amlodipine alone or higher-dose benazepril alone. The combination therapy resulted not only in greater reductions in systolic and diastolic blood pressures, but also in significantly improved arterial distensibility than either monotherapy. A significantly greater reduction in left ventricular mass with the combination regimen also suggested a cardiac benefit (Neutel et al. Am J Hypertens. 2004;17:37).

In closing, the speaker emphasized the benefits of lower-dose combination antihypertensive therapy in blood pressure reduction and target organ protection. He also pointed out the potential advantage of single-pill combination therapies. In one analysis of more than 5000 people, patients taking a single-pill combination antihypertensive regimen demonstrated better adherence than those taking two separate pills (Taylor et al. Congest Heart Fail. 2003;9:324). “The data suggest an additive effect with combination antihypertensive therapy, allowing greater efficacy and reduced side effects—as well as improved adherence with simplified treatment regimens,” Dr. Taylor concluded.


Pharmacologic Considerations in the
Use of Antihypertensive Combination Therapy

Approximately 58 million Ameri-cans have hypertension, and another 45 million meet the definition for prehypertension syndrome. “For many of these individuals, multiple drug therapy is needed to achieve systolic and diastolic blood pressure goals,” said Domenic A. Sica, MD, Professor of Medicine and Pharmacology, Division of Nephrology; Chief, Clinical Pharmacology and Hypertension Division; Virginia Commonwealth University Medical College, in Richmond (Table 1). According to Dr. Sica, co-administration of the various available antihypertensive agents requires an understanding of the pharmacologic basis for each combination.

The Dose-Response Factor
Numerous classes of antihypertensive agents are available for use in persons with hypertension, with many classes acting on multiple locations in the body. In many cases, said Dr. Sica, patients with hypertension should be considered for first-line therapy with a combination of agents rather than monotherapy. “The different agents represent a family of dose-response curves,” Dr. Sica explained. “With one small dose escalation in monotherapy, the majority of response is achieved. Any succeeding dose escalation provides a diminishing yield in blood pressure reduction, but a greater increase in side effects. Thus, it is often more effective to give initial combination therapy rather than sequential dose titration,” he said.

In combining drug classes in the treatment of hypertension, it is critical that these agents be complementary in action. “The use of a second agent should be additive or synergistic in efficacy, but not in toxic effects,” said Dr. Sica.

Pharmacokinetics and Pharmacodynamics

“The pharmacokinetics of combining antihypertensive agents are seldom of clinical concern; however, an understanding of the pharmacodynamic cross-talk between these agents is paramount,” Dr. Sica said. In the treatment of hypertension, two main pharmacodynamic interactions are key: that of 1) a diuretic with any other antihypertensive agent and 2) a calcium channel blocker with an ACE inhibitor.

The combination of a diuretic with another antihypertensive agent affords not only a reliable additive effect on blood pressure, but also the minimization of diuretic side effects in persons with hypertension. While the exact synergistic mechanism is not completely understood, it appears that the antihypertensive response is greater and longer with higher diuretic doses. The addition of an angiotensin-converting enzyme (ACE) inhibitor to a diuretic regimen, for example, results in a greater reduction in blood pressure and less peri-pheral edema than with monotherapy. “In many cases, initial treatment with a fixed combination antihypertensive regimen—rather than sequential addition of agents—allows for more effective and efficient achievement of blood pressure goals,” Dr. Sica said.

“In combining calcium antagonists and ACE inhibitors, the synergistic mechanism likely differs based on whether a dihydropyridine or non-dihydropyridine calcium antagonist is used,” Dr. Sica explained. Both drugs work to reduce blood pressure by working on different pathogenic pathways. “In addition, ACE inhibitors act to lessen the counterregulatory response of sympathetic activation—as occurs with dihydropyridine calcium channel blockers,” he noted.

In closing, Dr. Sica stressed the critical role of multiple drug therapy—including simplified fixed combination regimens—in treating persons with hypertension. “This includes first-line combination therapy in those who have high blood pressure of 20/10 mmHg or more over goal, diabetes, or chronic kidney disease,” he concluded.



Reducing Clinical Events with Combination Therapy: A Practical Approach

Research evidence suggests a critical role for combination antihypertensive therapy in the current and future management of hypertension (Table 1). Indeed, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) now recommends two blood pressure goals: < 140/90 mmHg in those with uncomplicated hypertension and < 130/80 mmHg in those with diabetes or chronic kidney disease. The JNC 7 guidelines recommend first-line combination therapy for any patient who presents with 20/10 mmHg or more above target blood pressure goals, said William J. Elliott, MD, PhD, Professor of Pre-ventive Medicine, Internal Medicine, and Pharmacology, Rush Medical College, Rush University Medical Center, Chicago. According to Dr. Elliott, several clinical trials also show less target organ damage and fewer cardiovascular events with combination versus monotherapy for hypertension.

Monotherapy versus Combination Therapy
In one meta-regression analysis of 24 clinical trials, only 2.5% of patients receiving mono-therapy had a blood pressure reductionof greaterthan 19/9mmHg (Elliott. Am J Hypertens. 2002; 15(pt 2):29A). In another meta-analysis, Staessen and colleagues found that differences in cardiovascular events were associated with differences in systolic blood pressure levels (Staessen et al. Lancet. 2001;358:1305).

In addition, several trials have found combination therapy to be superior to monotherapy in achieving blood pressure reduction and in minimizing side effects. In the randomized FACET study, 380 persons with diabetes received either fosinopril or amlodipine. As cases of uncontrolled blood pressure arose, these patients were allowed to receive both drugs. Over 4 years, those receiving both medications showed significantly fewer major cardiovascular events than either monotherapy group (Tatti et al. Diabetes Care. 1998;21:597). In the randomized, multicenter PROGRESS trial, 6105 patients with a history of stroke or TIA in the last 5 years received an ACE inhibitor plus either a diuretic or placebo. Over 4 years, reductions in blood pressure as well as recurrent stroke and cardiovascular events were significantly greater in the combination therapy group (PROGRESS. Lancet. 2001;358:1033). Similarly, Messerli and colleagues treated persons with hypertension with either higher-dose amlodipine or combination amlodipine plus benazepril. This study showed improved reduction in blood pressure and edema with the combination regimen. The ALERT study demonstrated a number of benefits with combination therapy over higher-dose monotherapy, including improved blood pressure, reduced arterial stiffness, and regression of left ventricular hypertrophy (Neutel et al. Am J Hypertens. 2004; 17:37).

Future Directions
According to Dr. Elliott, the results of the ACCOMPLISH study are awaited, and will serve to compare cardiovascular morbidity and mortality in persons with systolic hypertension who receive either amlodipine/benazepril or benazepril/ hydrochlorothiazide combination therapy. In closing, Dr. Elliott summarized that the research shows an important role for combination therapy as part of current and future antihypertensive treatment regimens, not only for reducing blood pressure but also for reducing the incidence of cardiovascular-associated morbidity and mortality.


Clinical Pearls: The Practical Use of Fixed-Dose Combination Therapy

The physician assistant plays a pivotal role in the identification, diagnosis, and treatment of hypertension, a disease that presently affects approximately 58 million Americans, said Candice R. Pellegrino, MPA-C, physician assistant, Department of Veterans Affairs, Michael E. DeBakey Veterans Hospital, and instructor, Department of Medicine, Baylor College of Medicine, Houston. According to Ms. Pellegrino, there is no substitute for a scrutinizing patient history and thorough assessment of each individual patient.

Patient History and Assessment
According to Ms. Pellegrino, in addition to a complete patient and family history, a thorough physical examination is critical in identifying and treating hypertension effectively. A physical examination should include blood pressure measurements in both arms and legs (including ABI); fundoscopy to rule out retinopathy; assessment for JVD and auscultation of carotids; palpation and auscultation of the heart, abdomen, and femoral arteries; auscultation of the lungs; evaluation for edema; and examination for changes in sensation. It is not uncommon to find blood pressure discrepancies between the upper extremities. When these two measures differ significantly, vascular involvement should be suspected, Ms. Pellegrino said. In addition, the speaker explained, it is helpful to have the patient lie supine for 5 minutes before beginning the examination.

Importantly, in patients in whom a complication or other underlying disease is suspected, appropriate further evaluation is needed. An EKG is performed in those with suspected cardiac involvement, and is followed by a cardiac work-up as appropriate. If PVD is present, other testing for ischemia should be considered. If there is evidence of left ventricular hypertrophy or coronary heart failure, an echo examination may be needed to rule out diastolic dysfunction. It is important to note that hypertension must be controlled, before proceeding with non-invasive cardiac ischemia testing, Ms. Pellegrino pointed out.

Treatment of Hypertension
The management of hypertension requires not only aggressive treatment of the hypertension itself, but also of
disease risk factors, Ms. Pellegrino explained. Hypertension should be treated and monitored aggressively, with frequent office visits, home monitoring, and phone calls.

According to Ms. Pellegrino, most cases of hypertension require combination therapy to reach blood pressure goals of < 140/90 mmHg in uncomplicated hypertension and < 130/80 mmHg in hypertension with diabetes or renal disease (Chobanian et al. JAMA. 2003; 289:2560). The severity of hypertension and presence of underlying comorbidity should guide the clinician in choosing the type and dosage of the antihypertensive agents used, she explained. Recent guidelines indicate use of combination therapy in any patient having a blood pressure of > 20/10 mmHg above goal. Effective two-drug combinations include: beta blocker/diuretic, ACE inhibitor/diuretic, ACE inhibitor/calcium channel blocker, and ARB/diuretic. Fixed dose combination therapies may offer benefits such as convenient dosing regimens, increased adherence, and lower risk of adverse effects.

Finally, clinicians need to identify and treat risk factors for disease, such as obesity, dyslipidemia, and diabetes, from day one, Ms. Pellegrino said. Thus, initial treatment may involve not only combination antihypertensive therapy, but also consideration of antiplatelet treatment, statin therapy, and glucose management. Importantly, if a patient shows little or no response to moderate dosing of multiple antihypertensive agents and no medical explanation is evident, renal artery stenosis should be considered, Ms. Pellegrino cautioned.

In closing, Ms. Pellegrino noted the importance of the role of physician assistants in providing accurate diagnosis, prompt and aggressive treatment, and effective patient education for hypertension and its associated comorbidity and complications. “It is important to remember not to assume non-compliance with antihypertensive therapy, to attack this disease quickly with appropriate and often combination therapies, and to target risk factors as well as the disease in this patient population,” she concluded.

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