Fixed-dose combination therapy in the treatment of hypertension: ready for prime time.

Hypertension, defined as a systolic blood pressure (BP) [greater than or equal to]140 mm Hg or a diastolic BP [greater than or equal to]90 mm Hg, remains the most common reason that physicians see patients on a continuous outpatient basis and prescribe chronic prescription medication. Patients with hypertension are at a two- to fourfold increased risk for cardiovascular (CV) disease, stroke, peripheral arterial disease and heart failure. Evidence from clinical trials has shown that effective, long-term control of BP to <140/90 mm Hg can reduce the incidence of stroke by nearly 40%, myocardial infarction (MI) by 25% and heart failure by more than 50%. (1) With about 65 million Americans having hypertension, only 54% of those being treated with pharmacologic therapy have their BP controlled to the currently recommended goal of <140/<90 mm Hg. (2) In clinical outcome trials, however, BP control rates are better than those achieved in clinical practice, with control rates approaching 70%. Reasons for the improved control rates in clinical trials include keeping to a fixed appointment schedule, an available formulary at no cost to the participant, a treatment algorithm with set titration instructions telling the clinician when to increase the dose or add another antihypertensive medication, and the "volunteer effect"--patients helping us to help them with the future hopes of helping others based on the results of the trial.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated that, in patients [greater than or equal to]55 years of age with one or more CV risk factors, an initial strategy with a thiazide-type diuretic was as effective in preventing CV outcomes as initial therapy with a calcium channel blocker (CCB) or an angiotensin converting enzyme (ACE) inhibitor. (3) In ALLHAT, however, only 27% of individuals were controlled on the initial antihypertensive medication. In fact, clinical trials suggest that most patients require 2 or more antihypertensive agents to reach the currently recommended BP goals of <140/90 mm Hg in those with hypertension and <130/80 mm Hg in those with hypertension and diabetes or chronic kidney disease.

While the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) suggested that fixed-dose combinations could be used in those with Stage 1 hypertension (BP between 140-159 mm Hg/90-99 mm Hg), it recommended fixed-dose combinations as initial therapy for patients who fit into the "20/10 rule" (for example, individuals with Stage 2 hypertension who have their initial BP [greater than or equal to]160/100 mm Hg and need a 20/10 mm Hg reduction in BP to achieve BP control). (4) Fixed-dose combinations often include an ACE inhibitor plus a thiazide-type diuretic, an angiotensin receptor blocker (ARB) plus a thiazide-type diuretic, a beta blocker plus a thiazide-type diuretic, or an ACE inhibitor plus a CCB.

In this edition of the Southern Medical Journal, Dr. David Nash reviews the rationale for combination therapy in treating hypertension, focusing on the fixed-dose combination of an ARB and thiazide-type diuretic. (5) He correctly points out that while all antihypertensive agents effectively lower BP, a fixed-dose combination achieves additional BP reduction with fewer adverse effects often seen with high-dose monotherapy. As an ARB is evidence-based in patients with diabetes mellitus, heart failure with reduced ejection fraction, and, when unable to tolerate an ACE inhibitor, in those post MI, they correctly point out specific situations when combining an ARB with a thiazide-type diuretic is particularly beneficial. In addition, they emphasize specific side effects that make ARB therapy particularly attractive; they are not associated with a cough often seen with ACE inhibitor therapy, or lower extremity edema, often seen with increasing doses of CCBs of the dihydropyridine-type, especially in women. In fact, ARB use has been associated with "placebo-like" tolerability. This allows the highest ARB dose, which has been associated with improved clinical outcomes, to be combined with a low-dose thiazide-type diuretic, which minimizes some of the metabolic effects (hyperglycemia, hypokalemia) that may be encountered when a thiazide diuretic is used as monotherapy.

Fixed-dose combination regimens that target complementary pathophysiologic BP-lowering mechanisms provide an effective initial approach to control BP. Agents such as an ARB-diuretic, ACE inhibitor-diuretic, or ACE inhibitor-CCB antagonize both the renin-angiotensin system (RAS) [ACE or ARB], that may be activated, as well as the volume retention [diuretic or CCB], that occurs in those with hypertension. In addition, when used as an initial therapy, fixed-dose combination agents combat what has been called "therapeutic inertia (TI)," which describes the physician's failure to either increase the dose of antihypertensive medication or add another medication to achieve BP control. This was first described by Berlowitz et al (6) who surveyed Veterans Affairs (VA) clinics and found that while 40% of hypertensive patients had BP [greater than or equal to]160/90 mm Hg despite an average of 6 annual clinic visits, increases in medications were prescribed in only 7% of those same clinic visits. More recently, in a study that surveyed 7253 hypertensive patients followed for one year from practices in South Carolina, there was a linear relationship between the degree of TI and BP control. Practitioners who suffered from the most TI (the least likely to increase antihypertensive medications) achieved control rates that were 25% at the first visit and 6% at the last visit, while those who had the least amount of TI increased their control rates from 53 to 77%. (7)

Fixed-dose combination therapy offers an effective, convenient, well-tolerated option that is almost always required in clinical trials for effective BP control and outcome improvement. With complementary mechanisms of action in a disease with a multifactorial pathophysiology, fixed-dose combination agents should be considered in many patients with hypertension as initial therapy in an effort to reduce TI, reach BP goals sooner, and better tolerate what is often lifelong therapy. Although an ARB plus CCB will soon be available in two new fixed-dose combinations, an ARB and thiazide diuretic, as described in this issue of the SMJ, meet all of the criteria for an effective fixed-dose combination therapy.

References

1. Neal B, MacMahon S, Chapman N, Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet 2000;356:1955-1964.

2. Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44:398-404.

3. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997.

4. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-1252.

5. Nash DT. Rationale for combination therapy in hypertension management: focus on angiotensin receptor blockers and thiazide diuretics. South Med J 2007;100:386-392.

6. Berlowitz DR, Ash AS, Hickey EC, et al. Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998;339:1957-1963.

7. Okonofua EC, Simpson KN, Jesri A, et al. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension 2006;47:345-351.

You don't get to choose how you're going to die. Or when. You can only
decide how you're going to live. Now.
--Joan Baez

Jan N. Basile, MD

From the Primary Care Service Line, Ralph H. Johnson VA Medical Center Professor of Medicine, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SC.

Reprint requests to Jan N. Basile, MD, Director, Primary Care Service Line, Ralph H. Johnson VA Medical Center, Professor of Medicine, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, 109 Bee Street, Charleston, SC 29401. Email: [e-mail]

Accepted December 14, 2006.