Combination Antihypertensive Drug Therapy: A Therapeutic Option Long Overdue


Am Fam Physician. 2000 May 15;61(10):2974-2977.

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Combination antihypertensive drug therapy has long been an infrequently exercised therapeutic option in the difficult battle to achieve target blood pressure levels. In this issue of American Family Physician, Skolnik and colleagues1 present a timely discussion on the many merits of this therapeutic approach.

Until recently, the therapeutic goal in virtually all patients with high blood pressure was a blood pressure of less than 140/90 mm Hg. However, this target level typically has been achieved in fewer than 50 percent of medically treated patients.2

The evidence-based sixth report of the Joint Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)3 appropriately assigned an even lower target blood pressure level (less than 130/85 mm Hg) for high-risk patients with renal disease, heart failure or diabetes mellitus. The rationale is that, at similar blood pressures, the absolute risk of morbidity and mortality from cardiovascular disease (as well as mortality from all causes) is much higher in these patients than in those who have hypertension and no comorbid conditions.

Over the years, target blood pressure levels have not been the primary subject of debate in hypertension therapy. Rather, debate has centered on the antihypertensive drug class that provides the greatest benefit to various subgroups of patients. The totality of evidence from clinical trials points to the following:

  1. Initial therapy with antihypertensive agents from a multiplicity of drug classes with diverse pharmacologic effects (diuretics, beta blockers, calcium antagonists and angiotensin-converting enzyme inhibitors) has been shown to reduce blood pressure–related morbidity and mortality.47

  2. Monotherapy will be ineffective in most high-risk patients with hypertension, including those with renal failure, diabetes mellitus or stage 3 hypertension (blood pressures of 180/110 mm Hg or greater). These patients will require combination therapy to achieve blood pressure control to the level of 140/90 mm Hg or less.

  3. Blood pressure control is probably more important than drug selection.

Drug selection is, however, important. Accordingly, one of the authors of this editorial (J.M.F) has argued previously that the concept of “preferred” drug therapy is more relevant to most practitioners in optimally integrating the concept of favored drug selection with the all-important goal of attaining the target blood pressure.8 Typically, a preferred drug is chosen for initial treatment. This drug is then titrated upward until the target blood pressure is achieved or the patient is being given the maximum tolerated dosage. When blood pressure control is not achieved, a second drug from a different class is added.

What does all of this have to do with combination drug therapy? Plenty. Therapy with the low to moderate doses of the two drugs in a combination agent more effectively lowers blood pressure than monotherapy with a higher dosage of either drug alone—and with fewer side effects.9

Given the newer, more appropriate lower target blood pressures for high-risk patients with hypertension, combination drug therapy will play an increasingly important role in attaining goal blood pressure. For example, the United Kingdom trial7 found that almost 30 percent of patients with type 2 diabetes and hypertension required three or more drugs to achieve an on-treatment blood pressure of 143/81 mm Hg (a systolic pressure fully 13 mm Hg higher than recommended in JNC VI3). Thus, it is relatively easy to deduce from available evidence that combination drug therapy will play an increasing role in achieving goal blood pressures.

The clinician is well advised to heed the important advice that Skolnik and colleagues1 provide about the merits of combination antihypertensive drug treatment. The move to combination antihypertensive drug therapy, even as initial therapy, in high-risk patients with hypertension (particularly those with blood pressures in excess of 170/105 mm Hg, diabetes mellitus or renal insufficiency) is long overdue. The many benefits that will accrue from adoption of this therapeutic strategy include improved blood pressure control, fewer drug-induced side effects (including metabolic effects) and lower drug acquisition costs.

Dr. Flack is professor and associate chairman for Clinical Research and Urban Health Outcomes and director of the Cardiovascular Epidemiology and Clinical Applications Program at Wayne State University School of Medicine, Detroit, and Detroit Medical Center, Detroit.

Dr. Bledsoe is assistant professor in the Department of Internal Medicine at Wayne State University School of Medicine and Detroit Medical Center.

Address correspondence to John M. Flack, M.D., M.P.H., Department of Internal Medicine, Detroit Receiving Hospital/University Health Center 2E, 4201 St. Antoine Blvd., Detroit, MI 48201.


show all references

1. Skolnik NS, Beck JD, Clark M. Combination antihypertensive drugs: recommendations for use. Am Fam Physician. 2000;61:3049–56....

2. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension. 1995;26:60–9 [Published erratum appears in Hypertension. 1996;27:1192]

3. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413–46 [Published erratum appears in Arch Intern Med. 1998;158:573]

4. Staessen JA, Fagar DR, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–64.

5. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–13.

6. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255–64.

7. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 . UK Prospective Diabetes Study Group. BMJ. 1998;317:713–20.

8. Flack JM. Optimal blood pressure on antihypertensive medication. Current Hypertension Reports. 1999;I:381–6.

9. Morgan TO, Anderson A, Jones E. Comparison and interaction of low dose felodipine and enalapril in the treatment of essential hypertension in elderly subjects. Am J Hypertens. 1992;5:238–43.



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