High Blood Pressure Medication Combinations

NEIL S. SKOLNIK, M.D., JONATHAN D. BECK, M.D., MATHEW CLARK, M.D., Abington Memorial Hospital, Jenkintown, Pennsylvania

Am Fam Physician. 2000 May 15;61(10):3049-3056.

Related Editorial

The recommendation for first-line therapy for hypertension remains a beta blocker or diuretic given in a low dosage. A target blood pressure of less than 140/90 mm Hg is achieved in about 50 percent of patients treated with monotherapy; two or more agents from different pharmacologic classes are often needed to achieve adequate blood pressure control. Single-dose combination antihypertension therapy is an important option that combines efficacy of blood pressure reduction and a low side effect profile with convenient once-daily dosing to enhance compliance. Combination antihypertensives include combined agents from the following pharmacologic classes: diuretics and potassium-sparing diuretics, beta blockers and diuretics, angiotensin-converting enzyme (ACE) inhibitors and diuretics, angiotensin-II antagonists and diuretics, and calcium channel blockers and ACE inhibitors.

The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)1 recommends that patients with hypertension and no comorbid illness begin antihypertensive drug therapy with a low dosage of a diuretic or beta blocker. This recommendation is supported by the results of a meta-analysis demonstrating that diuretics and beta blockers are the only agents shown to decrease the incidence of stroke and congestive heart failure in patients with hypertension.2 Diuretics administered in a low dosage have also been shown to decrease the incidence of coronary artery disease and total cardiovascular mortality.2

Although the documented decreases in morbidity and mortality make adequate treatment of hypertension important, the National Health and Nutrition Examination Survey (NHANES) report3 showed that blood pressure is controlled to a level below 140/90 mm Hg in only 27 percent of patients diagnosed with hypertension. Because monotherapy is effective in achieving this target goal in only about 50 percent of patients, treatment with two or more agents from different pharmacologic classes is often necessary to achieve adequate blood pressure control.4

The rationale for using fixed-dose combination therapy is to obtain increased blood pressure control by employing two antihypertensive agents with different modes of action and to enhance compliance by using a single tablet that is taken once or twice daily.5 Using low doses of two different agents can also minimize the clinical and metabolic effects that occur with maximal dosages of the individual components of the combined tablet.6 These potential advantages are such that some investigators have recommended using combination antihypertensive therapy as initial treatment, particularly in patients with target-organ damage or more severe initial levels of hypertension.7–9 Combination antihypertensive drugs are listed in Table 1.10

TABLE 1

Combination Drugs for the Treatment of Hypertension

Drug	Brand name	Cost (generic)*
Diuretic combinations
Amiloride and hydrochlorothiazide (5 mg/50 mg)	Moduretic	$18 (9 to 12)
Spironolactone and hydrochlorothiazide (25 mg/50 mg, 50 mg/50 mg)	Aldactazide	15 (1 to 13)
Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 50 mg/25 mg)	Dyazide	14 (9 to 11)
Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 75 mg/50 mg)	Maxzide-25 mg, Maxzide	15 (4 to 10)
Beta blockers and diuretics
Atenolol and chlorthalidone (50 mg/25 mg, 100 mg/25 mg)	Tenoretic	36 (4 to 27)
Bisoprolol and hydrochlorothiazide (2.5 mg/6.25 mg, 5 mg/6.25 mg, 10 mg/6.5 mg)	Ziac	33
Metoprolol and hydrochlorothiazide (50 mg/25 mg, 100 mg/25 mg, 100 mg/50 mg)	Lopressor HCT	23
Nadolol and bendroflumethazide (40 mg/5 mg, 80 mg/5 mg)	Corzide	47
Propranolol and hydrochlorothiazide (40 mg/25 mg, 80 mg/25 mg)	Inderide	35 (6 to 10)
Propranolol ER and hydrochlorothiazide (80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg)	Inderide LA	50
Timolol and hydrochlorothiazide (10 mg/25 mg)	Timolide	22
ACE inhibitors and diuretics
Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)	Lotensin HCT	24
Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg)	Capozide	28 (22)
Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 mg)	Vaseretic	33
Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)	Prinzide	30
Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)	Zestoretic	31
Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15 mg/25 mg)	Uniretic	17
Angiotensin-II receptor antagonists and diuretics
Losartan and hydrochlorothiazide (50 mg/12.5 mg, 100 mg/25 mg)	Hyzaar	38
Valsartan and hydrochlorothiazide (80 mg/12.5 mg, 160 mg/12.5 mg)	Diovan HCT	36
Calcium channel blockers and ACE inhibitors
Amlodipine and benazepril (2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg)	Lotrel	48
Diltiazem and enalapril (180 mg/5 mg)	Teczem	51
Felodipine and enalapril (5 mg/5 mg)	Lexxel	37
Verapamil and trandolapril (180 mg/2 mg, 240 mg/1 mg, 240 mg/2 mg, 240 mg/4 mg)	Tarka	43
Miscellaneous combinations
Clonidine and chlorthalidone (0.1 mg/15 mg, 0.2 mg/15 mg, 0.3 mg/15 mg)	Combipres	26 (11)
Hydralazine and hydrochlorothiazide (25 mg/25 mg, 50 mg/50 mg, 100 mg/50 mg)	Apresazide	15 (3 to 5)
Methyldopa and hydrochlorothiazide (250 mg/15 mg, 250 mg/25 mg, 500 mg/30 mg, 500 mg/50 mg)	Aldoril	16 (6 to 14)
Prazosin and polythiazide (1 mg/0.5 mg, 2 mg/0.5 mg, 5 mg/0.5 mg)	Minizide	21

Diuretics in Combination Antihypertensive Therapy

Diuretics are effective antihypertensive drugs. Treatment with a diuretic such as hydrochlorothiazide results in a dose-dependent blood pressure reduction that levels off with higher dosages (Table 2).11 In long-term trials, diuretics have been shown to reduce the incidence of stroke, congestive heart failure, coronary artery disease and total mortality from cardiovascular disease.

TABLE 2

Blood Pressure Reductions Achieved with Hydrochlorothiazide Monotherapy

Dosage (mg per day)	Blood pressure reduction (mm Hg)
Dosage (mg per day)	Systolic	Diastolic
50	23	17
25	21	14
12.5	14	11
6.25	7	6

Unfortunately, the degree of improvement in cardiovascular mortality is less than would have been expected based on epidemiologic data. One postulated but not yet proven explanation is that the higher diuretic dosages used in the large trials cause relative hypokalemia, as well as increased serum lipid levels, insulin resistance and uric acid levels. These adverse metabolic effects counteract the positive cardiovascular benefits of blood pressure reduction. Such effects do not occur when diuretics are administered in a low dosage, such as 6.25 or 12.5 mg per day of hydrochlorothiazide.11

Because diuretics blunt the sodium- and water-retaining effects of many other antihypertensive drugs, they are the most commonly used medication in combination antihypertensive agents. The JNC VI states clearly, "If a diuretic is not chosen as the first drug, it is usually indicated as a second-step agent because its addition will enhance the effects of other agents."1^(p2429)

POTASSIUM-SPARING AND THIAZIDE DIURETICS

The discrepancy between the JNC VI recommendations for first-line use of thiazide diuretics and the actual use of these agents in clinical practice may be attributable to physicians' concerns about the development of hypokalemia and hypomagnesemia, as well as the marketing of newer agents by pharmaceutical companies. Combination therapy with a potassium-sparing diuretic and a thiazide diuretic attempts to reduce the risk of adverse metabolic effects. Combination therapy does not obviate the need for serial monitoring of serum electrolyte levels, but it does decrease the incidence of thiazide-induced hypokalemia without an increased risk of hyperkalemia.12

Fixed-dose potassium-sparing–thiazide diuretic combinations have been in use for more than 20 years. Current combinations include spironolactone-hydrochlorothiazide (Aldactazide), triamterene-hydrochlorothiazide (Dyazide, Maxzide) and amiloride-hydrochlorothiazide (Moduretic). These combination drugs do not appear to differ significantly in efficacy or adverse effects.13 The described improvement in the bioavailability of Maxzide over Dyazide has not been shown to yield improved blood pressure control.14

All potassium-sparing–thiazide diuretic combinations seem to reduce blood pressure to the same degree as thiazide diuretics alone.15-18 In one large postmarketing surveillance study of patients treated with triamterene-hydrochlorothiazide,12 the incidence of hypokalemia was approximately one half to one third that expected in hydrochlorothiazide monotherapy. In addition, the amiloride-hydrochlorothiazide combination caused significantly less alteration of serum potassium levels than did hydrochlorothiazide given alone in dosages of 25 to 100 mg per day.15 The clinical applicability of the findings may be questionable because the studies used hydrochlorothiazide dosages that were significantly higher than those currently recommended.

The low dosages of hydrochlorothiazide (12.5 to 25 mg per day) advocated in the JNC VI provide significant blood pressure reduction while minimizing electrolyte abnormalities.19 It remains unclear whether the addition of a potassium-sparing agent confers additional benefit compared with a low dosage of hydrochlorothiazide alone.

BETA BLOCKERS AND DIURETICS

Beta blockers cause retention of sodium and water. Diuretics can cause mild volume reduction that leads to an increase in renin secretion by the kidney. The rationale for combining beta blockers with diuretics is twofold: beta blockers blunt the increase in the plasma renin level that is induced by diuretics, and diuretics decrease the sodium and water retention that is caused by beta blockers.6,20

The combination of a beta blocker and a diuretic produces additive effects compared with monotherapy using either agent alone. A recent study21 assessed the safety and efficacy of antihypertensive therapy using the cardioselective beta blocker bisoprolol alone and in combination with low dosages of hydrochlorothiazide. The dosages of bisoprolol were 2.5, 5 and 10 mg per day. The hydrochlorothiazide dosages were 6.25 and 25 mg per day. The study showed that monotherapy with either agent was more effective than placebo, but that when combination therapy was used, the beneficial effects were greater than when either agent was used alone (Figure 1).21

Bisoprolol and Hydrochlorothiazide

FIGURE 1.

Response of blood pressure to treatment with bisoprolol and hydrochlorothiazide (HCTZ).

Information from Frishman WH, Bryzinski BS, Coulson LR, DeQuattro VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med 1994;154:1461–8 [Published erratum appears in Arch Intern Med 1995;155:709].

In the same study,21 combination therapy was associated with a low incidence of adverse effects. Side effects for combined hydrochlorothiazide in a dosage of 6.5 mg per day and bisoprolol in all dosages included fatigue (9 percent of recipients), dizziness (6 percent), somnolence (3 percent), impotence (2 percent) and diarrhea (4 percent). When used in combination with bisoprolol, hydrochlorothiazide (6.25 mg) did not cause hypokalemia or any adverse effects on the lipid profile. Side effects increased with the use of higher dosages of bisoprolol or hydrochlorothiazide. The incidence of hypokalemia and hyperuricemia was greater for 25 mg per day of hydrochlorothiazide than for 6.25 mg per day. With higher bisoprolol dosages, the frequency and severity of asthenia, diarrhea, dyspepsia and somnolence increased significantly.

ACE INHIBITORS AND DIURETICS

Angiotensin-converting enzyme (ACE) inhibitors are among the best tolerated antihypertensive drugs and have been used extensively as initial agents in the treatment of hypertension. The JNC VI1 recommends ACE inhibitors as second-line agents in most patients with hypertension and as first-line choices only in selected patients, including those with left ventricular systolic dysfunction and those with diabetes and microalbuminuria or proteinuria.

The reninangiotensin-aldosterone axis is important in the maintenance of systemic blood pressure. By causing volume and sodium depletion, thiazide diuretics stimulate the production of renin and angiotensin. This leads to a relative increase in blood pressure and sodium retention, which counteracts some of the other antihypertensive effects of the thiazide diuretics. ACE inhibitors interfere with the conversion of angiotensin I to angiotensin II and thereby decrease angiotensin II levels. These effects lead to decreased sodium retention and an enhanced antihypertensive effect.

Synergism between ACE inhibitors and diuretics is especially prominent in black patients, a population in whom monotherapy with ACE inhibitors has been shown to be less effective than it is in white patients. One small study22 of black patients with hypertension (N= 38) compared monotherapy using 20 mg per day of enalapril with combination therapy consisting of 20 mg of enalapril plus 12.5 mg of hydrochlorothiazide per day. Combination therapy significantly reduced systolic, diastolic and 24-hour ambulatory blood pressure measurements compared with monotherapy. Combination therapy controlled blood pressure to a level of less than 140/90 mm Hg in 74 percent of patients.

Studies have shown that ACE inhibitor–diuretic combinations achieve blood pressure control in approximately 80 percent of patients.20,23-25 Typical results were obtained in one of the larger double-blind, placebo-controlled trials.23

In this study,23 505 patients with diastolic blood pressures of 100 to 114 mm Hg received placebo, lisinopril (10 mg per day), hydrochlorothiazide (12.5 or 25 mg per day) or the combination of lisinopril (10 mg per day) and hydrochlorothiazide (12.5 or 25 mg per day). All drug therapies were more effective than placebo in lowering blood pressure, but the combination antihypertensive therapies produced the greatest effect (Figure 2).23

Lisinopril and Hydrochlorothiazide

FIGURE 2.

Response of blood pressure to treatment with lisinopril and hydrochlorothiazide (HCTZ).

Information from Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. Arch Intern Med 1994;154:737–43.

No significant differences in blood pressure reduction were observed for the two dosages of hydrochlorothiazide, whether the drug was used alone or in a combination.23 Adverse metabolic effects were observed only for regimens containing hydrochlorothiazide in a dosage of 25 mg per day. Serum potassium levels were significantly lower only for monotherapy with 25 mg per day of hydrochlorothiazide. Serum glucose measurements increased with the 25-mg dosage used as monotherapy or in combination with lisinopril.

The study23 found that the combination consisting of 10 mg per day of lisinopril and 12.5 mg per day of hydrochlorothiazide was well tolerated. The most commonly observed side effects were pharyngitis (14 percent of recipients), increased cough (6 percent), dizziness (2 percent), headache (12 percent) and asthenia (4 percent). Cough was the only side effect that was more prevalent in this group than in the placebo group.

Based on this large study,23 antihypertensive drug combinations containing an ACE inhibitor and a lower dose of hydrochlorothiazide are more desirable. It is important to be aware that the doses of ACE inhibitor in the antihypertensive drug combinations do not reach the target doses of ACE inhibitors recommended for the treatment of congestive heart failure, which may be a limitation in these patients.26

ANGIOTENSIN-II ANTAGONISTS AND DIURETICS

In patients for whom ACE inhibitor–diuretic combinations are indicated but not tolerated because of cough, angiotensin-II receptor antagonist–diuretic combinations are available. Angiotensin-II receptor antagonists work by blocking specific angiotensin II subtype I, thereby selectively inhibiting the vasoactive properties of angiotensin II.

One study27 evaluated the efficacies of losartan in a dosage of 50 mg per day, hydrochlorothiazide in a dosage of 12.5 mg per day and combination therapy with 50 mg per day of losartan and 6.25 or 12.5 mg per day of hydrochlorothiazide. The treatments were compared with each other and with placebo (Figure 3).27 The greatest antihypertensive effect occurred with the combination of 50 mg of losartan and 12.5 mg of hydrochlorothiazide. This treatment reduced diastolic blood pressure to less than 90 mm Hg (or a reduction of 10 mm Hg or greater) in 78 percent of patients. The combination of losartan with the lower hydrochlorothiazide dose (6.25 mg) demonstrated no benefit over monotherapy with losartan. No significant differences in adverse events were attributable to the combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) compared with placebo.

Losartan and Hydrochlorothiazide

FIGURE 3.

Response of blood pressure to treatment with losartan and hydrochlorothiazide (HCTZ).

Information from MacKay JH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med 1996;156:278–85.

Calcium Channel Blockers and ACE Inhibitors

The combination of a calcium channel blocker and an ACE inhibitor is appealing on theoretic grounds. Although calcium antagonists exert much of their antihypertensive effect through a vasodilatory action, they also have diuretic and natriuretic properties.28 ACE inhibitors blunt the stimulation of the reninangiotensin-aldosterone axis that may result from this diuretic effect. These agents also inhibit the central sympathetic stimulation that may result from calcium antagonist–associated vasodilatation, although both classes of drugs are potent vasodilators.29

ACE inhibitors and calcium channel blockers work effectively in combination to lower blood pressure.30–32 In one representative study,33 diastolic blood pressures were reduced by 3.6 mm Hg more with a trandolapril-verapamil combination than with monotherapy using either agent. No increase in side effects was observed for treatment with combined trandolapril and verapamil.

Calcium antagonists and ACE inhibitors may also work together to favorably influence target-organ disease independent of their effect on blood pressure. Together they appear to have a renal-protective effect,34 to promote reduction of left ventricular mass35 and to decrease mediators of vascular disease.36 The relatively low dose of ACE inhibitor in some combinations may not confer the same degree of renal or cardiac protection that has been demonstrated for higher doses.

Calcium channel blocker–ACE inhibitor combinations may result in fewer or milder side effects than occur with either agent alone. The addition of an ACE inhibitor to therapy with a dihydropyridine calcium antagonist significantly reduces the incidence of peripheral edema and reflex tachycardia. Neither class of medications has prominent metabolic side effects, an advantage in patients with diabetes and renal disease.

Four fixed-dose combinations of calcium channel blockers and ACE inhibitors are currently available in the United States. These combinations have yet to be proved more efficacious than antihypertensive combinations containing diuretics.

Miscellaneous Combination Agents

Other combination antihypertensive agents that have existed for many years include diuretics with a direct-acting vasodilator (hydralazine-hydrochlorothiazide [Apresazide]), a central alpha-adrenergic agonist (methyldopa-hydrochlorothiazide [Aldoril] and clonidine-chlorthalidone [Combipres]) or a peripheral alpha-adrenergic blocker (prazosin-polythiazide [Minizide]). No trials have indicated survival benefit with their use.

The JNC VI specifically mentioned that the three nondiuretic classes represented in these combinations "are not well suited for initial monotherapy because they produce annoying adverse effects in many patients."1^(p2426) No studies have provided conclusive evidence of increased tolerance when these agents are taken orally in combination with a diuretic. Therefore, these combinations are not indicated for first-line therapy.

Final Comment

The JNC VI1 continues to recommend monotherapy with a diuretic or beta blocker as initial treatment for the undifferentiated patient with hypertension. At the same time, it is recognized that monotherapy will not provide adequate blood pressure control in a large proportion of patients, and that many patients will experience unacceptable side effects with higher dosages of a single agent. Fixed-dose combination antihypertensive medications are a useful and appropriate treatment option in this large group of patients.

To see the full article, log in or purchase access.

The Authors

show all author info

NEIL S. SKOLNIK, M.D., is associate director of the family practice residency program at Abington Memorial Hospital, Jenkintown, Pa., and professor of family and community medicine at Temple University School of Medicine, Philadelphia. Dr. Skolnik graduated from Emory University School of Medicine, Atlanta, and completed a family practice residency at Jefferson Medical College of Thomas Jefferson University, Philadelphia....

JONATHAN D. BECK, M.D., is a third-year resident and chief resident in the family practice residency program at Abington Memorial Hospital. Dr. Beck received his medical degree from Jefferson Medical College of Thomas Jefferson University.

MATHEW CLARK, M.D., is associate director of the family practice residency program at Abington Memorial Hospital and clinical associate professor of family medicine at Temple University School of Medicine. Dr. Clark graduated from Yale University School of Medicine, New Haven, Conn., and completed a family practice residency at Kaiser Foundation Hospital, Los Angeles.

Address correspondence to Neil Skolnik, M.D., Abington Family Medicine, 817 Old York Rd., Jenkintown, PA 19046. Reprints are not available from the authors.

REFERENCES

show all references

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

2. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 1997;277:739–45.

3. Burt VL, Culter 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]

4. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328:914–21 [Published erratum appears in N Engl J Med. 1994; 330:1689]

5. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881–4.

6. Sica DA. Fixed-dose combination antihypertensive drugs. Do they have a role in rational therapy? Drugs. 1994;48:16–24.

7. Moser M, Prisant LM. Low-dose combination therapy in hypertension [Editorial]. Am Fam Physician. 1997;56:1275–612791282.

8. Moser M. Current recommendations for initial therapy in hypertension: are they still valid? Introduction. Am J Hypertens. 1998;11:69S–72S.

9. Moser M, Black HR. The role of combination therapy in the treatment of hypertension. Am J Hypertens. 1998;11:73S–8S.

10. Drugs for hypertension. Med Lett Drugs Ther. 1999;41:23–8.

11. Neutel JM. Metabolic manifestations of low-dose diuretics. Am J Med. 1996;101:71S–82S.

12. Hollenberg NK, Mickiewicz CW. Postmarketing surveillance in 70,898 patients treated with a triamterene/hydrochlorothiazide combination (Maxzide). Am J Cardiol. 1989;63:37B–41B [Published erratum appears in Am J Cardiol. 1990;66:388]

13. Cocke TB, Fisch S, Gilmore HR, Okun R, Tamagna IG, Wipplinger K. Double-blind comparison of triamterene plus hydrochlorothiazide and spironolactone plus hydrochlorothiazide in the treatment of hypertension. J Clin Pharmacol. 1977;17:334–8.

14. Casner PR, Dillon KR. A comparison of the anti-hypertensive effectiveness of two triamterene/hydrochlorothiazide combinations: Maxzide versus Dyazide. J Clin Pharmacol. 1990;30:715–9.

15. Myers MG. Hydrochlorothiazide with or without amiloride for hypertension in the elderly. A dose-titration study. Arch Intern Med. 1987;147:1026–30.

16. Jeunemaitre X, Charru A, Chatellier G, Degoulet P, Julien J, Plouin PF, et al. Long-term metabolic effects of spironolactone and thiazides combined with potassium-sparing agents for treatment of essential hypertension. Am J Cardiol. 1988;62:1072–7.

17. Licht JG, Haley RJ, Pugh B, Lewis SB. Diuretic regimens in essential hypertension. A comparison of hypokalemic effects, BP control, and cost. Arch Intern Med. 1983;143:1694–9.

18. Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Multicenter Diuretic Cooperative Study Group. Arch Intern Med. 1981;141:482–6.

19. Flack JM, Cushman WC. Evidence for the efficacy of low-dose diuretic monotherapy. Am J Med. 1996;101:53S–60S.

20. Neutel JM, Black HR, Weber MA. Combination therapy with diuretics: an evolution of understanding. Am J Med. 1996;101:61S–70S.

21. Frishman WH, Bryzinski BS, Coulson LR, DeQuattro VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med. 1994;154:1461–8[Published erratum appears in Arch Intern Med 1995;155: 709]

22. Middlemost SJ, Tager R, Davis J, Sareli P. Effectiveness of enalapril in combination with low-dose hydrochlorothiazide versus enalapril alone for mild to moderate systemic hypertension in black patients. Am J Cardiol. 1994;73:1092–7.

23. Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. Arch Intern Med. 1994;154:737–43.

24. Guul SJ, Os I, Jounela AJ. The efficacy and tolerability of enalapril in a formulation with a very low dose of hydrochlorothiazide in hypertensive patients resistant to enalapril monotherapy. Am J Hypertens. 1995;8:727–31.

25. Townsend RR, Holland OB. Combination of converting enzyme inhibitor with diuretic for the treatment of hypertension. Arch Intern Med. 1990;150:1175–83.

26. Cohn JN. The management of chronic heart failure. N Engl J Med. 1996;335:490–8.

27. MacKay JH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med. 1996;156:278–85.

28. Hansson L, Himmelmann A. Calcium antagonists in antihypertensive therapy. J Cardiovasc Pharmacol. 1991;18(suppl 10):S76–S80.

29. Gennari C, Nami R, Pavese G, Gragnani S, Bianchini C, Buracchi P. Calcium-channel blockade (nitrendipine) in combination with ACE inhibition (captopril) in the treatment of mild to moderate hypertension. Cardiovasc Drugs Ther. 1989;3(suppl 1):319–25.

30. DeQuattro V, Lee D. Fixed-dose combination therapy with trandolapril and verapamil SR is effective in primary hypertension. Trandolapril Study Group. Am J Hypertens. 1997;10:138S–45S.

31. Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Enalapril-Felodipine ER Factorial Study Group. Am J Cardiol. 1997;79:431–5.

32. Messerli F, Frishman WH, Elliott WJ. Effects of verapamil and trandolapril in the treatment of hypertension. Trandolapril Study Group. Am J Hypertens. 1998;11:322–7.

33. Mancia G, Omboni S, Grassi G. Combination treatment in hypertension: the VeraTran Study. Am J Hypertens. 1997;10:153S–8S.

34. Ruggenenti P, Remuzzi G. Primary prevention of renal failure in diabetic patients: the Bergamo Nephrologic Diabetes Complication Trial. J Hypertens Suppl. 1998;16:S95–7.

35. Messerli F, Michalewicz L. Cardiac effects of combination therapy. Am J Hypertens. 1997;10:146S–52S.

36. Weber MA. Translating data on antihypertensive drugs into clinical practice. Am J Hypertens. 1998;11:89S–94S.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

Copyright © 2000 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

MOST RECENT ISSUE