Hypertension is the leading cause of patient visits to primary physicians.1 However, there is reason for concern about how effectively this common condition is being treated. A recent national survey2 found that only 27 percent of patients had their blood pressure reduced to less than 140/90 mm Hg, which is the therapeutic goal established by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).3 Blood pressure reduction to less than 140/90 mm Hg is optimal for the prevention of cardiovascular complications.4 In patients with diabetes or renal disease, the recommended goal for blood pressure is 130/85 mm Hg or lower.
Why is hypertension uncontrolled in almost three-fourths of patients? The Canadian Coalition for High Blood Pressure Prevention and Control5 found that approximately 50 percent of patients are not compliant with taking their medications. A second major problem, according to a recent survey,6 is that 82 percent of physicians fail to increase doses when indicated.
The problems of patient adherence to therapy and inadequate dosing might be resolved using two-drug, fixed-dose combinations. This approach is supported by the results of several controlled clinical trials. The Veterans Affairs Trial7 was carried out testing patients whose blood pressure remained greater than 140/90 mm Hg following two successive monotherapies. They were then randomly assigned to a two-drug combination. All possible two-drug combinations among six major classes of antihypertensive medications were tested. The combinations containing a diuretic were more effective than any others, achieving a systolic blood pressure less than 140 mm Hg in 77 percent of these resistant patients and a diastolic blood pressure less than 90 mm Hg in 69 percent. This was a significantly greater reduction than occurred with other combinations, including a calcium channel blocker plus an angiotensin-converting enzyme inhibitor.
In another recent double-blind trial8 involving a fixed-dose combination of low-dose bisopterol, the beta-blocking drug, plus hydrochlorothiazide, 6.25 mg per day, was compared with standard doses of amlodipine or enalapril monotherapy. Goal blood pressure (diastolic blood pressure less than 90 mm Hg or a diastolic reduction greater than 10 mm Hg) was attained in 71 percent of patients taking the fixed-dose combination, 69 percent of patients receiving amlodipine and 45 percent of patients taking enalapril. Side effects were few with all drugs and were least with combination therapy.
TABLE 1 Representative Fixed-Dose Antihypertensive Drug Combinations
| Combination drugs | Trade name | |
|---|---|---|
| Beta-adrenergic blockers and diuretics | ||
| Atenolol-chlorthalidone | Tenoretic | |
| Bisoprolol fumarate–hydrochlorothiazide | Ziac | |
| Metoprolol tartrate–hydrochlorothiazide | Lopressor | |
| HCT | ||
| Nadolol-bendroflumethiazide | Corzide | |
| Propranolol hydrochloride (extended release)–hydrochlorothiazide | Inderide LA | |
| Timolol maleate–hydrochlorothiazide | Timolide | |
| ACE inhibitors and diuretics | ||
| Benazepril hydrochloride–hydrochlorothiazide | Lotensin HCT | |
| Captopril-hydrochlorothiazide | Capozide | |
| Enalapril maleate–hydrochlorothiazide | Vaseretic | |
| Lisinopril-hydrochlorothiazide | Prinzide | |
| Angiotensin II receptor antagonists and diuretics | ||
| Losartan potassium–hydrochlorothiazide | Hyzaar | |
| Calcium antagonists and ACE inhibitors | ||
| Amlodipine besylate–benazepril hydrochloride | Lotrel | |
| Diltiazem malate (extended release)–enalapril maleate | Teczem | |
| Verapamil hydrochloride (extended release)–trandolapril | Tarka | |
| Felodipine–enalapril maleate | Lexxel | |
| Other combinations | ||
| Triamterene (37.5, 50 or 75 mg)–hydrochlorothiazide (25 or 50 mg) | Dyazide | |
| Spironolactone (25 or 50 mg)–hydrochlorothiazide (25 or 50 mg) | Aldactazide | |
| Amiloride hydrochloride (5 mg)–hydrochlorothiazide (50 mg) | Moduretic | |
| Guanethidine monosulfate (10 mg)–hydrochlorothiazide (25 mg) | Esimil | |
| Hydralazine hydrochloride (25, 50 or 100 mg)–hydrochlorothiazide (25 or 50 mg) | Apresazide | |
| Methyldopa (250 or 500 mg)–hydrochlorothiazide (15, 25, 30 or 50 mg) | Aldoril | |
| Reserpine (0.125 mg)–hydrochlorothiazide (25 or 50 mg) | Hydropres | |
| Reserpine (0.01 mg)–hydralazine hydrochloride (25 mg)–hydrochlorothiazide (15 mg) | Ser-Ap-Es | |
| Clonidine hydrochloride (0.1, 0.2 or 0.3 mg)–chlorthalidone (15 mg) | Combipres | |
| Methyldopa (250 mg)–chlorothiazide (150 or 250 mg) | Aldoclor | |
| Reserpine (0.125 or 0.25 mg)–chlorthalidone (25 or 50 mg) | Regroton | |
| Reserpine (0.125 mg)–chlorothiazide (250 or 500 mg) | Diupres | |
| Prazosin hydrochloride (1, 2 or 5 mg)–polythiazide (0.5 mg) | Minizide | |
ACE = angiotensin-converting enzyme.
Adapted with permission from Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2427.
The superiority of diuretic-containing combinations is demonstrated in other trials as well. The combination of hydrochlorothiazide plus captopril reduced systolic blood pressure by an average of 26.5 mm Hg and diastolic blood pressure by an average of 15.5 mm Hg.9 By contrast, a fixed-dose combination of diltiazem plus enalapril reduced diastolic blood pressure by an average of only 8.3 mm Hg. A list of five combination antihypertensives is provided in Table 1.
Thiazide-containing fixed-dose combinations not only provide greater antihypertensive activity but also encourage compliance by providing a simple one-pill once-daily method of administration. In addition, small doses of each component in the combination diminish the occurrence of adverse reactions. Certainly, while physicians may be concerned about side effects, the threat is not nearly so great as the risk of major cardiovascular events resulting from inadequately controlled blood pressure.4 According to the Canadian Coalition,5 the most important intervention in this regard is patient education. Patients are advised that although they may feel healthy at present, a persistently elevated blood pressure increases the risk of developing strokes, heart attacks and heart or kidney failure in the future. Controlling high blood pressure reduces these risks.
Most fixed-dose combinations usually are available in two strengths, permitting some flexibility in dosage. The greater reduction in blood pressure associated with the thiazide-containing combinations than with other drugs is probably related to the volume-depleting effect of the diuretic,10 an action unique among various classes of antihypertensive activity of other medicines.
The hypertension control rate of only 27 percent indicates that present methods of antihypertensive treatment are faulty. Physicians can do better. Combination medicine containing a thiazide as one of the components and more attention paid to compliance could lead the way to improvement.
