Several studies have demonstrated that reducing

AJH 2000;13:921 926 Clinically Additive Effect Between Doxazosin and Amlodipine in the Treatment of Essential Hypertension Sanem Nalbantgil, Istemi Nalbantgil, and Remzi Önder The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has reported that combinations of low doses of antihypertensive agents from different classes may provide additional antihypertensive efficacy and minimize the likelihood of dose-dependent adverse effects. Doxazosin and amlodipine, alone and in combination, were compared for efficacy in reducing blood pressure (BP) in 75 patients with predominantly moderate (Stage 2) hypertension. This was a double-blind, randomized, crossover study. After a 2-week washout period, patients in group A (n 37) received amlodipine 10 mg and patients in group B (n 38) received doxazosin 4 mg for 6 weeks. All patients then received reduced-dose combination therapy (amlodipine 5 mg and doxazosin 2 mg) for 6 weeks. Subsequently, patients received 6 weeks of monotherapy with the alternate medication (group A received doxazosin 4 mg and group B received amlodipine 10 mg). During both monotherapy periods, doxazosin and amlodipine significantly reduced systolic and diastolic BP (P <.001 v baseline). BP further decreased with combination therapy (P <.01 v monotherapy). The percentage of patients with Stage 2 hypertension who achieved a target BP of < 140/< 90 mm Hg increased from 78% with monotherapy to 94% with combination therapy. Fewer adverse effects were observed during combination therapy. It is concluded that there is an additional fall in blood pressure when reduced doses of doxazosin and amlodipine are used in combination for the treatment of hypertension, suggesting that doxazosin should be considered as an effective add-on treatment to calcium-channel blockers. Am J Hypertens 2000;13:921 926 2000 American Journal of Hypertension, Ltd. KEY WORDS: Hypertension, combination therapy, monotherapy, doxazosin, amlodipine. Several studies have demonstrated that reducing blood pressure (BP) in patients with hypertension reduces the risk of stroke, chronic renal failure, and overall cardiovascular morbidity and mortality. 1 3 However, first-line antihypertensive monotherapy is effective in reducing BP to within the normal range in only 50% to 60% of patients, leaving the remainder inadequately controlled and at continued risk. 4 7 Furthermore, it is known that the efficacy of monotherapy with increasing dosage of most antihypertensive agents is limited by a so-called ceiling effect, Received December 9, 1998. Accepted November 16, 1999. From the Ege University Medical School, Cardiology Department, Izmir, Turkey. Address correspondence and reprint requests to Sanem Nalbantgil, Mithat pasa cad 750 / 5, 35280, Izmir, Turkey; e-mail: sanemn@hotmail.com 2000 by the American Journal of Hypertension, Ltd. 0895-7061/00/$20.00 Published by Elsevier Science, Inc. PII S0895-7061(99)00279-4

922 NALBANTGIL ET AL AJH AUGUST 2000 VOL. 13, NO. 8 whereas the risk for adverse events generally continues to increase in a dose-dependent fashion, resulting in predictable patterns of both the types and incidence rates of adverse events. 8 However, in the past two decades, it has been observed that combination therapy with two antihypertensive drugs having different and complementary mechanisms of action can be highly effective in controlling BP. The beneficial effects of combination therapy frequently can be achieved when two antihypertensive medications are combined at reduced doses. Additionally, the judicious selection of agents to be used in combination often can result in the attenuation of adverse events caused by one drug as a result of the pharmacologic action of the other. 8 Recently endorsed by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI), 2 combination therapy is used to reduce BP in the treatment-refractory patient by harnessing two or more mechanisms that together produce either a clinically additive, synergistic, or potentiated effect. 4,9,10 Normalization of BP has been achieved in up to 80% of patients treated with some combination therapies. 5 Widely used combinations have included -blockers or angiotensin-converting enzyme (ACE) inhibitors, each with a diuretic, 11 14 and -blockers with -blockers. 15,16 There are also several reports of calcium-channel blockers used in combination with -blockers, 17 19 diuretics, 20,21 ACE inhibitors, 22 25 and even with other types of calcium-channel blockers. 26 Few studies have investigated the combination of an -blocker, such as doxazosin, with a calcium-channel blocker, such as amlodipine, in the treatment of hypertension, 27,28 although each of these drugs has been evaluated alone or in combination with other drugs. 29 34 The modes of action of calcium-channel blockers and -blockers are different. Whereas calcium-channel blockers mediate a decrease in vascular resistance by inhibiting the transmembrane influx of calcium ions into vascular smooth muscle, -blockers act via the antagonism of post-synaptic a -adrenergic receptors. Thus, by acting via different mechanisms, combination therapy may be anticipated to result in additional reductions in BP in hypertensive patients. The purpose of this study was to determine whether combination therapy with the -blocker doxazosin and the calcium-channel blocker amlodipine at reduced doses would be more effective in controlling Stage 1 or 2 hypertension than either drug used alone at conventional therapeutic doses. MATERIALS AND METHODS This was a 20-week, double-blind, randomized study with a two-arm crossover design. Patients with Stage 1or2( 180/ 110 mm Hg) 2 essential hypertension FIG. 1. Study design. This was a double-blind, randomized, two-arm, crossover study. were selected for the study. After a 2-week wash-out period, patients were randomized to two treatment groups. During the first 6 weeks of treatment, group A received amlodipine 10 mg and group B received doxazosin 4 mg on a daily basis. During the second 6 weeks of treatment, both groups received reduced daily doses of amlodipine (5 mg) plus doxazosin (2 mg). After the combination therapy phase of the study, the original daily monotherapy treatment regimens were reversed for the final 6 weeks: group A received doxazosin 4 mg, while group B received amlodipine 10 mg (Fig. 1). A patient history was taken on entry into the study and patients were given a clinical examination. To exclude a secondary cause of hypertension, measurements of plasma electrolyte levels, creatinine, and catecholamine excretion, as well as intravenous pyelography, were conducted for all patients. Patients with clinical evidence of severe hepatic or renal impairment, or for whom the individual study drugs were contraindicated, were excluded from the study. All patients gave written informed consent before entering the study. Good Clinical Practice (GCP) guidelines were observed and the study was performed in accordance with the Declaration of Helsinki (Hong Kong Revision, 1989). During the 18-week treatment period, sitting systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) were recorded weekly. BP and radial pulse rate were recorded only after patients had been inside the hospital for at least 15 min and sitting for at least 10 min. SBP and DBP were measured with a mercury sphygmomanometer at Korotkoff phases I and V, respectively, and the mean of three consecutive measurements was calculated. For each patient, BP and HR measurements were obtained from the same arm at each hospital visit and measurements were made by the same investigators using the same cuff and equipment. At the end of the wash-out period (Week 0) and at Weeks 6, 12, and 18 of treatment, electrocardiographic measurements, urinalysis, and blood tests were performed. Blood tests included hematocrit; erythrocyte, leukocyte, and platelet counts; determination of

AJH AUGUST 2000 VOL. 13, NO. 8 DOXAZOSIN AND AMLODIPINE IN HYPERTENSION 923 hemoglobin levels; determination fasting levels of glucose, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol; and levels of uric acid, creatinine, aspartic transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, and plasma sodium, potassium, calcium, and magnesium levels. Echocardiographic examinations were performed at the end of the wash-out period only. Doxazosin and amlodipine, whether used alone or in combination, were given as a single capsule. Dosages were fixed throughout the study. Patients were instructed to take their assigned medication in the morning. Clinical examinations were conducted between 15:00 and 17:00 h. To assess within-group changes in BP, HR, and laboratory test results, statistical analyses were performed using two-tailed paired Student s t tests for comparisons between data obtained at the end of the first monotherapy treatment period (Week 6) and at the end of the wash-out period (baseline; Week 0). Two-tailed independent Student s t tests were performed to compare all patient data obtained at the end of the combination therapy period (Week 12) and data obtained for each treatment group at the end of the wash-out period (Week 0), the end of the first monotherapy treatment period (Week 6), and the end of the second monotherapy treatment period (Week 18). Two-tailed independent Student s t tests also were employed for between-group comparisons at Weeks 0, 6, and 18. Values of P.05 were considered to be statistically significant for treatment effects. Adverse events (AE) and tolerability were assessed by nonleading questions posed by the investigators during scheduled hospital visits. RESULTS Seventy-five patients (44 men and 31 women) took part in the study. Thirty-seven were randomized to group A and 38 to group B. The overall mean BP ( SD) at baseline was 171 9/102 5 mm Hg (Table 1). Fifty-four of the 75 patients (72%) had hypertension rated as moderate in severity (Stage 2; SBP 160 179 mm Hg; DBP 100 109 mm Hg), with the remaining patients having SBP in the range of 140 159 mm Hg and DBP in the range of 90 99 mm Hg (Stage 1). At study entry, 56 patients (75%) had proved refractory to treatment with their previous single-agent antihypertensive therapy. All patients completed the study. Baseline demographic data for the patients participating in this study are presented in Table 1. At the end of the wash-out period, patients in groups A and B had similar mean SBP and DBP (Table 2). In group A, the mean SBP was 171 mm Hg and the mean DBP was 102 mm Hg, whereas in group B, the TABLE 1. BASELINE DEMOGRAPHIC DATA Demographic Mean ( SD) Range Number of patients 75 Male 44 Female 31 Age (years) 52.8 (7.9) 37 64 Duration of hypertension (months) 44.3 (18.2) 6 104 Systolic blood pressure (mm Hg) 171 (9) 144 180 Diastolic blood pressure (mm Hg) 102 (5) 91 109 Heart rate (beats/minute) 74 (6) 56 97 Left ventricular mass (g) 98 (24) 65 174 mean SBP was 171 mm Hg and the mean DBP was 102 mm Hg. In group A, treatment with amlodipine resulted in a decrease from baseline in the mean SBP to 142 mm Hg (P.001) and the mean DBP to 92 mm Hg (P.001). In group B, treatment with doxazosin resulted in a decrease in the mean SBP to 143 mm Hg (P.001) and the mean DBP to 94 mm Hg (P.001; Table 2, Fig. 2). No statistically significant differences in BP were TABLE 2. BLOOD PRESSURE AND HEART RATE AT BASELINE (WEEK 0) AND AT 6, 12, AND 18 WEEKS AFTER THE START OF THERAPY Amlodipine 10 mg Mean ( SD) Combination Therapy* Doxazosin 4mg Baseline (week 0) Group A Group B SBP (mm Hg) 171 (9) 171 (10) DBP (mm Hg) 102 (5) 102 (5) HR (beats/minute) 74 (6) 73 (6) Monotherapy (week 6) Group A Group B SBP (mm Hg) 142 (8) 143 (7) DBP (mm Hg) 92 (3) 94 (4) HR (beats/minute) 75 (6) 75 (6) Combination therapy (week 12) SBP (mm Hg) 130 (6) DBP (mm Hg) 87 (3) HR (beats/minute) 73 (6) Monotherapy (week 18) Group B Group A SBP (mm Hg) 141 (5) 143 (7) DBP (mm Hg) 90 (4) 93 (4) HR (beats/minute) 74 (7) 73 (7) DBP diastolic blood pressure; HR heart rate; SBP systolic blood pressure. * Amlodipine 5 mg doxazosin 2 mg; P.001 v baseline (Week 0); P. 0001 v baseline (Week 0) for both Group A and Group B; P.01 v monotherapy (Week 6) for both Group A and Group B; P.01 v combination therapy (Week 12); P 0.5 v combination therapy (Week 12).

924 NALBANTGIL ET AL AJH AUGUST 2000 VOL. 13, NO. 8 FIG. 2. Mean percent change ( SD) from baseline in systolic (SBP) and diastolic (DBP) blood pressures after 6 weeks of monotherapy (Week 6) with amlodipine 10 mg (solid bars) or doxazosin4mg(open bars) and after 6 weeks of combination therapy (amlodipine 5 mg doxazosin 2 mg; gray bars). Mean baseline SBP and DBP values were determined at the end of the wash-out period (Week 0) for all patients participating in the study (n 75). *P.001 v baseline; P.0001 v baseline; P.01 v monotherapy (Week 6). found between the two treatment regimens at the end of the first 6 weeks of monotherapy. The percentage of patients with Stage 2 hypertension who achieved the target BP with monotherapy was 78% (42/54), 88% in the amlodipine group and 68% in the doxazosin group. After 6 weeks of combination therapy, the mean SBP and DBP of both groups was further reduced, suggesting a clinical additive effect of the two drugs (Table 2, Fig. 2). The mean SBP for the combined groups was reduced to 130 mm Hg (P.01 compared with Week 6 and P.0001 compared with Week 0). Likewise, the mean DBP for the combined groups was reduced to 87 mm Hg (P.01 compared with Week 6 and P.0001 compared with Week 0). Overall, 94% (51/54) of patients with Stage 2 hypertension achieved the target BP of 140/ 90 mm Hg. On reverting to monotherapy with the alternate medication for the final 6 weeks of treatment, the mean SBP in group A (doxazosin) increased to 143 mm Hg (P.005 v combination therapy) and the mean DBP increased to 93 mm Hg (P.01 v combination therapy) (Table 2, Fig. 2). In group B (amlodipine), the mean SBP increased to 141 mm Hg (P.01 v combination therapy) and the mean DBP increased to 90 mm Hg (P.05 v combination therapy). The increases in both SBP and DBP at Week 18 were slightly greater in the doxazosin group than in the amlodipine group when compared with SBP and DBP values obtained after combination therapy (Week 12). There were no significant changes in mean HR at the Weeks 6, 12, or 18 for either treatment group compared with mean HR values obtained at Week 0. No significant changes in laboratory test results occurred in either group (Table 3). In general, doxazosin and amlodipine were well tolerated. Adverse events were observed less frequently during low-dose combination therapy than during monotherapy. Overall, headache, dizziness, flushing, fatigue, and edema were observed most frequently in the monotherapy phases. As expected, during treatment with amlodipine, edema was observed and postural hypotension was seen with doxazosin therapy. Side effects were mild, and all patients continued with their medication without the need for discontinuation or abbreviation of therapy to counteract side effects. DISCUSSION The purpose of combination therapy in the treatment of hypertension is to obtain better control of BP, particularly in difficult-to-control patients in whom single-agent antihypertensive treatment has failed to normalize BP or control is achieved only at the risk TABLE 3. LIPID PROFILES OF PATIENTS RECEIVING AMLODIPINE, DOXAZOSIN, AND COMBINATION THERAPY Mean ( SD) (mg/dl) Lipid Wash-out Amlodipine 10 mg Doxazosin 4mg Combination Therapy* Total cholesterol 231.4 (19.2) 229.3 (16.3) 228.7 (17.0) 230.0 (15.8) LDL cholesterol 148.8 (14.9) 147.8 (15.2) 145.9 (12.4) 147.1 (13.6) HDL cholesterol 41.8 (3.9) 42.0 (4.0) 42.4 (3.6) 42.4 (3.8) Triglyceride 154.0 (19.4) 155.2 (20.4) 152.8 (14.8) 152.0 (18.2) HDL high-density lipoprotein; LDL low-density lipoprotein. * Amlodipine 5 mg doxazosin 2 mg.

AJH AUGUST 2000 VOL. 13, NO. 8 DOXAZOSIN AND AMLODIPINE IN HYPERTENSION 925 of significantly reduced tolerability. In choosing combinations of antihypertensive drugs from different classes, it may be possible to achieve a greater therapeutic response while minimizing adverse effects by using relatively low doses of each drug in combination. This study demonstrated that combination therapy with reduced doses of doxazosin, an -blocker, and amlodipine, a calcium-channel blocker, is an effective treatment for hypertension, especially in patients who are refractory to single-agent antihypertensive therapy. At the time of study entry, 75% of the patients were refractory to their previous single-agent antihypertensive therapy. Combination therapy with conservative doses of doxazosin (2 mg) and amlodipine (5 mg) produced significantly greater decreases in mean SBP and DBP than those achieved with higher doses of either medication alone. In the case of doxazosin, the effectiveness of a 2-mg dose is particularly significant because the recommended dosing range is 1 to 16 mg and doses less than 4 mg often are not considered to be of therapeutic value in all but the mildest cases of hypertension. In addition to the overall reduction in mean SBP and DBP, the number of patients with Stage 2 hypertension who achieved a target BP of 140/ 90 mm Hg also increased from 42/54 (78%) after monotherapy to 51/54 (94%) after combination treatment. Because the therapeutic dosage range for doxazosin is relatively broad compared with that of antihypertensives from other drug classes, 8 it is likely that titration of doxazosin in small increments can be used to effectively tailor individual therapeutic regimens to achieve effective control of BP while minimizing the incidence of adverse events. Because the study was internally validated by the crossover monotherapy-combination therapy-monotherapy design, and reduced doses of both drugs were administered during combination therapy, the improvement in BP control obtained with combination therapy indicates that there was a clinically additive effect of the two agents on each other. This conclusion is supported by similar findings in other studies utilizing different agents in combination, including a smaller study (n 13) using doxazosin in combination with amlodipine. 13,16,35 The benefits of combination therapy also cannot be attributed to gradual accrual of therapeutic benefit over the first 12 weeks of treatment because mean blood pressures in the two treatment groups increased on cessation of combination therapy and return to monotherapy. In this study patients were assigned to fixed-dose treatment regimens during both monotherapy treatment phases and the combination therapy phase. It is important to note that both amlodipine and doxazosin were initiated at higher than recommended starting doses because it was important for the objective of the study to maintain an invariant dosage regimen. Dosage adjustment would have made the results more difficult to interpret and necessitated a larger study population to discern statistically significant differences in treatment effects. However, it is important to recognize that upward titration of doxazosin from 1 mg daily is recommended to decrease the chance of a first-dose hypotensive effect. Likewise for amlodipine, 10 mg is not a recommended starting dose for the treatment of hypertension and 5 mg is the most commonly prescribed dose worldwide. 36 The results of this study also demonstrate that lowdose combination therapy was associated with a lower incidence of side effects than monotherapy with either drug alone. This has been documented with other agents 5 and may be a result of the higher doses used during monotherapy or due to a mutual neutralization by each drug of the other s side effects. 4,8 No changes in patient lipid profiles were reported during this study. In other studies 37 39 with doxazosin, plasma total and LDL-cholesterol levels have been mildly but significantly reduced, while HDL-cholesterol levels have increased or remained stable. It is likely that the comparatively low doxazosin dose (2 to 4 mg) and the small study size combined to conceal the expected beneficial changes to the lipid profile. In conclusion, the results of this study and those from other studies suggest that, even for established first-line antihypertensive agents, the addition of a complementary agent increases drug efficacy across a wider range of patients and improves tolerability. Indeed, such combination therapy has been recommended by JNC VI. 2 The data reported here suggest that doxazosin should be considered as effective add-on medication to calcium-channel blockers, such as amlodipine. REFERENCES 1. Staessen J, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bullpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757 764. 2. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413 2446. 3. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G: Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition. Lancet 1991;337:872 876. 4. Ménard J: Critical assessment of combination therapy development. Blood Press 1993;2(suppl 1):5 9. 5. Rangoonwala B, Schulz W, Bauer B: Fixed dose combinations of ACE inhibitors. Br J Clin Pract 1996;50: 454 465.

926 NALBANTGIL ET AL AJH AUGUST 2000 VOL. 13, NO. 8 6. Sever P: The heterogeneity of hypertension: why doesn t every patient respond to every antihypertensive drug? J Hum Hypertens 1995;9(suppl 2):S33 S36. 7. Dahlöf B, Eggertsen R, Hansson L: Calcium antagonists combined with -blockers or ACE inhibitors in the treatment of hypertension. J Cardiovasc Pharmacol 1988;12(suppl 6):S104 S108. 8. MacConnachie A, Maclean D: Low dose combination antihypertensive therapy: additional efficacy without additional adverse effects? Drug Saf 1995;12:85 90. 9. Waeber B, Brunner H: Main objectives and new aspects of combination treatment of hypertension. J Hypertens 1995;13(suppl 2):S15 S19. 10. Messerli F: Combination therapy in hypertension. J Hum Hypertens 1992;6(suppl 2):S19 S21. 11. Mitchell I, Lodge R, Lawson A: Adjuvant effect of bendrofluazide on propranolol in hypertension. Scot Med J 1972;17:326 329. 12. O Brien E, MacKinnon J: Propranolol and polythiazide in treatment of hypertension. Br Heart J 1972;34:1042 1044. 13. Omvik P, Lund-Johansen P: Combined captopril and hydrochlorothiazide therapy in severe hypertension: long-term haemodynamic changes at rest and during exercise. J Hypertens 1984;2:73 80. 14. Pool J, Gennari J, Goldstein R, Kochar MS, Lewin AJ, Maxwell MH, McChesney JA, Mehta J, Nash DT, Nelson EB: Controlled multicenter study of antihypertensive effect of lisinopril, hydrochlorothiazide, and lisinopril plus hydrochlorothiazide in the treatment of 394 patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol 1987;9(suppl 3):S36 S42. 15. Lund-Johansen P: Pharmacology of combined a-bblockade. II. Haemodynamic effects of labetalol. Drugs 1984;28(suppl 2):35 50. 16. Prichard B: Combined alpha- and beta-receptor inhibition in the treatment of hypertension. Drugs 1984; 28(suppl 2):51 68. 17. Dahlöf B, Andersson O: A felodipine-metoprolol extended-release tablet: its properties and clinical development. J Hum Hypertens 1995;9(suppl 2):S43 S47. 18. Eriksson M, Nyberg G, Lidman K, Olofsson B, Bergstrand R: Aiming for steady 24-hour plasma concentrations: a comparison of two calcium antagonist and beta-blocker combinations. Blood Pressure 1993; 2(suppl 1):16 21. 19. MacCarthy E: Dihydropyridines and beta-adrenoceptor antagonists as combination treatment in hypertension. J Hypertens 1987;5(suppl 4):S133 S137. 20. Sever P, Poulter N: Calcium antagonists and diuretics as combined therapy. J Hypertens 1987;5(suppl 4): S123 S126. 21. Hallin L, Andrén L, Hansson L: Controlled trial of nifedipine and bendroflumethiazide in hypertension. J Cardiovasc Pharmacol 1983;5:1083 1085. 22. Sleight P: Cardiac benefits of ACE inhibitors and calcium antagonists alone and in combination. J Cardiovasc Pharmacol 1994;23(suppl 1):S39 S42. 23. Nalbantgil I, Önder R, Nalbantgil S: Sustained-release verapamil and trandolapril, alone and in combination, in the treatment of obese hypertensive patients: a double-blind pilot study. Curr Ther Res 1996;57:990 997. 24. Levine J, Ferdinand K, Cargo P, Laine H, Lefkowitz M: Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension. Am J Hypertens 1995;8:494 499. 25. Brouwer R, Bolli P, Erné P, Bühler FR: Antihypertensive treatment using calcium antagonists in combination with captopril rather than diuretics. J Cardiovasc Pharmacol 1985;7(suppl 1):S88 S91. 26. Nalbantgil I, Önder R, Kiliçcioglu B, Turkoglu C: Combination therapy with verapamil and nitrendipine in patients with hypertension. J Hum Hypertens 1993;7: 305 308. 27. Brown M, Dickerson J: Alpha-blockade and calcium antagonism: an effective and well-tolerated combination for the treatment of resistant hypertension. J Hypertens 1995;13:701 707. 28. Donnelly R, Elliott HL, Meredith PA, Howie CA, Reid JL: Combination of nifedipine and doxazosin in essential hypertension. J Cardiovasc Pharmacol 1992;19:479 486. 29. Pool J: Doxazosin: a new approach to hypertension and benign prostatic hyperplasia. Br J Clin Pract 1996;50: 154 163. 30. Mroczek W, Burris J, Allenby K: A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1988;12(suppl 7):S79 S84. 31. Nalbantgil I, Kiliçcioglu B, Önder R, Isler M: Evaluation of the antihypertensive effect of amlodipine using 24- hour ambulatory blood pressure measurement. Curr Ther Res 1993;53:621 629. 32. Glasser S, Chrysant S, Graves J, Rofman B, Koehn DK: Safety and efficacy of amlodipine added to hydrochlorothiazide therapy in essential hypertension. Am J Hypertens 1989;2:154 157. 33. Cappuccio F, Markandu N, Singer D, MacGregor G: Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and predictors of response. J Hypertens 1993;11:839 847. 34. Langdon C: Doxazosin: a study in a cohort of patients with hypertension in general practice an interim report. Am Heart J 1991;121:268 273. 35. Brown M, Dickerson J: a-adrenoceptor blockade and Ca blockade: a new combination for the treatment of hypertension. Br J Clin Pharmacol 1994;37:474P. 36. NDTI (based on 1994 data). Plymouth Meeting, PA: IMS America, Ltd, 1995. 37. Grimm R Jr, Flack J, Grandits G, Elmer PJ, Neaton JD, Cutler JA, Lewis C, McDonald R, Schoenberger J, Stamler J: Long-term effects on plasma lipids of diet and drugs to treat hypertension. JAMA 1996;275:1549 1556. 38. Levy D, Walmsley P, Levenstein M: Principal results of the Hypertension and Lipid Trial (HALT): a multicenter study of doxazosin in patients with hypertension. Am Heart J 1996;131:966 973. 39. Langdon C, Packard R: Doxazosin in hypertension: results of a general practice study in 4809 patients. Br J Clin Pract 1994;48:293 298.