Combination Calcium Channel Blocker Therapy in the Treatment of Hypertension. Domenic A. Sica, MD

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1 Current Concepts of Pharmacotherapy in Hypertension Combination Calcium Channel Blocker Therapy in the Treatment of Hypertension Domenic A. Sica, MD Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first- or second-step therapy; thus, the popularity of such drug combinations as an angiotensin-converting enzyme (ACE) inhibitor/diuretic, an angiotensin-receptor blocker/diuretic, or a β blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/β blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful. (J Clin Hypertens. 2001;3: ) Le Jacq Communications, Inc. From the Division of Clinical Pharmacology and Hypertension, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA Address for correspondence/reprint requests: Domenic A. Sica, MD, Professor of Medicine and Pharmacology; Chairman, Clinical Pharmacology and Hypertension, Box MCV Station, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA Ten calcium channel blockers (CCBs) are currently marketed in the United States. These agents are employed in the treatment of hypertension, angina, and/or supraventricular arrhythmias. Nimodipine is approved for short-term use in patients who have suffered a subarachnoid hemorrhage. Diltiazem, nicardipine, and verapamil are the only CCBs currently available in intravenous formulations. Long-term treatment with CCBs is typically by the oral route. Long-acting CCBs are now the preferred mode of therapy in the treatment of hypertension and/or angina when a CCB is opted for (Table I). 1 CCBs are a heterogeneous group of compounds, with distinctive structures and pharmacologic properties. There are three distinct subclasses of CCBs, which explains the differences observed with these agents. These subclasses are the phenylalkylamines (e.g., verapamil), the benzothiazepines (e.g., diltiazem) and the dihydropyridines (e.g., nifedipine, amlodipine, felodipine). All currently available CCBs are vasodilators and thereby reduce blood pressure. The relative potency of CCBs as vasodilators varies, with dihydropyridine-type compounds, such as nifedipine, regarded as the most potent subclass, and verapamil, diltiazem, and bepridil as somewhat less potent. In vitro, several calcium antagonists (e.g., nifedipine, nisoldipine, and isradipine) bind with some selectivity to the L-type calcium channel present in blood vessels, whereas verapamil binds equally well to cardiac and vascular L-type calcium channels. 2,3 The applicability of these in vitro findings to treatment response in humans remains ill-defined. In vitro, all CCB subclasses both depress sinus node activity and slow atrioventricular conduction. Only verapamil and diltiazem delay atrioventricular conduction or cause sinus node depression at doses in common use clinically. 1 Similarly, all CCB subclasses exhibit a concentration-dependent negative inotropic effect in vitro, but only verapamil and diltiazem do so in vivo. The disparities between the in vitro and in vivo effects may relate, in part, to the sympathetic activation triggered by dihydropyridine-induced vasodilation, 322 THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001

2 Table I. Dosing Information for Calcium Channel Blockers Currently Marketed in the United States DRUG APPROVED FORM, STRENGTH, TIME TO ELIMINATION COMMENTS INDICATIONS AND DOSE PEAK EFFECT HALF-LIFE Amlodipine Hypertension; Tablet: 2.5, 5.0, 6 12 h h No effect of grapefruit juice (Norvasc ) chronic stable and 10 mg once daily on pharmacokinetics; vasospastic angina available as a fixed-dose combination with benazepril Bepridil Refractory angina Tablet: 200, 300, 2 3 h h Can cause torsade de (Vascor ) 400 mg once daily pointes-type ventricular tachycardia Diltiazem Hypertension; Immediate- and h 2 5 h Contraindicated in patients (Tiazac ) chronic stable and sustained-release: (immediate) with sick-sinus syndrome (Cardizem ) vasospastic angina; mg once daily 2.5 h and 2nd- or 3rd-degree atrial fibrillation 6 11 h atrioventricular block or flutter; (sustained) paroxysmal SVT Felodipine Hypertension Sustained-release: h h Grapefruit juice causes a (Plendil ) 2.5, 5.0, 10.0 mg two-fold or more in once daily felodipine bioavailability; metabolized by CYP 3A4 ; available as a fixed-dose combination with enalapril Isradipine Hypertension Tablet: 2.5, h 8 12 h Sustained-release form (Dynacirc ) mg twice daily in development Nicardipine Hypertension; Immediate h 8 h Available in intravenous (Cardene ) angina release tablet: form for hypertension mg three treatment times daily sustained-release 8 h tablet: mg once daily Nifedipine Hypertension; Immediate-release 0.5 h 2 h Immediate-release capsule (Adalat ) angina capsule: 10, 20 should not be used for (Procardia ) mg (dose varies control of essential (Procardia-XL ) by indication); hypertension or acute sustained-release reduction of blood pressure capsule: 30, 60, 90 mg once daily Nimodipine Subarachnoid Capsule: 60 mg 1 h 1 2 h Crosses the blood-brain (Nimotop ) hemorrhage every 4 h for 21 days barrier readily; oral therapy should commence within 96 h of hemorrhage Nisoldipine Hypertension Sustained-release 6 12 h 7 12 h Grapefruit juice significantly (Sular ) tablet: 10, 20, 30, nisoldipine bioavailability 40 mg once daily Verapamil Hypertension; Immediate-release h h Nocturnally indicated forms (Calan ) angina; atrial tablet: dose varies of verapamil available (Calan-SR ) fibrillation or by indication; (Covera-HS ) flutter; sustained release (Verelan PM ) paroxysmal SVT tablet: mg/day 4 6 h h CYP 3A4 =cytochrome P 3A4 ; SVT=supraventricular tachycardia; AV=atrioventricular Adapted with permission from N Engl J Med. 1999;341: VOL. III NO. V SEPTEMBER/OCTOBER 2001 THE JOURNAL OF CLINICAL HYPERTENSION 323

3 which blunts any direct negative chronotropic and inotropic effects. HYPERTENSION In the United States, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil are currently approved for the treatment of patients with hypertension (Table I). Each of these drugs lowers both systolic and diastolic blood pressure during long-term oral administration at the recommended doses. Most are available in long-acting formulations that permit once-daily administration (Table I). Verapamil is also available as a delayed-onset and sustained-release formulation indicated for nocturnal dosing. 4 In the United States, CCBs are currently recommended as first-line therapy for hypertension only if there is a compelling reason not to administer a thiazide diuretic or a β blocker. 5 Patients with severe hypertension, such as renal failure and hemodialysis patients, present an obvious exception to this maxim. These patients typically require multiple agents for adequate control of blood pressure because of either inadequate control with single-drug therapy or unacceptable side effects from high doses of a single agent. 6 This pattern of requiring multidrug therapy is also very common in patients with a wide range of comorbid conditions, such as diabetes. 7 Consequently, effective drug combinations are needed to safely and efficiently bring blood pressure to goal in many hypertensives. CCBs are considered a single class of drugs because of their mechanism of action, yet they comprise a heterogeneous group of drugs that includes verapamil, diltiazem, and the dihydropyridine group. The intraclass differences that exist among the CCBs reside in each drug s predominant site of action. Hence, using combinations of CCBs from different groups has been observed to result in additive clinical effects in both the treatment of angina pectoris 8 13 and hypertension Early laboratory investigations provide a theoretic basis for the additive nature of CCB response. These studies suggested a synergistic effect on receptor binding, 22 as well as increased drug concentrations, when diltiazem and a dihydropyridine CCB were concurrently used DUAL CALCIUM CHANNEL BLOCKER THERAPY Pharmacokinetic Aspects. A pharmacokinetic interaction importantly contributes to the additive response of different CCB subclasses. Diltiazem and verapamil are known inhibitors of the cytochrome (CY) P 450 system. 27 In particular, verapamil and diltiazem inhibit the CYP 3A -mediated biotransformation of drugs. A sampling of drugs that undergo CY P-3A-mediated biotransformation include simvastatin, 28 lovastatin, 29 cyclosporine, 27 and the aforementioned dihydropyridine CCBs In principle, the interaction between verapamil or diltiazem and a dihydropyridine CCB can be exploited clinically to more effectively treat the hypertensive patient. Diltiazem seems to inhibit the clearance of nifedipine in a dose-dependent manner This interaction occurs quickly and is nearly maximal within 3 days of dosing. 26 Less well appreciated is the fact that nifedipine influences the pharmacokinetics of diltiazem. Early observations showed that pretreatment with nifedipine increased diltiazem concent rations, presumably secondarily to both a decrease in its hepatic clearance and an increase in its bioavailability. 23 Pharmacodynamic Aspects. The pharmacodynamic interaction of CCBs results in greater vasodilation than if only a single CCB is given. For example, the step-up in forearm blood flow that accompanies amlodipine treatment is increased by an additional 50% when verapamil is coadministered. 20 The mechanism of this augmentation is poorly worked out. It is likely that it is related, at least in part, to drug-mediated alterations in receptor affinity. Drug-induced alterations in receptor binding of CCBs differ from compound to compound. For example, dihydropyridines inhibit the receptor binding of coadministered dihydropyridines; diltiazem enhances receptor binding, 22 whereas verapamil inhibits the receptor binding of nitrendipine. 30,31 Despite the supposedly negative effect of verapamil on nitrendipine binding, its clinical effect is additive, if not synergistic, in reducing blood pressure, a finding that, not surprisingly, contradicts the in vitro binding data. 32 An important consideration in CCB pharmacodynamic interaction is the close correlation between the pharmacodynamic effects of nifedipine and its plasma concentration. A higher plasma level of nifedipine, and presumably of other dihydropyridine CCBs, achieves a greater hemodynamic effect. 31 Although appealing, the clinical relevance of the dual CCB pharmacodynamic interaction, in the treatment of coronary artery disease and/or systemic hypertension, requires additional study. Angina Pectoris. The largest body of literature assessing the use of dual CCB therapy is in the area of ischemic heart disease. As in the treatment of hypertension, the use of combination CCB therapy offers clinical benefit to patients who exhibit a subtherapeutic response to single-agent antianginal therapy, particularly when an alternative, such as a β blocker, is contraindicated (Table II) THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001

4 On the basis of favorable responses observed in these studies, it has been suggested that the vasodilator effects of diltiazem are additive to those of a dihydropyridine CCB. The high incidence of adverse effects observed in some of these studies is cause for concern. 8 This may occur because of increased nifedipine concentrations, or simply because the compounds have comparable adverse event profiles. 8 Dual CCB therapy may be particularly useful when treatment options for symptomatic coronary artery disease are limited by contraindications to other more traditional agents, such as β blockers. Hypertension. In 1991, Kaesemeyer et al. 19 assessed the combined use of nifedipine 120 mg/day, verapamil 480 mg/day, and spironolactone 200 mg/day to control blood pressure when captopril 550 mg/day and verapamil 480 mg/day had previously failed. A subsequent case series reported by Comerio et al. 15 noted that the combination of verapamil and lacidipine reduced blood pressure to a greater degree ( 20 mm Hg systolic and 10 mm Hg diastolic) than either agent alone. This reduction was independent of any noteworthy change in heart rate. Moreover, the renin-angiotensin-aldosterone system was not unduly activated by this CCB combination (Table III). Kaesemeyer et al. 17 subsequently observed similar additive responses with verapamil and nifedipine in a retrospective review of combination verapamil and nifedipine therapy in 27 patients with moderate to severe hypertension, uncontrolled on two or more separate classes of drugs. Twenty-four of these 27 patients (88%) had their blood pressure reduced to <160/90 mm Hg. Edema occurred in seven subjects (25.9%). A verapamil-to-nifedipine ratio of 4:1 seemed to be an optimum combination in this group of moderate to severe hypertensives. Unfortunately, this dosing ratio of verapamil-to-nifedipine is not easily applied in current clinical practice, on the basis of these studies. Kaesemeyer et al. 17 used both short- and long-acting forms of verapamil and nifedipine and gave a maximum dose of 480 and 120 mg of verapamil and nifedipine, respectively. These doses are far in excess of what is currently viewed as acceptable for each of these drugs. Moreover, dual CCB therapy has not been carefully studied with short-acting CCBs. Clinical Implications of Combined CCB Therapy. Dual CCB administration has been suggested as an effective means of therapy for over a decade; unfortunately, too many questions remain for this to be viewed as a standard form of therapy. For example, is low-dose dual CCB therapy as effective and safe as Table II. Clinical Trials Evaluating Dual Calcium Channel Blocker Therapy in Angina REFERENCE DISEASE AND STUDY DESIGN MONOTHERAPY DOSAGE OF RESULTS OF NUMBER OF SUBJECTS (MEAN DOSAGE) DUAL THERAPY DUAL THERAPY Prida et al. 8 Coronary R/P-C; D-B Diltiazem Diltiazem Intolerable artery spasm mono; O-L dual, mg/d; mg/d adverse effects in n=9 cross-over nifedipine (206 mg/d); 33% (3/9); clinical mg/d nifedipine improvement in mg/d 22% (2/9); no (61 mg/d) improvement in 44% (4/9) Pucci et al. 9 Stable effort D-B/P-C; 4 4 Diltiazem 60 Diltiazem 60 Prolongation of angina 400-mg once daily mg 1 and mg 1 with exercise time to n=12 Latin-square felodipine 10 felodipine 10 ischemic threshold mg 1 mg 1 and to peak exercise; 1 patient with hypotension Frishman Stable effort R/PL, D-B Diltiazem Diltiazem Improved exercise et al. 10 angina mono; O-L dual, ( (320 tolerance and in n=13 cross-over mg/d) and mg/d) and angina attacks; nifedipine nifedipine nifedipine mg/d mg/d concentrations (95 mg/d) (52 mg/d) with dual therapy Toyosaki Stable effort R/P-C/D-B, Diltiazem 120 Diltiazem 120 exercise time; et al. 11 angina cross-over mg/d and mg/d with nifedipine n=11 nifedipine 40 nifedipine 40 concentrations mg/d mg/d with dual therapy R=randomized; P-C=placebo-controlled; D-B=double-blind; O-L=open-label; PL=placebo Adapted with permission from Ann Pharmacother. 1996;30: VOL. III NO. V SEPTEMBER/OCTOBER 2001 THE JOURNAL OF CLINICAL HYPERTENSION 325

5 maximum CCB monotherapy? There are no direct comparisons in the literature that directly answer this question. Indirectly, the studies of Andreyev et al. 12 and Nalbantgil et al. 21 indicate that two CCBs given together in low doses achieve better blood pressure control than moderate-dosage CCB monotherapy. Also, is dual CCB therapy most effective with low dosage of two agents, or is the combination of a high and low dose of two agents preferable? Kaesemeyer et al. 17 observed that two CCBs given together in Table III. Clinical Trials to Evaluate Dual Calcium Channel Blocker Therapy in Hypertension REFERENCE DISEASE AND STUDY DESIGN MONOTHERAPY DOSAGE OF RESULTS OF NUMBER OF SUBJECTS (MEAN DOSAGE) DUAL THERAPY DUAL THERAPY Comerio et al. 15 Hypertension R/D-B Lacidipine 4 mg/d; Lacidipine 4 mg/d Combined lacidipine and n=13 verapamil 240 mg/d with verapamil reduced BP verapamil 240 mg/d from 160±11/101±7 to 140±11/92±5 Kiowski et al. 20 Hypertension O-L, Amlodipine 44.5 Amlodipine 44.5 forearm blood flow n=8 cross-over µg/min/100 ml µg/min/100 ml (2.9±1.7 to a maximum of forearm tissue 2.5 h of 23.6±7.6 ml with of forearm tissue amlodipine); further with increase to 34.4±9.8 verapamil 40 ml/min/100 ml with µg/min/100 ml of verapamil forearm tissue Andreyev et al. 12 Hypertension O-L, Diltiazem 240 mg/d; Diltiazem 120 mg/d Better BP control and stable cross-over nitrendipine 20 mg/d with compared with diltiazem effort angina nitrendipine 20 mg/d monotherapy but not n=16 nitrendipine monotherapy; better ischemic control with dual therapy Nalbantgil et al. 21 Hypertension R/P-C/D-B, Verapamil 240 mg/d Verapamil 120 mg/d Improved BP control and n=40 cross-over and with fewer adverse effects with nitrendipine 20 mg/d nitrendipine 10 mg/d dual therapy Kaesemeyer et al. 17 Mild Retrospective Verapamil BP controlled in 100% hypertension analysis mg/d (23/23) and leg edema in n=23 with 30% (7/23) nifedipine mg/d Kaesemeyer et al. 17 Moderate to Retrospective Verapamil BP controlled in 89% severe analysis mg/d (24/27) and leg edema in hypertension with 26% (7/27) n=27 nifedipine 180 mg/d or verapamil 480 mg/d with nifedipine mg/d Saseen et al. 18 Hypertension R/D-B, three- Nifedipine-SR Nifedipine-SR Both combinations n=16 period cross- 30 mg/d 30 mg/d with either systolic and diastolic BP over diltiazem-sr more than nifedipine 180 mg/d or alone; verapamil and verapamil-sr diltiazem nifedipine 180 mg/d; plasma concentrations by cross-over to 49% and 21%, respectively; diltiazem or verapamil 50% of subjects with constipation in the nifedipine and verapamil group R=randomized; D-B=double-blind; O-L=open-label; P-C=placebo-controlled; BP=blood pressure; SR=sustained release Adapted with permission from Ann Pharmacother. 1996;30: THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001

6 moderate dosages could effectively control blood pressure in patients with mild hypertension. Alternatively, in patients with moderate to severe hypertension, high-dose combination CCB therapy is required to gain blood pressure control. 10 For dual CCB therapy to become a viable treatment option, various combinations of CCBs must be formally tested and compared with traditional combinations of antihypertensive agents. Moreover, because different combinations of CCBs have not been directly compared with one another, it is unknown whether verapamil or diltiazem is the most effective agent added to a dihydropyridine CCB. Who are potential candidates for dual CCB therapy? Patients with inadequate blood pressure control while taking multiple antihypertensive agents can be considered for dual CCB therapy. In addition, partial responders to maximal tolerated doses of a single CCB who have relative contraindications to other medication classes are suitable candidates. Unfortunately, until more definitive treatment information becomes available, dual CCB therapy should be considered only as a secondary treatment option. REFERENCES 1 Abernethy D, Schwartz JB. Calcium-antagonist drugs. N Engl J Med. 1999;341: Morel N, Buryi V, Feron O, et al. The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits. Br J Pharmacol. 1998;125: Soldatov NM, Bouron A, Reuter H. Different voltage-dependent inhibition by dihydropyridines of human Ca2+ channel splice variants. J Biol Chem. 1995; 270: Sica DA. Impact of antihypertensive therapy on the ratepressure product: the role of chronotherapeutics. Eur Heart J. 1999;1(Suppl B): B24 B33. 5 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157: Ikeda Y, Sakemi T, Yamada M, et al. 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