Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine Cardiovascular Community...

transcript

Sex- and A e-Related Antihypertensive E # ects of dmlodipine

Robert A. Kloner, MD, PhD, James R. Sowers, MD, Gerald F. DiBona, MD, Michael Gaffney, PhD, and Marilee Wein, RPh for the Amlodipine Cardiovascular

Community Trial Study Group*

This community-based study assessed whether there were age, sex, or racial differences in response to amlodipine 5 to 10 mg once daily in patients with mild to moderate essential hypertension. This prospective, open-label trial had a 2-week placebo period, a 4-week upward drug titration/efficacy period, and a 12-week drug maintenance period. There were 1,084 evaluable patients (mean age 55.5 years; 65% men and 35% women; 79% white and 2 1% black; 75% <65 and 25% 265 years old). At the end of the titration/efficacy phase, the mean 2 SD blood pressure (BP) decreased by -16.3 t 12.3/-12.5 + 5.9 mm Hg, (p =zO.OOOl). Amlodipine produced a goal BP response (sitting dia; stolic BP 190 mm Hg, or a 10 mm Hg decrease) in 86.0% of patients overall. The BP response was greater in women (91.4%) than in men (83.0%, p rO.OOl), and

Aan mlodipine is an intrinsically long-acting calcium

tagonist used as once-daily therapy for the treatment of systemic hypertension and angina.lm5 This agent is well tolerated,6 and like other calcium channel blockers, may be used in the presence of many concomitant disorders frequently present in hypertensive patients. Unlike most other calcium channel blockers, amlodipine has been used safely in patients with New York Heart Association classes II and III heart failure. The Amlodipine Cardiovas- cular Community Trial (ACCT) was designed to further assess the efficacy and safety of amlodipine as monotherapy in a large, mildly to moderately hypertensive population comprising men and women of various racial/ethnic backgrounds and ages. We specifically sought to determine whether there were age, sex, or racial differences in response to amlodipine.

METHODS Patient selection: The study included men and

women between the ages of 21 and 80 years who had mild to moderate hypertension. Patients were re-

From The Heart Institute of Samaritan Hospital, and University of South- ern California, Los Angeles, California; Endocrinology and Hyperten- sion Division, Wayne State University College of Medicine, Detroit, Michi on; Department of Internal Medicine, University of Iowa Schoo of Medicine, Iowa City, Iowa; and the U.S. Pharmaceuticals 9 Group, Pfizer, Inc. New York, New York. This study was su ported by the U.S. Pharmaceuticals Group, Pfizer Inc., New Yor , New R York. Manuscript received August 1 1, 1995; revised manuscript received ond accepted November 7, 1995.

Address for reprints: Robert A. Kloner, MD, PhD, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los An eles, California 90017.

*See Appendix for list of Members o P vascular Community Trial Study Group.

the Amlodipine Cardio-

greater in those 265 years old (91.5%) than in those <65 years old (84.1%, p 10.01); however, it was similar between whites and blacks (86.0% vs 85.9%, re- spectively, p = NS). The sex difference in BP respanse could not be fully explained by diirences in age, weight, dose (mg/kg), race, baseline BP, or compliance, and there were no differences among women based on use of hormone replacement thempy. Amlodipine was well tolerated; mild to moderate edema was the most common adverse effect. Thus, amlodipine was effe&e and safe as once-a-day monothempy in the w of mild to moderate hypertension in a community-based population. Women had a greater BP response to amlodipine.

(Am J Cardiol 1996;77z713-722)

quired to have an average of 2 sitting diastolic blood pressures (BPS), obtained during office visits on 2 separate but consecutive weeks, between the range of 95 and 110 mm Hg during a placebo run-in phase, before which all antihypertensive medications had been discontinued.

Women who were pregnant, lactating, or of childbearing potential were excluded from the study. Patients were also excluded for the follow- ing reasons: all forms of secondary hypertension; a history of cerebrovascular accident, transient ischemic attacks, or myocardial infarction in the 6 months preceding the study; angina pectoris re- quiring therapy with long-acting nitrates, p-adre- noceptor blockers or calcium-channel blockers; left ventricular ejection fraction of ~40% or New York Heart Association class 211 heart failure; and second- or third-degree heart block or significant cardiac arrhythmia. Patients with major hemato- logic, renal (serum creatinine 22.0 mg/dl), he- patic (serum ghttamic oxaloacetic transaminase or bilirubin >50% above the upper limits of normal), metabolic, gastrointestinal, endocrine, or cardiac dysfunction were not included. However, patients with stable type II diabetes mellitus (no significant change in drug therapy or drug dose in the 3 months preceding the study and fasting blood glucose <200 mg/dl) and no other coexisting conditions could enter the study. Patients were not eligible to participate if they had been taking an investigational drug within 1 month of entering the study, required continued therapy with other agents used to treat hypertension, or had known sensitivity to dihydropyridine calcium channel blockers. Patients with a history of noncompliance

SYSTEMIC HYPERTENSlON/AMLODIPINE CARDIOVASCULAR COMMUNITY TRIAL RESULTS 713

l After tapering of antihypertensive drugs, placebo given for 2 wk

l Amlodipine 5 mg l Patients at goal BP l Optional given once daily for 2 wk; (sitting diastolic BP continuation of titrated to 10 mg once daily c90 mm Hg &r IO amlodipine therapy after 2 wk if needed to mm Hg decrease) at optimal dose achieve sitting diastolic BP receive amlodipine <90mmHg&~by therapy maintained at IOmm Hg optimal phase II dose

t t t t 0 2 4 6

FIGURE 1. Amlodipine Cardiovascular Community Trial study proiwol.

or conditions that might have interfered with compliance were not enrolled. Patients were also excluded if their body weight was >40% over ideal weight.

Study design: This was a prospective, open-label, 18-week, multicenter study conducted at 127 sites. The trial consisted of 4 phases (Figure 1) : a 2-week placebo run-in phase (phase I) ; a 4-week titration/ efficacy phase (phase II) during which amlodipine 5 to 10 mg was administered once daily; a 12-week maintenance phase (phase III) during which patients were maintained on their final phase-II dose of amlodipine; and an optional long-term follow-up phase (phase IV).

Patients with an average sitting diastolic BP 590 mm Hg or a 10 mm Hg decrease from baseline were considered to be re- sponders to therapy and could continue in the maintenance phase of the study (phase III). During this 1Zweek period, patients were maintained at their final phase II dose of amlodipine and were evaluated at 4-week in- tervals. At the discretion of the investigator, the amlodipine dose

could be titrated upward or downward once during this phase. Hemodynamic measures and body weight were determined, adverse effects monitored, and compliance evaluated at each office visit. In addition, at the end of week 18, a physical examination, serum chemistries, fasting plasma lipids and lipoprotein levels, hemoglobin Al, levels, and oral glucose tolerance tests were repeated. Patients had the option of continuing on long-term amlodipine therapy under the supervision of their investigators (phase IV). These data are not yet fully analyzed.

At study entry, medical histories were obtained and patients underwent complete physical and routine laboratory examinations. Patients were in- structed to maintain their current pattern of activity and dietary habits, including salt (sodium chloride) intake (except in patients who were to be enrolled in the salt-intake subprotocol during phase III), throughout the study. All antihypertensive medications were stopped 2 weeks before entering phase I. At the end of the first and second weeks of phase I, hemodynamic variables, body weight, adverse effects, and compliance were assessed. An optional third placebo week could be added if needed to qual- ify patients. At the end of phase I, routine laboratory evaluations were repeated and baseline fasting plasma lipid and lipoprotein and glycosylated hemoglobin (hemoglobin A,,) levels were determined. A subgroup of 128 patients also had oral glucose tolerance tests. Patients with average sitting diastolic BP between 95 and 110 mm Hg, as recorded at the end of 2 consecutive weekly visits in phase I, were eligible to enter the titration/efficacy phase.

Hemodynamic assessments: BP determinations were made throughout the study by the same clini- cian using the same sphygmomanometer and the patient’s same arm, with an appropriately sized cuff. Measurements were obtained at approximately the same time of day for each visit, 24 hours after the last dose of study medication. Diastolic BP was determined at the point at which there was cessation of sound (Korotkoff phase V). Sitting BP and heart rate were measured after the patient had been in a sitting position for 3 minutes; these measures were repeated 2 minutes later. Likewise, standing BP and heart rate were assessed after the patient had been in a fully upright position for 3 minutes and again 2 minutes later. A third measurement was obtained if the differences between the 2 sitting or 2 standing diastolic BPS were > 10 mm Hg. The average of the 2 closest measures was then used.

Compliance: Compliance with therapy was assessed by pill count at each visit. To continue in the study, patients had to have taken between 80% and 120% of the prescribed amount of study medication for a particular interval on any 2 consecutive visits.

At the beginning of phase II, patients were treated with amlodipine 5 mg once daily. After 2 weeks, if sitting diastolic BP was 189 mm Hg, and this rep- resented a decrease of 210 mm Hg, patients re- mained on the 5 mg dose; otherwise, the dose was titrated’ upward to 10 mg once daily, unless pre- cluded by adverse effects. At the end of weeks 4 and 6, hemodynamic measures and body weight were determined and adverse effects and compliance evaluated. Serum chemistries, fasting plasma lipids and

labomtory assessments: Routine serum chemistries included a complete blood count with differential and platelet count, a sequential multiple analyzer-18 test (fasting sample), and urinalysis. Plasma lipid and lipoprotein and hemoglobin Al, levels were determined from fasting plasma samples. For patients undergoing glucose tolerance tests at weeks 2 and 18, fasting blood samples were also used to determine baseline glucose and insulin levels. After fasting blood samples were drawn, these patients drank 75 g of glucose solution, then continued to fast until after blood samples for glucose and insulin levels

714 THE AMERICAN JOURNAL OF CARDIOLOGY” VOL. 77 APRIL 1, 1996

1 lipoprotein levels, and urinalysis were repeated at the end of week 6.

TABLE I Mean Sitting Blood Pressure (mm Hg) and Heart Rate (beats/min) at Baseline (phase I) to End of Titration/Efficacy (phase II) for All Evaltiable Patients

Phase SBP DBP HR

All (n = 1,084) I 153.8 ? 15.7 100.5 + 4.1 74.7 +- 10.2 II 137.5 + 13.7” 88.0 + 6.8” 75.7 + 9.9” Change -16.3 2 12.3 -12.5 2 5.9 1.1 f 9.3

Men (n = 702) I 153.1 + 15.6 100.8 2 4.2 73.5 t 9.4 II 138.1 + 13.4” 88.9 + 7.0’ 74.7 + 9.91 Change -15.02 11.9 -11.9 2 5.9 1.2 ? 7.7

Women (n = 382) I 155.1 + 15.9* 100.1 2 3.9’ 76.8 + 11.3$ II 136.5 2 14.3” 86.4 2 6.3” 77.7 + 9.7 Change -18.7 + 12.6$ -13.7 % 5.6$ 0.9 r 11.6

White (n = 857) I 153.1 5 15.3 100.5 c 4.1 74.7 2 9.3 II 137.3 2 13.6” 88.0 + 7.0’ 75.6 e 9.7” Change -15.8 2 12.4 -12.5 z 6.0 0.9 2 8.0

Black (n = 227) I 156.6 t 16.8T 100.8 ? 4.1 74.5 + 13.2 II 138.5 2 14.4’ 88.2 k 6.3’ 76.2 + 10.5 Change -18.2 2 11.5f -12.6 t 5.4 1.7 t 12.9

<65yr(n=812) I 151.0 2 14.5 100.7 + 4.2 74.8 + 10.6 II 135.8 +- 13.4’ 88.6 + 6.8” 75.8 2 10.0” Change -15.1 ? 11.4 -12.0 & 5.8 1 .O t 9.6

265 (n = 272) yr I 162.4 + 16.2* 100.2 2 3.7 74.3 2 9.0 II 142.5 + 13.p 86.3 2 6.6’ 75.6 -c 9.5§ Change -19.8 + 13.9$ - 13.9 + 5.9* 1.2 t 8.1

l p <0.05, f p zzo.01, ’ p ~0.0001, significantly different from comparison group; p p 10.05, ” p ~0.001, ’ p ~0.0001 versus baseline.

Values ore expressed ~1s mean + SD. DBP = diastolic blood pressure; HR = heari rate; SBP = systolic blood pressure.

could be drawn at 1 and 2 hours after glucose inges- tion. All laboratory analyses were conducted at a central testing facility (SmithKline Beecham Clini- cal Laboratories, Van Nuys, California).

safety assessments: The study protocol and consent form were approved by the appropriate institu- tional review board at each center. Risks and benefits of participation in the study were explained to each study candidate, and written informed consent was obtained before study entry. The incidence, severity, and drug-relatedness of all observed or volunteered adverse experiences were recorded at each office visit. Patients were withdrawn from the study if a serious adverse effect or laboratory abnormality occurred.

Patients and study medication: Of the 1,384 patients who entered phase I of the study, 1,095 entered phase II and were included in the safety analysis. Of these patients, follow-up BP measures were not available in 11; therefore, 1,084 patients were included in the efficacy analysis. A total of 160 patients ( 14.6%) discontinued therapy during phase II. Reasons for discontinuation of therapy during phase II included inadequate therapeutic response, adverse effects, intercurrent illness, noncompliance, protocol violations, lack of follow- up, and other miscellaneous reasons. Discontinuation due to adverse effects occurred in 29 patients (2.6%-in 3 patients not related to study drug and in 26 patients possibly related to study drug). Four patients entered phase III but had no follow-up visits; thus, for phase III, 920 patients were evaluable. Of these 920 patients, 84 patients

(9.1%) were withdrawn from the study. In phase III, 54 patients (5.9%) discontinued due to adverse effects (in 7 patients not related to study drug, in 47 patients possibly related to study drug).

Statistical analyses: Differences in continuous variables stratified by sex, age ( <65 years of age vs ~65 years of age), and race (white vs black) at baseline were assessed by analysis of variance, whereas baseline differences in categorical variables were analyzed by chi-square tests. The effect of amlodipine treatment on study variables was assessed by paired t tests on the change from baseline (end phase I) measurement to that at the end of the titration/efficacy phase (end phase II). For responding patients, the changes from baseline to the ends of phases II and III were analyzed by repeated-measures analysis of variance. The categorical responses of reaching goal BP and final dose at the end of phase II were analyzed by categorical methods. Analysis of variance was used to assess the effects of baseline BP, age, sex, and race on the change from baseline. Mul- tiple regression was used to adjust for covariates in Tables IIA and IIB. A p value <0.05 was considered statistically significant.

Among the 1,084 evaluable patients, 65% were men and 35% were women, 79% were white and 21% were black, 75% were ~65 and 25% were 265 years old, and the mean age was 55.5 years. Mean duration of hypertension was 11.1 + 9.7 years, but was considerably longer in elderly patients ( 15.6 + 11.6 years) than in younger patients (9.6 + 8.4 years, p ~~0.0001), and was somewhat longer in blacks (12.6 2 10.0 years) than in whites (10.7 + 9.5 years, p ~0.01). Five hundred sixty-two patients (52%) had mild hypertension (diastolic BP between 95 and 99 mm Hg) and 522 (48%) had moderate hypertension (diastolic BP between 100 and 109 mm Hg) . Most patients (8 1%) were taking 2 1 antihypertensive medication (average: 1.3 agents/patient) before entering the study. This included 382 patients (35.2%) taking calcium channel blockers and 328 (30.3%) taking angiotensin-converting enzyme in- hibitors.

The concomitant conditions reported most often at baseline were hyperlipidemia (41% ) , arthritis (40%)) and diabetes (including hyperglycemia) or glucose intolerance (9%). Approximately 74% of patients reported musculoskeletal disorders (mainly arthritis), 63% reported other cardiovascular disorders, 17% reported renal or genito- urinary disorders, and 9% reported pulmonary disorders.

The mean dose of amlodipine overall was 8.4 + 2.3 mg/day at the end of phases II and III. Mean dosages at the end of the titration/efficacy phase

SYSTEMIC HYPERTENSION/AMLODIPINE CARDIOVASCULAR COMMUNITY TRIAL RESULTS 715

TABLE IIA Effect of Baseline BP, Weight, and Dose on Sex Difference in BP Response to Amlodipine

Mean Difference in BP Change in Women (n = 382) Minus That of Men (n = 702)

Baseline BP- and Baseline BP-, Age, Baseline BP-, Age-, and Variables Age-Adjusted and Weight-Adjusted Dose (mg/kg)-Adjusted

Sitting systolic BP (mm Hg) -2.4 -1.5 -2.2 p Value 0.002 0.066 0.004

Sitting diastolic BP (mm Hg) -2.0 -1.3 -2.1 p Value 0.0001 0.004 0.0001

BP = blood pressure.

TABLE 118 Effect of Baseline BP, Gender, Weight, and Dose on Age Difference in BP Response to Amlodipine

Variable

Mean Difference in BP Change in Those zz 65 Years (n = 272) Minus That of Those < 65 Years (n = 812)

Baseline Baseline Baseline Baseline Unadiusted BP-Adiusted Sex-Adiusted Weight-Adiusted DoseAdiusted

Sitting systolic BP (mm Hg) p Value

Sitting diastolic BP (mm Hg) p Value

BP = blood Pressure.

-4.7 +o. 1 +0.1 +0.6 +0.2 0.0001 0.87 0.90 0.44 0.79

’ -1.9 -1.9 -1.9 -1.6 -1.8 0.0001 0.000 1 0.0001 0.0001 0.000 1

were 8.6 f- 2.3 mglday for men and 8.1 ? 2.4 mg/ day for women (p sO.Ol), 8.4 + 2.3 mg/day for whites and 8.6 + 2.3 mglday for blacks, and 8.6 2 2.3 mglday for those ~65 and 8.1 ? 2.4 mg/day for those ~65 years (p ~0.01). Of note, significantly more dosages for men were titrated after 2 weeks to the 10 mg level than for women (p ~0.01) ; this was also true for dosages of those aged <65 years versus 265 years (p ~0.01). However, when dosage was normalized for weight, women were found to have been taking 0.114 mg/kg compared with 0.097 mg/ kg for men, a small but statistically significantly greater adjusted dosage (p ~0.0001). There was no such difference in older versus younger patients when dosage was normalized for weight.

ures 3 to 5 (p <O.OOOl ). For all evaluable patients, mean sitting BP (systolic/diastolic) decreased from a baseline of 153.8 + 15.7/100.5 2 4.1 mm Hg to 137.5 + 13.7/88.0 + 6.8 mm Hg at the end of phase II; changes in standing BP were similar.

Mean baseline sitting systolic BP and sitting and standing heart rate were slightly but significantly higher among all evaluable women than among men. Men had slightly but significantly higher baseline diastolic BP (Table I). Mean BP changes from baseline to the end of titration/efficacy (phase II) for all evaluable patients overall and stratified by sex, age, and race are shown in Figures 3 and 4.

Overall compliance at the end of phases II and III was 99 + 6%, and according to subgroup, ranged between 98% and 99% throughout the study, without significant differences between men and women, whites and blacks, and younger and older patients.

Hemodynamic variables: Amlodipine 5 to 10 mg once daily produced a goal BP response in 86.0% of patients overall by the end of titration/efficacy (phase II) (Figure 2). The percentage of patients achieving goal BP response with amlodipine therapy was greater in women (91.4%) than in men (83.0%, p sO.OOl), and in those aged ~65 years (91.5%) than <65 years (84.1%, p sO.Ol), but was similar for whites (86.0%) and blacks (85.9%, p = NS).

Changes in BP from baseline were significantly greater in women than in men for sitting and standing systolic and diastolic BP (p ~0.0001; Table I; Fig- ures 3 and 4). This differential effect was observed over the long term among responding patients during maintenance therapy (phase III) (Figure 5). When data were adjusted for baseline BP, age, weight, or dose (mg/kg) , statistically significant differences were still observed according to sex (Table IIA). There were no differences in the decrease in sitting systolic and diastolic BP for women taking hormone replacement therapy (n = 99; -18.1 & 13.4/-14.1 + 5.8 mm Hg) and those not taking hormone replacement therapy (n = 283, -18.9 + 12.3/-13.5 2 5.6 mm Hg, p = NS ) at the end of phase II.

Mean baseline systolic BP was higher in blacks Significant decreases in BP from baseline with than in whites (Table I). Changes from baseline

amlodipine were observed overall and in each sub- (Figures 3 and 4) were greater in blacks than in group at the end of titration/efficacy (phase II) and whites for sitting and standing systolic BP (p throughout the study, as shown in Table I and Fig- ~0.01 ), but not diastolic BP, among all evaluable

716 THE AMERICAN jOURNAL OF CARDIOLOGY@ VOL. 77 APRIL 1, 1996

j-p SO.0011 rp SO.01 7

Response rate 50 6)

0 Overall Men Women White Black <65 265

(n=1084) (n=702) (n=382) (n=857) (n=227) (n=812) (n=272) Gender Race Age (yr)

FIGURE 2. Percentage of patients achieving goal blood pressure (BP) response with amlodipine therapy overall and according R sex, race, and age. Goal BP response was defined as a sitting diastolic BP ~90 mm Hg or a 10 mm Hg decrease in sitting diastolic BP.

patients. However, when adjusted for baseline differences, the changes from baseline were no longer significantly different between blacks and whites. Significant BP reduction was maintained among blacks and whites who responded to therapy and entered phase III (Figure 5 ) .

Among white patients, there was a subgroup of 64 Hispanic patients. For Hispanic patients, the mean reduction in systolic BP from baseline to end of the efficacy phase (-16.4 ? 12.0 mm Hg) was similar to that of non-Hispanic white patients (- 15.8 + 12.5 mm Hg); mean reduction in diastolic

1 BP from baseline to the end of the efficacy phase was also similar in Hispanic patients ( - 12.1 + 5.5 mm Hg) compared with non-Hispanic white patients ( - 12.5 l?r 6.1 mm Hg).

Systolic BP, but not diastolic BP, was higher at baseline in patients 265 years of age compared with those <65 years of age (Ta- ble I). The magnitude of change in systolic and diastolic BP was greater among those 265 years of age (Table I and Figures 3 and 4; p ~0.0001). However, after adjustment for baseline differences in systolic BP between patients aged ~65 and ~65 years, the systolic changes no longer showed a significant age effect (Table IIB ) . _.

Among patients responding to therapy who entered phase III, sustained BP reduction was observed throughout the study in younger and older patients (Figure 5 ) . There was a minimal increase in sitting ( 1.1 ? 9.3 beats/min, p ~0.001) and standing ( 1.6 +- 8.5 beats/min, p ~0.0001) heart rate at the end of the titration/efficacy phase among all evaluable patients.

Overall weight and laboratory analysis: Bodl mass index (calculated as weight [kg]/height [m 1) did not change significantly from baseline for all patients or when stratified by sex, race, or age at the end of

Men Women White Black <65yr >65yr (n=857) (n=227) (n=812) (n=272)

Mean change in sitting systolic BP from baseline to

end phase II (mm Hg)

Mean change in sitting diastolic BP from baseline to

end phase II (mm Hg)

-12.5S.O -12.6t5.4

5 m from baseline in sitting systoic and diasiok bkmd pressure (BP) with ambdipine at end of the tilra- overall and slratikd by sex, race, and age. All changes from baseline within

Me& change in standing sysiolic BP from baseline to end phase II

(mm Hg)

Mean change in standinkj diastolic BP from baseline to end phase II

(mm Hg)

-40 C 0

(n=1083)

m -15.9f13.4

Men Women (n=701) (n=382)

White Black (n=856) (nF227)

<65yr >65yr (wall) (n=?72)

GlrryJy

-19.7t14.1 - l f .l8T

p 5 o.ooo1 1 1 p 5 0.01 _1 I p 5 0.0001 1

FlGUdE 4. M&m changes 2 SD from baseline in standing sysblic bnd diastolic blood pressure (BP) with amlodipine at end of the titration/efficacy phase (phase II) for all evaluable patients overall and stratified by sex, race, and age. All changes from baseline within groups were statistically significant (p 5 0.0001).

g-&a- . . -11.9i6.5

-L . L A- r -1136.7 i’ I 1_ -12.;16.9

-L I -

L-000011 < . 1,,0.olM1~

FI( 5. Mean changes 2 SD from -baseline in sitting systolic and diastolic blood pressure (BP) in responding patients at the end of maintenance therapy (end of se wiihin groups were statisticul

HI) with amlodipine, overall, and stmt%ed by significant (p 5 0.0001).

sex, race, and age. All changes from baseline

All Men Womb White Black < 65 yr 2 65 yr

0 (rM20) (n=585) (n=3+) (n=729) (n-191) (n=678) (n=242)

Ivie& change in -10 -

sitting sysiolic BP from baseline to -20 -

end phase III (mm W) -30 -

Mean charige in sitting diast6k BP from baseline to

end phase III (mm W

718 THE AMERICAN JOURNAL OF CARDIOLOGY” VOL. 77 APRIL 1, 1996

phase II for all evaluable patients, or throughout the study for patients responding to therapy who entered phase III; no differences in change between groups were observed.

No significant differences for most variables of routine serum chemistries or urinalysis were observed in the study overall or according to subgroups of patients. In contrast, over the long term among responding patients, small but statistically significant decreases in total, low-density lipoprotein, and very low density lipoprotein cholesterol and triglycerides, and an increase in high-dengity lipoprotein cholesterol were observed overall by the end of phase III (Table III). Differences were observed for changes in total and very low density lipoprotein cholesterol and triglycerides when data were stratified by race. For both fasting plasma glucose and hemoglobin A,, , small increases were observed over the course of the study (Table IV). Likewise, the small decreases in plasma creatinine and uric acid concentration were statistically significant.

There were 128 responding patients who had glucose tolerance tests at baseline (week 2) and week 18 while taking amlodipine. In these patients, the expected transient increase in serum glucose 1 hour after glucose challenge was somewhat higher during therapy ( 171 t 59 @J/ml) than at baseline ( 164 -+ 55 PIUlml, p <0.05), but did not differ at hour 2 from baseline measures at that time. Serum insulin levels did not differ at week 18 from baseline measures at any time during the glucose tolerance test. There were no significant differences between baseline (116 + 77 pIU/ml) and week 18 (111 -+ 71 @/ml) for insulin area under the curve values, or for the ratio of the insulin area under the curve to glucose area under the curve (0.4 + 0.2 at baseline and week 18).

Adverse effects: The most common adverse effects

phase II (4 weeks of treatment) were edema, head- ache, fatigue, and dizziness. The incidence of head- ache (8.8%)) fatigue (4.2%), and dizziness (4.4%) during phases II and III (after 16 weeks of treatment) was similar to that reported for amlodipine-treated patients in double-blind, placebo-controlled studies. There were no cardiovascular deaths; there were 3 myocardial infarctions.

Over the course of the full 16 weeks of treatment, edema, the most common adverse effect, occurred in 24% of treated patients, and was more common in women. The edema was dose-related, with the incidence in patients receiving 10 mg/day being twice that in the 5 mg group. Because of the design of this study, more than half (69%) of the patients were receiving 10 mg. This is markedly higher than the current usage data in the United States, where 78% of amlodipine prescriptions for the treatment of hypertension are at the 5 mg starting dose.7 In double- blind, placebo-controlled studies, 3% of amlodipine patients taking 5 mg reported edema and 10.8% of patients taking 10 mg reported edema.8

DISCUSSION The ACCT results showed that amlodipine mono-

therapy was effective in treating a broad range of patients with mild to moderate hypertension, rep- resenting a heterogeneous patient population com- monly encountered in a community-based practice. The overall efficacy rate of 86% was somewhat higher than that reported with amlodipine in the recent Treatment of Mild Hypertension Study (82.5%) ,‘j and confirms the beneficial effect of this agent in hypertensive patients reported in a series of smaller trials.2*3*9-20 The response to amlodipine monotherapy in ACCT compared favorably with the effect of diltiazem monotherauv observed in a recent

and those occurring in >2% of all patients during comparative trial (59% response rate) .2’

TABLE III Baseline Lipids (mg/dl) and Change to the End of Maintenance Therapy (phase Ill) far Responding Patients

Cholesterol

Group Phase Total Cholesterol HDL LDL” VLDLb Triglycerides

Overall (n = 841) I 2 16.2 + 39.8 50.1 c 13.9 133.9 f 34.1 30.1 * 14.4 172.2 + 134 IllA -2.5 + 22.4 1 3.4 of: 7.0 ” -4.1 t 19.3 xX -1.0 + 10.3 ’ -13.6? 102’

Men (n = 542) I 211.5k37.9 46.3 5 11.9 132.8 f 31.6 29.8 + 14.2 179.3 + 155 MA -3.1 + 22.2 1 3.1 2 6.9” -A.3 2 18.5 xX -1.0 2 10.5 ” -17.7 + 121 x

Women (n = 299) I 224.9 + 41.6 5 56.8 2 14.7 5 135.8 t 37.9 30.7 + 14.7 159.4~ 81.1 * IIIA -1.4 k 22.8 A.0 k 7.1 xX -3.8 f 20.7’ -1.1 2 9.9 -6.1 -+ 53.7 ”

White (n = 661) I 2 17.2 ? 38.5 49.0 t 13.6 134.0 z? 33.8 32.2 2 14.7 184.7 r 139 IIIA -3.5 + 22.3 xX 3.5 2 7.0 xx -4.5 -r- 19.7 xX -1.5 + 10.6’ -17.7 k 105”#

Black (n = 180) I 212.6 2 44.1 53.9 + 14.2 5 133.6 2 35.1 22.8 2 10.2 5 126.3 + 101 5 IIIA 1.1 &22.6* 3.2 + 6.8 xX -2.6 -t 17.7 0.7 + a.7 t 1 .A 5 91 .O l

<65 (n = 620) yr I 2 16.2 + 40.0 49.8 -c 13.9 133.6 _c 34.2 30.4 t 1 A.5 178.5 + 147 WA -2.1 2 22.7 ” 3.3 + 7.0 xx -3.7 ir 19.5 xX -1.0 2 10.6 ” -15.0 + 115’

265 (n = 221) yr I 216.4 + 39.3 50.7 ? 13.8 134.8 t 33.8 29.3 + 13.9 154.5 + 84.0 + IIIA -3.6 + 21.7 ” 3.7 t 6.9 ” -5.0 -c 18.9 * -1.1 + 9.2 -9.5 + 52.6 ’

’ 790 overall, 499 n = for men, 291 for 6 16 for whites, women, 174 for blacks, 575 for there aged 165 years, 2 15 for those aged 265 yews. b 789 overall, 498 n = for men, 291 for 615 for whites, women, 174 for blocks, 574 for those aged ~65 years, 215 for Aore aged 265 yeas. * p <0.05, + p ~0.0 1, $ p ~0.0001, significantly different from compcwiron group; ” p <0.05,’ p ~0.01, ’ p ~0.001, xX p ~0.0001 versus baseline. HDL = highdensity lipoprotein, LDL = low-density lipoprotein, VLDL = very low density lipoprotein; A = change. Values ore expressed os meon 2 SD.

SYSTEMIC HYPERTENSlON/AMLODIPINE CARDlOVASCUlAR COMMUNITY TRIAL RESULTS 719

TABLE IV Effect of Theropy on Fasting Glucose, Hemoglobin Arc, Plasma Creatinine, and Plosmo Uric Acid at End of Maintenance Phose (phase Ill)

Variable Number of

Patients Boseline Maintenance

Therapy Change

Posting glucose (mg/dl) All subjects 842 01.9 + 21.6 104.6 2 27.7 2.7 t- 17.3$ Hyperglycemic* 72 45.1 ? 35.0 164.3 + 54.3 19.3 -c 38.3* Euglycemic” 770 97.8 2 14.3 99.0 2 14.2 1.2 k 12.8*

Hemoglobin Al, (mg/dl) All subjects 798 4.44 + 0.56 4.47 + 0.63 0.04 f 0.40' Hyperglycemics 68 5.45 5 0.92 5.66 + 1.09 0.21 2 0.69* Euglycemic” 730 4.34 f 0.40 4.36 2 0.42 0.02 t 0.36

Plasma creotinine (mg/dl) 856 1.01 + 0.21 0.99 k 0.20 -0.02 + O.llf Plasma uric acid (mg/dl) 856 6.24 + 1.57 5.91 -+ 1.50 -0.33 + 0.97:

BP in blacks, and was not observed after adjusting for this variable. There was no difference in diastolic BP changes between black and white patients. Of note, the overall response rate to the drug was the same in black and white patients (86%).

* p <0.05; t p so.01; * p s0.0001.

5 Glycemic status determined from patient history. Terminology for hyperglycemia included “diabetes

mellitus, glucose intolerance, hyperglycemia, and/or increased blood sugar.”

Values are expressed as mean -c SD.

A goal of this study was to determine whether different subgroups of patients responded differently to amlodipine. One unexpected result was the obser- vation that the response rates and absolute decrease in BP with amlodipine was greater in women than in men. The greater decrease in BP in women than in men occurred even after adjustment for baseline BP, age, weight, and dose in milligram per kilogram values. Compliance was similar between women and men, and therefore did not account for the difference in BP response. Twenty-six percent of women in ACCT were receiving hormone replacement therapy. However, when changes in BP were compared in women according to use or nonuse of hormone replacement therapy, no differences were observed; thus, the use of hormone replacement therapy in women did not account for the greater response rates to amlodipine compared with those of men. The reason for the difference in response of the drug by sex is not known, but may include differences between men and women in vascular reactivity or distribution and metabolism of the drug. It is also conceivable that potential differences in the incidence of heavy physical activity and alcohol consumption between the sexes could contribute to differences in BP response. The clinical significance of the sex difference, including whether this translates into differences in outcome or target organ damage, remains to be determined. However, some studies suggest that even relatively small differences in BP in general can have prognostic significance.22923

There is a general lack of information and reporting regarding differential response to antihypertensive medicines in women versus men. This is the first report that we are aware of showing a greater response rate in women to amlodipine. Although the mechanism for this difference in subgroup response is not known, it does have important therapeutic implications. Women who are not responding well to

other antihypertensive medicines may benefit from a trial of amlodipine. In addition, there may be differences in the pathophysiology of hypertension between men and women; antihypertensive agents such as amlodipine may be used as probes to better un- derstand these differences.

There were other differences in subgroup response to amlodipine. Elderly patients had a greater therapeutic response rate than younger patients. This difference in response by age was independent of the sex difference. The greater decrease in systolic BP in the elderly was related to a higher baseline systolic BP, and was not observed after adjusting for this variable. The reason for the greater decrease in diastolic BP in the elderly remains to be determined. The greater decrease in systolic BP in blacks than in whites also was related to a higher baseline systolic

Several other types of differences have been de- scribed between hypertensive men and women.” Epidemiologic studies have shown that prevalence rates for hypertension tend to be greater in men than in women during the first half of life, but, after men- opause, women tend to have higher prevalence rates. The greatest prevalence of controlled and uncon- trolled hypertension is among black women. The Framingham study showed that the prognosis for hypertension tended to be better in women than in men.25 This may help explain why some trials failed to show treatment benefit in hypertensive women. Whereas clinical trials have shown reductions in morbidity and mortality in men treated for h sion, data in women have been equivocal2 1

perten- -29 In a

number of these trials, black women clearly had reductions in mortality after therapy, whereas results in white women have been inconsistent. Neverthe- less, Anastos et al% suggested that “the attributable risk percent” (the proportion of end points that could be eliminated by removing hypertension) for cardiovascular complications of hypertension is higher for women than for men. These researchers also pointed out that there is a dearth of information regarding the effects of antihypertensive agents and side effects in women. The present study showed small improvements in the lipid profiles for both women and men. Women had a higher incidence of edema with amlodipine than did men, although as previously stated, this was in combination with a greater therapeutic response. A higher relative dose may have explained more edema but did not fully explain the sex difference in BP response.

Although a recent, retrospective, case-controlled study3’ suggested that hypertensive patients receiving calcium channel blockers had a greater rate of myo-

720 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 77 APRIL 1, 1996

cardial infarction ( 16 infarcts/ 1,000 patient years) than patients taking diuretics and p blockers ( 10 infarcts/ 1,000 patient years), that study included short-acting calcium channel blockers not indicated by the Food and Drug Administration for the treatment of hypertension. In the present prospective trial, the rate of myocardial infarction with amlodipine, extrapolated per 1,000 patient years, was 10-a rate similar to that observed with diuretics and 0 blockers in the recent case-controlled study.3o A longer-term interim analysis including 7,849 patient-months exposure time revealed an even lower rate of infarction at 7.6/1,000 patient years. Hence, amlodipine therapy did not appear to be associated with an excess of myocardiaf infarctions in this community-based hypertensive population.

Acknowledgment: We acknowledge the help of Ca- thy Davisson in preparation of this manuscript.

APPENDIX MembenoftheAmlodipineCordio~xukrCommunit/TriolShrdyGrwp:

Ralph Althouse, MD, Fdmonds, WA, Kenneth P. Anderson, DO, Des Moines, IA; Richard G. Appel, MD, Winston-Salem, NC; Mark M. Applefeld, MD, Baltimore, MD; George R. Aronoff, MD, Louisville, KY; John S. Banas, MD, Morristown, NJ; Vinod K. Bansal, MD, Maywood, 1L, Allan Barker, MD, Salt Lake City, UT; Lewis T. Barton, MD, Salt Lake City, UT; Barney Beaver, DO, Columbus, OH; Joseph Bellomo, MD, Dallas, TX; Joan Ryder Benz, MD, PhD, Cedar Rapids, IA; Martin S. Bilsker, MD, Miami, n, Cheryl Brannon, DO, Bala Cynwyd, PA; Gerald L. Braverman, MD, Indianapolis, IN; Kevin F. Browne, Jr, MD, Lakeland, FQ Hubert Burton, MD, Salt Lake City, UT; Vin- cent Canzanello, MD, Winston-Salem, NC; Antonio R. Caracta, MD, Staten Island, NY; Christos Carvounis, MD, East Meadow, NY; David B. Case, MD, New York, NY; Robert E. Cronin, MD, Dallas, TX; William C. Cushman, MD, Memphis, TN; Ralph E. Cutler, MD, Loma Linda, CA; Grant Deger, MD, Bel- lingham, WA; Henry DeMots, MD, Portland, OR: Dorothy DiNardo-Ekery, MD, El Paso, TX; Donald J. DiPette, MD, Galveston, TX; Paul L. Douglass, MD, Atlanta, GA; Douglas Duffy, MD, Marshfield, W1: George Dunea, MD, Chicago, 1L; Clifford Ehrlich, MD, Lansdale, PA; Kameel F. Farag, MD, Los Angeles, CA; James C. Ferraro, DO, Pittsburgh, PA; Alan D. Forker, MD, Kansas City, MO; Barry H. Forman, MD, New Haven, CT, Linda Francisco, MD, Wichita, KS; Michael P. Gabris, MD, Syracuse, NY; Joseph P. Galichia, MD, Wichita, KS; Lawrence E. Glassberg, MD, Hartsdale, NY; Raymond Graf, MD, Corpus Christi, TX; Elliott I. Greenspan, DO, Detroit, MI; Stephen R. Grubb, MD, Charleston, WV; Burritt L. Haag, MD, Springfield, MA, Jennifer Hamilton, MD, Baltimore, MD; Herschel R. Harter, MD, iulonroe, LA; L.T.C. James A. Hasbargen, MD, Fitzsimmons Army Medical Center, CO, Robert L. Haynie, MD, Cleveland, OH; Theodore Herman, MD, Buffalo, NY; Michael C. Hindman, MD, Durham, NC; Jeffrey Hubbard, MD, Fresno, CA; Dearing Johns, MD, Charlottesville, VA; Anil Joshi, MD, Yonkers, NY; William D. Kaebny, MD, Denver, CO; Lois Anne Katz, MD, New York, NY; George Kaysen, MD, PhD, Martinez, CA; Kent Kirchner, MD, Jackson, MS; John Kitaji, MD, Mon- terey, CA; Jim Charles Kizziar, MD, Little Rock, AR; Kenneth S. Kleinman, MD, Tarzana, CA; Norman J. Kramer, MD, Charlotte, NC; Justine Krawczyk, MD, Buffalo, NY: Niranjan Lal, MD, Kalamazoo, MI; William Lamb, Jr, DO, Pittsburgh, PA; Gary M. Lattin, MD, Reading, PA; Arthur Lee, MD, San Jose, CA; Jon Levine, MD, Nashville, TN; Robert Lindeman, MD, Albuquerque, NM; Barry S. Lindenberg, MD, Schenectady, NY; Francisco Llach, MD, Los Angeles, CA; Henry Philen Lobstein, MD, Fort Worth, TX; J. Devon Lowden, MD, Atlanta, GA; Lionel Mailloux, MD, Manhasset, NY: Thomas C. Marbury, MD, Orlando, FL.; Kevin J. Martin, MD, St. Louis, MO, Charles John McAl- lister, MD, Clearwater, IQ David McCarty, DO, Longmont, CO; Charles Mc- Coy, MD, Providence, RI; Barry K. McLean, MD, Birmingham, AL; Ravindra L. Mehta, MD, San Diego, CA; Donald M&my, MD, Houston, TX; Maj. Joseph S. Moss, MD, Wright Patterson AFB, OH; John Jay MunseII, MD, Lake Bluff, IL; Raymond Murray, MD, East Lansing, MI; V. Shrinivas Murthy, MD, Mil- waukee, WI; J.V. Nixon, MD, Richmond, VA; Suzanne Oparil, MD, Birming- ham, AL; Richard O’Donovan, MD, New Orleans, LA; Thomas S. Parker, MD, Austin, TX; Arturo Pascual, MD, Detroit, MI; James G. Peden, Jr, MD, Green- ville, NC; Stan Peskce, MD, Macon, GA, Alice Petrulis, MD, Cleveland, OH; Joseph Pitone, DO, Stratford, NJ; David W. Ploth, MD, Charleston, SC; George Porter, MD, Portland, OR; Richard A. Preston, MD, Miami, FL; Henry A. Punzi, MD, Carrollton, TX; Ken Radack, MD, Cincinnati, OH; Surrender Raina, MD, Stockton, CA; Benjamin Rosin, MD, Torrance, CA: Edward Ross, MD, Gaines- ville, FL; Carlos Rot&u, MD, Washington, DC.; Jon L. RuckIe, MD, Tacoma, WA; Michael Ruddy, MD, New Brunswick, NJ; Michael R. Rudnick, MD, Philadelphia, PA; Albert0 Saenz, MD, Columbia, SC; Deeb N. Salem, MD, Boston, MA; Stephen Sandroni, MD, Jacksonville, n, KamaIjit Sethi, MD,

Washington, DC.; Geza Simon, MD, Minneapolis, MN; Donald A. Skor, MD, St. Louis, MO; Jerry Smucker, MD, Cincinnati, OH; Samuel M. Sobol, MD, San Francisco, CA; Jay M. Sosenko, MD, Miami, FL; Samuel Spitalewitz, MD, Brooklyn, NY; Bradley D. Sporkin, MD, Mine& NY; Paul Stander, MD, Phoenix, AZ; Timothy J. Story, MD, Indianapolis, IN; Richard M. Sweet, MD, Minneapolis, MN; Melvin Tonkon, MD, Anaheim, CA; Gary R. Truex, MD, San Francisco, CA; Robert Paul Tally, MD, Mesa, AZ, Hector 0. Ventura, MD, New Orleans, LA; William M. Vosik, MD, Kearney, NE; Darrell D. Walter, MD, Covina, CA; Warren Wexelman, MD, Brooklyn, NY: Thomas B. Wieg- mann, MD, Kansas City, MO; Edward J. Zajac, MD, Chicago, IL; Edward T. Zawada, MD, Sioux Falls, SD; Steven Zelenkofske, DO, Bala Cynwyd, PA: and Paul Ziajka, MD, Orlando, FL.

1. Barges RA, Dodd MG. Amlodipine. Cardiovusc Drug Rev 1990;8:25-44. 2. Mroczek WJ, Burris JF, Allenby KS. A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Car- diovasc Pharmacol 1988;12(suppl l):S79-S84. 3. Frishman WH, Brobyn R, Brown RD. Johnson BF, Reeves RL, Womb& DG. A randomized placebo-controlled comparison of amlodipine and atenolol in mild to moderate systemic hypertension. J Cardiovusc Pharmacol 1988;12(suppl7):S103-SlO6. 4. Taylor SH. Usefulness of amlodipine for angina pectoris. Am J Cardiol 1994;73:28A-33A. 5. Chahine RA, Feldman RL, Giles TD, Raizner AE, Weiss RJ, Nicod P, and the Investigators of Study 160. Efficacy and safety of amlodipine in vasospastic angina: an interim report of a multicenter, placebo-controlled trial. Am Heart J 1989;118:1128-1130. 6. Neaton JD, Grimm RH Jr, Prineas RJ, Stander J, Graadits GA, Elmer PJ, Cutler IA, Flack JM, Schoenberger IA, McDonald R, Lewis CE, Liebson PR, for the Treatment of Mild Hypertension Study Research Group. Treatment of mild hypertension study: final results. JAMA 1993;270:713-724. 7. NDTI’ (based on 1994 data), IMS America, Ltd. 1995. Plymouth Meeting, PA. 8. Physicians’ Desk Reference. 48th ed. Montvale, NJ: Medical Economics Data Production Co; 1994. Production information for amlodipine besylate. 9. Webster J, Robb OJ, Jeffers TA, Scott AK, Petrie JC, Tyler HM. Once daily amlcdipine in the treatment of mild to moderate hypertension. Br J Clin P/tar- mcol 1987;24:713-719. IO. Heber ME, Brigden G, Al-Khawaja I, Raftery EB. 24.hour blood pressure control with the once daily calcium antagonist, amlodipine. Br J Clin Phonnacol 1989;27:359-365. 11. Burris JF, Ames BP, Applegate WB, Ram CVS, Davidov ME, Mroczek WJ. Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension. J Cardiovusc Pha-01 1988;12(suppl 7):S98-S102. 12. de Bruijn B, Cocco G, Tyler HM, and Coinvestigators. Multicenter placebo- controlled comparison of amlodipine and atenolol in mild to moderate hypertension. .I Cardiovasc Phamacol 1988;12(suppl7):S107-S109. 13. Lorimer AR, Smedsrud T, Walker P, Tyler HM. Comparison of amlodipine and verapamil in the treatment of mild to moderate hypertension. J Cardiovmc Phanmcol 1988;12(suppl):S89-S93. 14. Englert R, Beressem P, van Manteuffel E, Stafunsky M, Kramar M. An open, parallel, comparative evaluation of amlodipine and nitrendipine in the monotherapeutic treatment of mild and moderate essential hypertension. J Car- diovasc Phamcol 1991;17(suppl l):S22-S24. 15. Waeber B, Barges ET, Christeler P, Guillaume-Gentil M, Hollenstein U, Mannhart M. Amlodipine compared to nitrendipine in hypertensive patients: the effects on toleration in relationship to the onset of action. Cardiology 1992;8O(suppl 1):46-53. 16. Velasco M, Urbina A, Silva H, Fonesca R, Guevara J, Hernandez R, Her- nandez Pieretti 0. A double-blind, parallel, comparative evaluation of amlodipine vs. captopril in the monotherapeutic treatment of mild and moderate essential hypertension. J Cardiovasc Phamcol 1991;17(suppl l):SI9-S21. 17. Lacourciere Y, Poirier L, Provencher P. Comparison of the effects of amlodipine and captopril on clinic and ambulatory blood pressure. J Hum Hyper- tens 1992;6(suppl l):S25-S28. 18. Omvik P, Thawlow E, Herland OB, Eide I, Midha R, Turner RR. Double- blind, parallel, comparative study on quality of life during treatment with amlodipine or enalapril in mild or moderate hypertensive patients: a multicentre study. J Hypertens 1993;11:103- 113. 19. Rofman BA. Long-term open evaluation of amlodipine versus hydrochlorothiazide in patients with essential hypertension. .I Curdiovusc Pharmcol 1988;12(suppl7):S94-S97. 20. Varrone I, and the Investigators of study AML-NY-86-002. The efficacy and safety of amlodipine in the treatment of mild and moderate essential hypertension in general practice. J Cardiovmc Phamum~Z 1991;17(suppl I):S30-s33. 21. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Hen- derson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N En& JMed 1993;328:914-921.

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Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine Cardiovascular Community...

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