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Treatment of hypertension in patients ≥65 years of age: experience with amlodipine
CLINICAL THERAPEUTICSWOL.
22, NO. 12,200O
Treatment of Hypertension in Patients 265 Years of Age: Experience with Amlodipine Christopher Lmgdon,
MB, BS
The Holyport Surgery, Holyport, Maidenhead, Berkshire, United Kingdom
ABSTRACT Background: Hypertension is a common finding in patients ~65 years of age that contributes to cardiovascular morbidity and mortality, but many patients are untreated or their hypertension inadequately controlled. Recent randomized controlled studies have demonstrated the benefits of treating hypertension in the elderly. Objective: This study was undertaken to assess the efficacy and tolerability of amlodipine, a long-acting calcium channel blocker, in elderly (~65 years of age) patients with mild to moderate hypertension (diastolic blood pressure 95 to 114 mm Hg). Methods: This was an open-label, multicenter, IO-week, general-practice study involving patients >18 years of age. Patients with malignant or secondary hypertension or unstable angina were excluded, as were those who had experienced an acute myocardial infarction or stroke in the preceding 3 months or had been treated with an alpha-blocker in the preceding 6 months. Patients were assigned to 1 of 4 treatment schedules: amlodipine monotherapy or combination therapy and amlodipine given once daily in the morning or in the evening. Approximately 50% of patients would receive a morning dose, and -80% would receive amlodipine as monotherapy. The paired t test was used to assess the significance of differences from baseline values, with significance set at P < 0.05. Results: A total of 5135 patients received amlodipine and were included in the tolerability analysis. Of these, 3511 of 3628 patients (96.8%) ~65 years and 147 1 of 1507 patients (97.6%) ~65 years (including 336 of 349 [96.3%] 975 years) were included in the efficacy analysis. Significant reductions (P < 0.05) in blood pressure were noted in all groups after 4 and 8 weeks of treatment. The equivalence of efficacy in all age groups was seen in terms of reduction in blood pressure (reduction of 21/15 mm Hg in patients ~65 years of age, 25/16 mm Hg in those ~65 years of age, and 2607 mm Hg in those ~75 years of age) compared with baseline. Therapy was successful in 2878 patients (82.0%) ~65 years of age, in 1238 patients (84.2%) 265 years of age, and in 284 patients Accepted
for publication
October 13, 2000.
Printed in the USA. Reproduction
0149.2918/00/$19.00
in whole or part is not permitted.
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CLINICAL THERAPEUTICS@
(84.5%) 275 years of age. The incidence of adverse events was similar in all age groups (18.0%, ~6.5 years; 22.3%, 265 years; and 24.1%, 275 years), with no statistically significant differences between groups. Tolerability was rated as good or excellent in all patients, with no significant differences between groups. Conclusions: Once-daily amlodipine was effective in the treatment of mild to moderate hypertension in this patient population and demonstrated a low frequency of adverse events, a high degree of tolerability, and improved well-being. Moming rather than evening dosing appeared to confer a slight advantage. Key words: amlodipine, calcium channel blocker, elderly, tolerability, efficacy, quality of life. (C& Z’hel: 2000;22;14731482)
INTRODUCTION Hypertension is a well-recognized risk factor for cardiovascular and cerebrovascular morbidity and mortality, which cause at least half of deaths in the elderly population.’ Despite the significant impact of hypertension on the health of the elderly, many elderly patients with hypertension remain untreated or have inadequately controlled hypertension; the reason for this became clear in a survey of physicians’ attitudes toward the treatment of elevated blood pressure (BP) in an otherwise healthy 75-year-old male.2 The thresholds at which the respondents would initiate treatment were generally higher than those recommended in current guidelines.3,4 The physicians surveyed were aware that treating hypertension reduces a patient’s risk of stroke, but they were less certain how treating hypertension affected the risk of myocardial infarction and death. These in-
1474
vestigators suggested that their findings were unlikely to be solely due to attitudes toward the elderly and were more likely to reflect physicians’ concerns about the safety of treating the elderly. Hypertension is a common diagnosis in the elderly.4 Blood vessels become less compliant with age, leading to increased peripheral vascular resistance and elevated BP.5 Estimates of the number of elderly people with hypertension depend on the population studied, the method of detection (isolated or serial measurements), and the definition of hypertension. According to the World Health Organization (WHO)/ International Society of Hypertension (ISH) classification of hypertension as diastolic BP (DBP) 290 mm Hg or systolic BP (SBP) 2140 mm Hg,6 hypertension occurs in 60% to 71% of elderly Americans, depending on race.4 Although the current guidelines have different thresholds for intervention in the general population, the thresholds for initiating treatment in the elderly are identical to those in younger patients. As in younger patients, intervention may depend on target-organ disease or other cardiovascular risk factors. Effective treatment may lead to cost savings in the long term. In 1 study of hypertensive patients with type 2 diabetes, tight control of blood pressure substantially reduced the cost of complications, increased the interval without complications, and was cost-effective compared with other health care programs.7 This is likely to be especially true in elderly populations. Each of the 5 main antihypertensive drug classes (diuretics, beta-blockers, calcium channel blockers, angiotensinconverting enzyme [ACE] inhibitors, and alpha-blockers) have similar efficacy in reducing BP,8 and all are effective in treating
C. LANGDON
hypertension in the elderly! The WI-IO/ISH guidelines’s state that the beneficial effects of treatment in the outcome trials are due to BP reduction, and all 5 drug classes are recommended as first-line therapy, depending on concomitant risk factors and diseases. It is widely acknowledged that a more cautious approach is needed in the treatment of elderly hypertensive patients compared with younger patients, largely because of the physiologic changes associated with aging. ‘g3All treatment guidelines stress that antihypertensive drugs should be initiated at a low dose in the elderly to minimize adverse events, particularly postural effects.3s”,6 Diuretics and beta-blockers are both recommended as first-line treatment for elderly hypertensive patients,3 but their use may be inadvisable in hypertensive patients with diabetes, dyslipidemia, gout, heart failure, peripheral vascular disorders, or asthma.3,4*6 Many treatment guidelines recognize the value of calcium channel blockers, ACE inhibitors, and alpha-blockers in patients with these disorders.3,4 Like younger patients, the elderly should be monitored closely for first-dose hypotension and changes in renal function after initiation of therapy with an ACE inhibitor. Calcium channel blockers can be prescribed in the presence of a wide range of cardiovascular risk factors9 and often improve quality of life to; they are therefore particularly suitable in the elderly. Amlodipine is a long-acting calcium channel blocker of the dihydropyridine group that lowers BP by causing peripheral vasodilatation, which reduces peripheral resistance. Its half-life of 35 to 50 hours permits once-daily dosing.” Thus, an occasional missed dose is unlikely to cause problems such as “myocardial stunning,”
which may be seen with missed doses of shorter-acting hypotensive agents. Controlled double-blind studies have shown that amlodipine significantly reduces both standing and supine BP, with these reductions maintained throughout the 24-hour dosing interval.‘* This paper reports the findings of an open-label, multicenter clinical study designed to assess the efficacy and tolerability of amlodipine in elderly patients (265 years of age) with mild to moderate hypertension. The results of this study are discussed in relation to other published studies of antihypertensive therapy.
PATIENTS
AND METHODS
This lo-week, open-label, multicenter, general-practice study included patients with mild to moderate essential hypertension from -1000 practices in the United Kingdom. To be included in the study, patients had to be ~-18 years of age and to have given written informed consent. Sitting DBP had to be between 95 and 114 mm Hg. Patients with malignant or secondary hypertension or unstable angina were excluded from the study, as were those who had experienced an acute myocardial infarction or stroke in the preceding 3 months or had been treated with an alpha-blocker in the preceding 6 months. Women of childbearing potential who were not using contraception also were excluded. Each general practitioner was assigned 4 possible treatment schedules in which to enter patients. The first pair of schedules comprised patients receiving no adjunctive antihypertensive therapy. These patients were either previously untreated or had discontinued therapy before the study in accordance with the manufacturer’s rec-
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ommendations because of inadequate efftcacy, unacceptable adverse events, or poor compliance. The second pair of schedules comprised patients who were to continue their adjunctive antihypertensive therapy (ie, diuretics, beta-blockers, nifedipine, or lisinopril) unchanged. For each pair of schedules, one arm required patients to take a single daily dose of amlodipine in the morning, while the other arm required patients to take a single daily dose in the evening. Approximately 50% of patients would receive a morning dose, and -80% of patients would receive amlodipine as monotherapy. Patients were required to visit their physician on 4 occasions during the study. Patients could be withdrawn from the study at any time at their own request, if their health was considered to be compromised, or if they showed poor compliance. At each visit, body weight, BP, and heart rate were recorded, and details of any concomitant illnesses or additional medications were noted. BP and heart rate determinations were performed using the same arm of the patient at each visit. On each occasion, SBP and DBP (mean of 2 consecutive measurements) were determined after the patient had been sitting quietly for 5 minutes. DBP coincided with the phase V (disappearance) Korotkoff sound. BP was measured to the nearest 2 mm Hg. Heart rate was determined immediately before BP was measured in the sitting position. At the initial visit, a detailed medical history was taken, physical examination was performed, and patient well-being (quality of life) was assessed. After 2 weeks, patients were reassessed and BP was measured. Patients whose sitting DBP was still between 95 and 114 mm Hg at this second visit entered an g-week open titration/maintenance phase and received
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an initial 5-mg dose of amlodipine in the morning or the evening, according to their treatment schedule. At the third visit, after 4 weeks of treatment (week 6), adverse events were recorded and drug compliance was estimated from returned tablet counts. The dose was then increased to 10 mg once daily, unless DBP was ~90 mm Hg or adverse events contraindicated the increase. Patients continued taking their optimum dose for 4 more weeks; if adverse events occurred, the dose could be decreased. At the fourth visit (week 10 of the study), adverse events were recorded, drug compliance was estimated, and tolerance, efficacy, and the patient’s well-being were assessed. Therapeutic success was defined as a final DBP ~90 mm Hg or a reduction ~10 mm Hg from baseline. A decision was made at this visit whether to continue amlodipine treatment. Throughout the study, the relationship of adverse events to amlodipine treatment was assessed by the investigator.
Statistical Analysis Statistical analyses were performed using SAS@ version 6.04 (SAS Institute, Inc, Cary, North Carolina). Data were analyzed on an intent-to-treat basis. The paired t test was used to assess the significance of differences from baseline values. For all statistical tests, a significance level of 0.05 was set, and P values represented intragroup changes. Data and discussion referring to the r65-year age group include data from the r75-year age subgroup.
RESULTS A total of 5135 patients received amlodipine and were included in the tolerability analysis. Of these, 35 11 of 3628 patients
C. LANGDON
(96.8%) ~65 years and 1471 of 1507 patients (97.6%) ~65 years (including 336 of 349 [96.3%] 275 years) provided assessable efficacy data. A total of 153 patients were excluded because of baseline sitting DBP ~95 mm Hg, no baseline BP measurement, or no assessable treatment visit. Approximately two thirds of patients received amlodipine at a final dose of 5 mg once daily (~65 years of age, 2263 patients [62.4%]; 265 years, 1033 patients [68.5% 1; 875 years, 248 patients [7 1. I%]). The mean final daily doses in the z65- and r75-year age groups were slightly lower than that in the <65-year age group (Table I). Four patients ~65 years of age and 4 patients 65 to 74 years of age had their dose reduced to 2.5 mg/d during the study. Compliance was excellent, with 4703 patients (91.6%) apparently taking ~75% of their study medication. Concomitant diseases, which were recorded for 28% of the patients 265 years of age, predominantly concerned the mus-
culoskeletal (163/1507; tory (64/1507; 4.2%), (70/1507; 4.6%) systems, bolic disorders also were
10.X%), respiraand circulatory although metafrequent.
Efficacy Assessment Significant reductions in BP were recorded in all groups after 4 and 8 weeks of amlodipine therapy (P < 0.05). Amlodipine was at least as effective in the z65and z75-year age groups as in younger patients, despite differences in doses between age groups. The equivalence of efficacy in younger and older groups was evident both in terms of reduction in BP (Figure 1) and percentage of therapeutic successes (defined as a final DBP ~90 mm Hg or a reduction of ~10 mm Hg: ~65 years of age, 2878 [82.0%]; 265 years, 1238 [84.2%]; 275 years, 284 [84.5%]). Elderly patients showed greater reductions in BP, from a higher baseline, than did younger patients (Table I, Figure 1). In all 3 age groups, the
Table I. Efficacy results. Patients’ Age, y
Assessable patients Final dose, mg/d (no. [%+I of patients) 2.5 5 IO Mean final dose, mgld Mean baseline SBP/DBP, mm Hg Mean SBP/DBP at last assessable visit, mm Hg Final DBP s90 mm Hg, no. (%) Therapy success, no. (%)s
<65
265*
275
3511
1471
336
4 (0.1) 2191 (62.4) 1316 (37.5) 6.9 168.8003.6 148.1/89.1’ 2391 (68.1) 2878 (82.0)
5 (0.3) 1008 (68.5) 458 (31.1) 6.6 18 I .3/104.2 156.3/88.3* 1059 (72.0) 1238 (84.2)
0 (0.0) 239 (71.1) 97 (28.9) 6.4 186.1/104.9 160.0/88.1~ 237 (70.5) 284 (84.5)
SBP = sitting systolic blood pressure; DBP = sitting diastolic blood pressure. *Includes patients in the 275year age subgroup. tPercentages may not total 100 due to rounding error. OF’< 0.05 versus baseline, paired r test. “Final DBP ~90 mm Hg or a reduction of 210 mm Hg.
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Age, Y ~65
I -20
-25
n DBP 0 SBP
-30
Figure
275
L
1 Mean reduction in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) during amlodipine therapy. *Includes patients in the r75-year age subgroup.
reduction in BP was accompanied by a decrease in heart rate of 1 to 2 beats/min. Although statistically significant (P < 0.05), this decrease was not considered clinically relevant.
Tolerability Assessment The incidence of adverse events was similar in all age groups (18.0% [n = 6551 in the <65-year age group, 22.3% [n = 3361 in the 265-year age group, and 24.1% [n = 841 in the >75-year age group). There was no statistically significant difference in the frequency of adverse events between the morning and evening dosing groups (18.6% [n = 5191 and 20.2% [n = 4731, respectively). Adverse events in the entire study population were predominantly vasodilatory (edema, 5.3%; headache, 4.3%; flushing/ 1478
269
hot flushes, 2.4%; dizziness/vertigo, 2.3%). None of the events related to vasodilation occurred significantly more frequently in any age group (Table II). Edema developed at an even rate during treatment and was not associated with generalized fluid retention, since mean body weight decreased -0.3 kg during the study. Headache, dizziness, and flushing occurred most frequently in the first week of therapy. With the exception of dizziness, postural events were rare; there was only 1 report of postural hypotension in an elderly patient and no reports of syncope. Amlodipine had no reported adverse cognitive effects, with only 1 elderly patient reporting confusion. Five myocardial infarctions and 5 deaths occurred during the study. Of the 5 deaths, 1 resulted from myocardial infarction; this was the only
C. LANGDON
Table II. Number (%) of adverse events. Patients’ Age, y
Assessable patients Edema Headache Flushing/hot flushes Dizziness/vertigo
<65
265’
275
3626 176 (4.9) 155 (4.3) 71 (2.0) 76 (2.1)
1507 94 (6.2) 64 (4.2) 52 (3.5) 40 (2.7)
349 23 (6.6) 17 (4.9) 9 (2.6) 9 (2.6)
*Includespatients in the >75-year age subgroup. H 265 Years of age’ q 875 Years of age
60
50
2
40
S ‘2
30
B 8
20
10 0? Excellent Tolerability
Good Tolerability
I
Improved Quality of Life
Figure 2. Tolerability and quality of life during amlodipine the r75-year age subgroup.
death possibly related to treatment with amlodipine. The low incidence of adverse events in these elderly patients was reflected in the overall impression of tolerability and wellbeing (Figure 2). Tolerability was rated as good or excellent in the majority of patients in both elderly groups (~65 years of age, 89.2% [n = 12311; ~75 years, 87.2% [n = 2721); these results were similar to those reported overall (90.7% [n = 30211). The high
No Change in Quality of Life
therapy. *Includes patients in
level of tolerability and improved well-being were reflected in the fact that 185% of patients were prescribed amlodipine by their general practitioner after study completion.
DISCUSSION The results of this study confirm the efflcacy and tolerability of amlodipine in the treatment of elderly patients with mild to moderate hypertension.
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Previously, treatment of elderly patients with hypertension was limited; increased BP in this age group was regarded as a physiologic consequence of aging without pathologic significance.i3 After several randomized trials in elderly patients demonstrated a dramatic reduction in cardiovascular morbidity and mortality with antihypertensive treatment,‘“-‘9 withholding treatment based on age is no longer considered justifiable. Based on the positive results of outcome trials, it is now recommended that treatment for hypertension be initiated in patients 580 years of age.3,4,7 The evidence for initiating treatment in patients >80 years of age is inadequate, but there is general consensus that preexisting therapy should be continued after a patient’s 80th birthday.@ In the present study, equivalent efficacy was demonstrated in the younger and older age groups, with significant decreases in BP recorded. Although the success of amlodipine therapy was evident, the possibility of bias in the observed reductions in BP is inherent in an openlabel design. There are few other detailed studies of antihypertensive therapy in the elderly, particularly in patients 275 years of age. However, in a comparable study, the alpha,-blocker doxazosin was equally effective in younger (~65 years) and older (265 and 275 years) patients.i9 The results of the Systolic Hypertension in Europe (Syst-Eur) triali and the Shanghai Trial of Nifedipine in the Elderly (STONE) study*O support the use of calcium channel blockers in hypertensive patients aged 260 years. In the Syst-Eur trial, elderly European patients with isolated systolic hypertension were started on nitrendipine; median follow-up was 2 years. In the STONE study, which had a mean follow-up of 30 months, elderly Chinese hypertensive pa-
1480
tients were given nifedipine. Both trials demonstrated significant reductions in the incidence of cardiovascular events. In the elderly population in the present trial, the incidence of adverse events was low. The absence of reported adverse cognitive effects with amlodipine in this study is supported by data suggesting that amlodipine has positive effects on cognitive function,*’ and a recent study found that amlodipine did not affect regional cerebral blood flow in elderly patients, as assessed by single-photon emission computed tomography.** Five elderly patients experienced myocardial infarction during the present study, reflecting the higher cardiovascular morbidity in this age group. One of these patients died; this was the only death possibly related to study treatment. Although the difference in the incidence of adverse events between groups was not statistically significant in the present study, the incidence of adverse events is important from a clinical perspective. In addition to efficacy and tolerability, other issues of importance in choosing any drug for the elderly are compliance and quality of life, and these are particularly pertinent in an asymptomatic condition requiring long-term treatment such as hypertension.‘O Simple dosing schedules are known to enhance compliance, and drugs should be prescribed on a once-daily basis whenever possible. Compliance with amlodipine in this study was excellent, with >90% of patients taking 275% of their trial medication, reflecting both the tolerability and convenience of amlodipine therapy. CONCLUSIONS This study confirms the efficacy and tolerability of amlodipine in the treatment of
C. LANGDON
mild to moderate essential hypertension in general practice. Once-daily amlodipine, alone or with adjunctive antihypertensive therapy, was as effective in elderly patients (265 years of age) as in younger patients, despite the use of lower mean daily doses in the elderly. It should be noted, however, that the study protocol excluded patients with a range of conditions that may sometimes exist in an elderly population. The results of the present study thus cannot be extrapolated to excluded patients. In addition to confirming the effectiveness of amlodipine, this study also demonstrated a low frequency of adverse events, a high degree of tolerability, and improved well-being. Morning rather than evening dosing appeared to confer a slight advantage.
ACKNOWLEDGMENT This study was sponsored by Pfizer Ltd, Sandwich, Kent, United Kingdom. Address correspondence to: Christopher Langdon, MB, BS, The Holyport Surgery, Stroud Farm Road, Holyport, Maidenhead, Berks, SL6 2LH, United Kingdom. REFERENCES Lever AF, Ramsay LE. Treatment of hypertension in the elderly. J Hypertens. 1995;13:571-579. Ford GA, Asghar MN. Management of hypertension in the elderly: Attitudes of general practitioners and hospital physicians. Br J Clin Pharmacol. 1995;39:465-469. Ramsay L, Williams B, Johnston G, et al. Guidelines for management of hypertension: Report of the Third Working Party of the British Hypertension Society. J Hum Hypertens. 1999; 13:569-592.
4. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI). Rockville, Md: National Institutes of Health; 1997. Publication 98-4080. 5. Belmin J. Current aspects of arterial hypertension: Hypertension in the aged. Presse Med. 1999;28:862-869. 6. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999;17:151-183. 7. UK Prospective Diabetes Study Group. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40. Br Med J. 1998;317:720-726. 8. Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study (TOMHS). Final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993;270:7 13-724. 9. Bittar N. Maintaining long-term control of blood pressure: The role of improved compliance. Clin Cardiol. 1995; 18(Suppl 3):12-16. 10. Reid JL, Meredith PA, Donnelly R, Elliott HL. Pharmacokinetics of calcium antagonists. J Cardiovasc Pharmacol. 1988;12 (Suppl 7):S22-S26. 11. Julius S. Amlodipine in hypertension: An overview of the clinical dossier. J Cardiovast Pharmacol. 1988; 12(Suppl 7):S27s33. 12. Andrews FM, Withey SB. Social Indicators of Well Being: Americans’ Perception of Life Quality. New York: Plenum; 1976.
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13. National Heart Foundation of Australia. Treatment of mild hypertension in the elderly. &led .i Amt. 198 1;2:398402. 14. DahlGf B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lmcet. 1991;338: 1281-1285. 15. Medical Research Council Working Party. Stroke and coronary heart disease in mild hypertension: Risk factors and the value of treatment. BMJ (Clin Res Ed). 1988; 296:1X-1570. 16. Vokonas PS, Kannel WB, Cupples LA. Epidemiology and risk of hypertension in the elderly: The Framingham Study. J Hypertens. 1988;6(Suppl 1):3-9. 17. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 199 1;265: 3255-3264.
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18. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757-764. 19. Langdon CG, Packard RS. Doxazosin in hypertension: Results of a general practice study in 4809 patients. Br J Clin Pruct. 1994;48:293-298. 20. Gong L, Zhang W, Zhu V, et al. Shanghai Trial of Nifedipine in the Elderly (STONE). .I Hypertens. 1996;14:1237-1245. 21. Testa MA, Turner RR, Simonson DC, et al. Quality of life and calcium channel blockade with nifedipine GlTS versus amlodipine in hypertensive patients in Spain. Gastrointestinal Therapeutic System. J Hypertens. 1998;16:1839-1847. 22. Pandita-Gunawardena ND, Clarke SE. Amlodipine lowers blood pressure without affecting cerebral blood flow as measured by single photon emission computed tomography in elderly hypertensive subjects. Age Ageing. 1999;28:451-457.
22, NO. 12,200O
Treatment of Hypertension in Patients 265 Years of Age: Experience with Amlodipine Christopher Lmgdon,
MB, BS
The Holyport Surgery, Holyport, Maidenhead, Berkshire, United Kingdom
ABSTRACT Background: Hypertension is a common finding in patients ~65 years of age that contributes to cardiovascular morbidity and mortality, but many patients are untreated or their hypertension inadequately controlled. Recent randomized controlled studies have demonstrated the benefits of treating hypertension in the elderly. Objective: This study was undertaken to assess the efficacy and tolerability of amlodipine, a long-acting calcium channel blocker, in elderly (~65 years of age) patients with mild to moderate hypertension (diastolic blood pressure 95 to 114 mm Hg). Methods: This was an open-label, multicenter, IO-week, general-practice study involving patients >18 years of age. Patients with malignant or secondary hypertension or unstable angina were excluded, as were those who had experienced an acute myocardial infarction or stroke in the preceding 3 months or had been treated with an alpha-blocker in the preceding 6 months. Patients were assigned to 1 of 4 treatment schedules: amlodipine monotherapy or combination therapy and amlodipine given once daily in the morning or in the evening. Approximately 50% of patients would receive a morning dose, and -80% would receive amlodipine as monotherapy. The paired t test was used to assess the significance of differences from baseline values, with significance set at P < 0.05. Results: A total of 5135 patients received amlodipine and were included in the tolerability analysis. Of these, 3511 of 3628 patients (96.8%) ~65 years and 147 1 of 1507 patients (97.6%) ~65 years (including 336 of 349 [96.3%] 975 years) were included in the efficacy analysis. Significant reductions (P < 0.05) in blood pressure were noted in all groups after 4 and 8 weeks of treatment. The equivalence of efficacy in all age groups was seen in terms of reduction in blood pressure (reduction of 21/15 mm Hg in patients ~65 years of age, 25/16 mm Hg in those ~65 years of age, and 2607 mm Hg in those ~75 years of age) compared with baseline. Therapy was successful in 2878 patients (82.0%) ~65 years of age, in 1238 patients (84.2%) 265 years of age, and in 284 patients Accepted
for publication
October 13, 2000.
Printed in the USA. Reproduction
0149.2918/00/$19.00
in whole or part is not permitted.
1473
CLINICAL THERAPEUTICS@
(84.5%) 275 years of age. The incidence of adverse events was similar in all age groups (18.0%, ~6.5 years; 22.3%, 265 years; and 24.1%, 275 years), with no statistically significant differences between groups. Tolerability was rated as good or excellent in all patients, with no significant differences between groups. Conclusions: Once-daily amlodipine was effective in the treatment of mild to moderate hypertension in this patient population and demonstrated a low frequency of adverse events, a high degree of tolerability, and improved well-being. Moming rather than evening dosing appeared to confer a slight advantage. Key words: amlodipine, calcium channel blocker, elderly, tolerability, efficacy, quality of life. (C& Z’hel: 2000;22;14731482)
INTRODUCTION Hypertension is a well-recognized risk factor for cardiovascular and cerebrovascular morbidity and mortality, which cause at least half of deaths in the elderly population.’ Despite the significant impact of hypertension on the health of the elderly, many elderly patients with hypertension remain untreated or have inadequately controlled hypertension; the reason for this became clear in a survey of physicians’ attitudes toward the treatment of elevated blood pressure (BP) in an otherwise healthy 75-year-old male.2 The thresholds at which the respondents would initiate treatment were generally higher than those recommended in current guidelines.3,4 The physicians surveyed were aware that treating hypertension reduces a patient’s risk of stroke, but they were less certain how treating hypertension affected the risk of myocardial infarction and death. These in-
1474
vestigators suggested that their findings were unlikely to be solely due to attitudes toward the elderly and were more likely to reflect physicians’ concerns about the safety of treating the elderly. Hypertension is a common diagnosis in the elderly.4 Blood vessels become less compliant with age, leading to increased peripheral vascular resistance and elevated BP.5 Estimates of the number of elderly people with hypertension depend on the population studied, the method of detection (isolated or serial measurements), and the definition of hypertension. According to the World Health Organization (WHO)/ International Society of Hypertension (ISH) classification of hypertension as diastolic BP (DBP) 290 mm Hg or systolic BP (SBP) 2140 mm Hg,6 hypertension occurs in 60% to 71% of elderly Americans, depending on race.4 Although the current guidelines have different thresholds for intervention in the general population, the thresholds for initiating treatment in the elderly are identical to those in younger patients. As in younger patients, intervention may depend on target-organ disease or other cardiovascular risk factors. Effective treatment may lead to cost savings in the long term. In 1 study of hypertensive patients with type 2 diabetes, tight control of blood pressure substantially reduced the cost of complications, increased the interval without complications, and was cost-effective compared with other health care programs.7 This is likely to be especially true in elderly populations. Each of the 5 main antihypertensive drug classes (diuretics, beta-blockers, calcium channel blockers, angiotensinconverting enzyme [ACE] inhibitors, and alpha-blockers) have similar efficacy in reducing BP,8 and all are effective in treating
C. LANGDON
hypertension in the elderly! The WI-IO/ISH guidelines’s state that the beneficial effects of treatment in the outcome trials are due to BP reduction, and all 5 drug classes are recommended as first-line therapy, depending on concomitant risk factors and diseases. It is widely acknowledged that a more cautious approach is needed in the treatment of elderly hypertensive patients compared with younger patients, largely because of the physiologic changes associated with aging. ‘g3All treatment guidelines stress that antihypertensive drugs should be initiated at a low dose in the elderly to minimize adverse events, particularly postural effects.3s”,6 Diuretics and beta-blockers are both recommended as first-line treatment for elderly hypertensive patients,3 but their use may be inadvisable in hypertensive patients with diabetes, dyslipidemia, gout, heart failure, peripheral vascular disorders, or asthma.3,4*6 Many treatment guidelines recognize the value of calcium channel blockers, ACE inhibitors, and alpha-blockers in patients with these disorders.3,4 Like younger patients, the elderly should be monitored closely for first-dose hypotension and changes in renal function after initiation of therapy with an ACE inhibitor. Calcium channel blockers can be prescribed in the presence of a wide range of cardiovascular risk factors9 and often improve quality of life to; they are therefore particularly suitable in the elderly. Amlodipine is a long-acting calcium channel blocker of the dihydropyridine group that lowers BP by causing peripheral vasodilatation, which reduces peripheral resistance. Its half-life of 35 to 50 hours permits once-daily dosing.” Thus, an occasional missed dose is unlikely to cause problems such as “myocardial stunning,”
which may be seen with missed doses of shorter-acting hypotensive agents. Controlled double-blind studies have shown that amlodipine significantly reduces both standing and supine BP, with these reductions maintained throughout the 24-hour dosing interval.‘* This paper reports the findings of an open-label, multicenter clinical study designed to assess the efficacy and tolerability of amlodipine in elderly patients (265 years of age) with mild to moderate hypertension. The results of this study are discussed in relation to other published studies of antihypertensive therapy.
PATIENTS
AND METHODS
This lo-week, open-label, multicenter, general-practice study included patients with mild to moderate essential hypertension from -1000 practices in the United Kingdom. To be included in the study, patients had to be ~-18 years of age and to have given written informed consent. Sitting DBP had to be between 95 and 114 mm Hg. Patients with malignant or secondary hypertension or unstable angina were excluded from the study, as were those who had experienced an acute myocardial infarction or stroke in the preceding 3 months or had been treated with an alpha-blocker in the preceding 6 months. Women of childbearing potential who were not using contraception also were excluded. Each general practitioner was assigned 4 possible treatment schedules in which to enter patients. The first pair of schedules comprised patients receiving no adjunctive antihypertensive therapy. These patients were either previously untreated or had discontinued therapy before the study in accordance with the manufacturer’s rec-
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ommendations because of inadequate efftcacy, unacceptable adverse events, or poor compliance. The second pair of schedules comprised patients who were to continue their adjunctive antihypertensive therapy (ie, diuretics, beta-blockers, nifedipine, or lisinopril) unchanged. For each pair of schedules, one arm required patients to take a single daily dose of amlodipine in the morning, while the other arm required patients to take a single daily dose in the evening. Approximately 50% of patients would receive a morning dose, and -80% of patients would receive amlodipine as monotherapy. Patients were required to visit their physician on 4 occasions during the study. Patients could be withdrawn from the study at any time at their own request, if their health was considered to be compromised, or if they showed poor compliance. At each visit, body weight, BP, and heart rate were recorded, and details of any concomitant illnesses or additional medications were noted. BP and heart rate determinations were performed using the same arm of the patient at each visit. On each occasion, SBP and DBP (mean of 2 consecutive measurements) were determined after the patient had been sitting quietly for 5 minutes. DBP coincided with the phase V (disappearance) Korotkoff sound. BP was measured to the nearest 2 mm Hg. Heart rate was determined immediately before BP was measured in the sitting position. At the initial visit, a detailed medical history was taken, physical examination was performed, and patient well-being (quality of life) was assessed. After 2 weeks, patients were reassessed and BP was measured. Patients whose sitting DBP was still between 95 and 114 mm Hg at this second visit entered an g-week open titration/maintenance phase and received
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an initial 5-mg dose of amlodipine in the morning or the evening, according to their treatment schedule. At the third visit, after 4 weeks of treatment (week 6), adverse events were recorded and drug compliance was estimated from returned tablet counts. The dose was then increased to 10 mg once daily, unless DBP was ~90 mm Hg or adverse events contraindicated the increase. Patients continued taking their optimum dose for 4 more weeks; if adverse events occurred, the dose could be decreased. At the fourth visit (week 10 of the study), adverse events were recorded, drug compliance was estimated, and tolerance, efficacy, and the patient’s well-being were assessed. Therapeutic success was defined as a final DBP ~90 mm Hg or a reduction ~10 mm Hg from baseline. A decision was made at this visit whether to continue amlodipine treatment. Throughout the study, the relationship of adverse events to amlodipine treatment was assessed by the investigator.
Statistical Analysis Statistical analyses were performed using SAS@ version 6.04 (SAS Institute, Inc, Cary, North Carolina). Data were analyzed on an intent-to-treat basis. The paired t test was used to assess the significance of differences from baseline values. For all statistical tests, a significance level of 0.05 was set, and P values represented intragroup changes. Data and discussion referring to the r65-year age group include data from the r75-year age subgroup.
RESULTS A total of 5135 patients received amlodipine and were included in the tolerability analysis. Of these, 35 11 of 3628 patients
C. LANGDON
(96.8%) ~65 years and 1471 of 1507 patients (97.6%) ~65 years (including 336 of 349 [96.3%] 275 years) provided assessable efficacy data. A total of 153 patients were excluded because of baseline sitting DBP ~95 mm Hg, no baseline BP measurement, or no assessable treatment visit. Approximately two thirds of patients received amlodipine at a final dose of 5 mg once daily (~65 years of age, 2263 patients [62.4%]; 265 years, 1033 patients [68.5% 1; 875 years, 248 patients [7 1. I%]). The mean final daily doses in the z65- and r75-year age groups were slightly lower than that in the <65-year age group (Table I). Four patients ~65 years of age and 4 patients 65 to 74 years of age had their dose reduced to 2.5 mg/d during the study. Compliance was excellent, with 4703 patients (91.6%) apparently taking ~75% of their study medication. Concomitant diseases, which were recorded for 28% of the patients 265 years of age, predominantly concerned the mus-
culoskeletal (163/1507; tory (64/1507; 4.2%), (70/1507; 4.6%) systems, bolic disorders also were
10.X%), respiraand circulatory although metafrequent.
Efficacy Assessment Significant reductions in BP were recorded in all groups after 4 and 8 weeks of amlodipine therapy (P < 0.05). Amlodipine was at least as effective in the z65and z75-year age groups as in younger patients, despite differences in doses between age groups. The equivalence of efficacy in younger and older groups was evident both in terms of reduction in BP (Figure 1) and percentage of therapeutic successes (defined as a final DBP ~90 mm Hg or a reduction of ~10 mm Hg: ~65 years of age, 2878 [82.0%]; 265 years, 1238 [84.2%]; 275 years, 284 [84.5%]). Elderly patients showed greater reductions in BP, from a higher baseline, than did younger patients (Table I, Figure 1). In all 3 age groups, the
Table I. Efficacy results. Patients’ Age, y
Assessable patients Final dose, mg/d (no. [%+I of patients) 2.5 5 IO Mean final dose, mgld Mean baseline SBP/DBP, mm Hg Mean SBP/DBP at last assessable visit, mm Hg Final DBP s90 mm Hg, no. (%) Therapy success, no. (%)s
<65
265*
275
3511
1471
336
4 (0.1) 2191 (62.4) 1316 (37.5) 6.9 168.8003.6 148.1/89.1’ 2391 (68.1) 2878 (82.0)
5 (0.3) 1008 (68.5) 458 (31.1) 6.6 18 I .3/104.2 156.3/88.3* 1059 (72.0) 1238 (84.2)
0 (0.0) 239 (71.1) 97 (28.9) 6.4 186.1/104.9 160.0/88.1~ 237 (70.5) 284 (84.5)
SBP = sitting systolic blood pressure; DBP = sitting diastolic blood pressure. *Includes patients in the 275year age subgroup. tPercentages may not total 100 due to rounding error. OF’< 0.05 versus baseline, paired r test. “Final DBP ~90 mm Hg or a reduction of 210 mm Hg.
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Age, Y ~65
I -20
-25
n DBP 0 SBP
-30
Figure
275
L
1 Mean reduction in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) during amlodipine therapy. *Includes patients in the r75-year age subgroup.
reduction in BP was accompanied by a decrease in heart rate of 1 to 2 beats/min. Although statistically significant (P < 0.05), this decrease was not considered clinically relevant.
Tolerability Assessment The incidence of adverse events was similar in all age groups (18.0% [n = 6551 in the <65-year age group, 22.3% [n = 3361 in the 265-year age group, and 24.1% [n = 841 in the >75-year age group). There was no statistically significant difference in the frequency of adverse events between the morning and evening dosing groups (18.6% [n = 5191 and 20.2% [n = 4731, respectively). Adverse events in the entire study population were predominantly vasodilatory (edema, 5.3%; headache, 4.3%; flushing/ 1478
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hot flushes, 2.4%; dizziness/vertigo, 2.3%). None of the events related to vasodilation occurred significantly more frequently in any age group (Table II). Edema developed at an even rate during treatment and was not associated with generalized fluid retention, since mean body weight decreased -0.3 kg during the study. Headache, dizziness, and flushing occurred most frequently in the first week of therapy. With the exception of dizziness, postural events were rare; there was only 1 report of postural hypotension in an elderly patient and no reports of syncope. Amlodipine had no reported adverse cognitive effects, with only 1 elderly patient reporting confusion. Five myocardial infarctions and 5 deaths occurred during the study. Of the 5 deaths, 1 resulted from myocardial infarction; this was the only
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Table II. Number (%) of adverse events. Patients’ Age, y
Assessable patients Edema Headache Flushing/hot flushes Dizziness/vertigo
<65
265’
275
3626 176 (4.9) 155 (4.3) 71 (2.0) 76 (2.1)
1507 94 (6.2) 64 (4.2) 52 (3.5) 40 (2.7)
349 23 (6.6) 17 (4.9) 9 (2.6) 9 (2.6)
*Includespatients in the >75-year age subgroup. H 265 Years of age’ q 875 Years of age
60
50
2
40
S ‘2
30
B 8
20
10 0? Excellent Tolerability
Good Tolerability
I
Improved Quality of Life
Figure 2. Tolerability and quality of life during amlodipine the r75-year age subgroup.
death possibly related to treatment with amlodipine. The low incidence of adverse events in these elderly patients was reflected in the overall impression of tolerability and wellbeing (Figure 2). Tolerability was rated as good or excellent in the majority of patients in both elderly groups (~65 years of age, 89.2% [n = 12311; ~75 years, 87.2% [n = 2721); these results were similar to those reported overall (90.7% [n = 30211). The high
No Change in Quality of Life
therapy. *Includes patients in
level of tolerability and improved well-being were reflected in the fact that 185% of patients were prescribed amlodipine by their general practitioner after study completion.
DISCUSSION The results of this study confirm the efflcacy and tolerability of amlodipine in the treatment of elderly patients with mild to moderate hypertension.
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Previously, treatment of elderly patients with hypertension was limited; increased BP in this age group was regarded as a physiologic consequence of aging without pathologic significance.i3 After several randomized trials in elderly patients demonstrated a dramatic reduction in cardiovascular morbidity and mortality with antihypertensive treatment,‘“-‘9 withholding treatment based on age is no longer considered justifiable. Based on the positive results of outcome trials, it is now recommended that treatment for hypertension be initiated in patients 580 years of age.3,4,7 The evidence for initiating treatment in patients >80 years of age is inadequate, but there is general consensus that preexisting therapy should be continued after a patient’s 80th birthday.@ In the present study, equivalent efficacy was demonstrated in the younger and older age groups, with significant decreases in BP recorded. Although the success of amlodipine therapy was evident, the possibility of bias in the observed reductions in BP is inherent in an openlabel design. There are few other detailed studies of antihypertensive therapy in the elderly, particularly in patients 275 years of age. However, in a comparable study, the alpha,-blocker doxazosin was equally effective in younger (~65 years) and older (265 and 275 years) patients.i9 The results of the Systolic Hypertension in Europe (Syst-Eur) triali and the Shanghai Trial of Nifedipine in the Elderly (STONE) study*O support the use of calcium channel blockers in hypertensive patients aged 260 years. In the Syst-Eur trial, elderly European patients with isolated systolic hypertension were started on nitrendipine; median follow-up was 2 years. In the STONE study, which had a mean follow-up of 30 months, elderly Chinese hypertensive pa-
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tients were given nifedipine. Both trials demonstrated significant reductions in the incidence of cardiovascular events. In the elderly population in the present trial, the incidence of adverse events was low. The absence of reported adverse cognitive effects with amlodipine in this study is supported by data suggesting that amlodipine has positive effects on cognitive function,*’ and a recent study found that amlodipine did not affect regional cerebral blood flow in elderly patients, as assessed by single-photon emission computed tomography.** Five elderly patients experienced myocardial infarction during the present study, reflecting the higher cardiovascular morbidity in this age group. One of these patients died; this was the only death possibly related to study treatment. Although the difference in the incidence of adverse events between groups was not statistically significant in the present study, the incidence of adverse events is important from a clinical perspective. In addition to efficacy and tolerability, other issues of importance in choosing any drug for the elderly are compliance and quality of life, and these are particularly pertinent in an asymptomatic condition requiring long-term treatment such as hypertension.‘O Simple dosing schedules are known to enhance compliance, and drugs should be prescribed on a once-daily basis whenever possible. Compliance with amlodipine in this study was excellent, with >90% of patients taking 275% of their trial medication, reflecting both the tolerability and convenience of amlodipine therapy. CONCLUSIONS This study confirms the efficacy and tolerability of amlodipine in the treatment of
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mild to moderate essential hypertension in general practice. Once-daily amlodipine, alone or with adjunctive antihypertensive therapy, was as effective in elderly patients (265 years of age) as in younger patients, despite the use of lower mean daily doses in the elderly. It should be noted, however, that the study protocol excluded patients with a range of conditions that may sometimes exist in an elderly population. The results of the present study thus cannot be extrapolated to excluded patients. In addition to confirming the effectiveness of amlodipine, this study also demonstrated a low frequency of adverse events, a high degree of tolerability, and improved well-being. Morning rather than evening dosing appeared to confer a slight advantage.
ACKNOWLEDGMENT This study was sponsored by Pfizer Ltd, Sandwich, Kent, United Kingdom. Address correspondence to: Christopher Langdon, MB, BS, The Holyport Surgery, Stroud Farm Road, Holyport, Maidenhead, Berks, SL6 2LH, United Kingdom. REFERENCES Lever AF, Ramsay LE. Treatment of hypertension in the elderly. J Hypertens. 1995;13:571-579. Ford GA, Asghar MN. Management of hypertension in the elderly: Attitudes of general practitioners and hospital physicians. Br J Clin Pharmacol. 1995;39:465-469. Ramsay L, Williams B, Johnston G, et al. Guidelines for management of hypertension: Report of the Third Working Party of the British Hypertension Society. J Hum Hypertens. 1999; 13:569-592.
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13. National Heart Foundation of Australia. Treatment of mild hypertension in the elderly. &led .i Amt. 198 1;2:398402. 14. DahlGf B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lmcet. 1991;338: 1281-1285. 15. Medical Research Council Working Party. Stroke and coronary heart disease in mild hypertension: Risk factors and the value of treatment. BMJ (Clin Res Ed). 1988; 296:1X-1570. 16. Vokonas PS, Kannel WB, Cupples LA. Epidemiology and risk of hypertension in the elderly: The Framingham Study. J Hypertens. 1988;6(Suppl 1):3-9. 17. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 199 1;265: 3255-3264.
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18. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757-764. 19. Langdon CG, Packard RS. Doxazosin in hypertension: Results of a general practice study in 4809 patients. Br J Clin Pruct. 1994;48:293-298. 20. Gong L, Zhang W, Zhu V, et al. Shanghai Trial of Nifedipine in the Elderly (STONE). .I Hypertens. 1996;14:1237-1245. 21. Testa MA, Turner RR, Simonson DC, et al. Quality of life and calcium channel blockade with nifedipine GlTS versus amlodipine in hypertensive patients in Spain. Gastrointestinal Therapeutic System. J Hypertens. 1998;16:1839-1847. 22. Pandita-Gunawardena ND, Clarke SE. Amlodipine lowers blood pressure without affecting cerebral blood flow as measured by single photon emission computed tomography in elderly hypertensive subjects. Age Ageing. 1999;28:451-457.