High blood pressure (≥140/90 mm Hg) is a serious public health care problem and a major risk factor for cardiovascular disease and stroke.1–3 The incidence of hypertension increases with age affecting approximately 30%–45% of adults worldwide, and by age 60 approximately two-thirds of the population will develop the disease.4–7 In the Framingham Heart Study, 90% of adults who had normal blood pressure at age 55 years then went on to develop hypertension.3 Current clinical practice guidelines from the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), published in December 2013, advocate general sitting blood pressure goals of 140/90 mm Hg for hypertensive patients younger than 60 years of age and 150/90 mm Hg for patients aged 60 years or older.8
Small changes in blood pressure are known to reduce the risk and mortality from cardiovascular events and stroke.1,2,9,10 Small decreases in blood pressure (10 mm Hg systolic; 5 mm Hg diastolic) are known to lower the risk of stroke and heart failure by up to 50% and myocardial infarction by up to 25%.9,11–14 Furthermore, the risk of mortality associated with stroke and ischemic heart disease has been estimated to double with each 20 mm Hg increase in systolic blood pressure or with each 10 mm Hg in diastolic blood pressure from normotensive readings.2
Recent post hoc analyses have also emphasized the importance of an increased visit-to-visit variability of blood pressure in predicting cardiovascular events. Rothwell et al showed that visit-to-visit blood pressure variability was an independent and strong predictor of cardiovascular events.15,16 To prevent stroke most effectively, blood pressure–lowering drugs should reduce mean blood pressure without increasing variability; ideally, they should reduce both.16
Data from randomized controlled trials suggest that treating hypertension in older patients, including octogenarians, may substantially reduce the risk of cardiovascular disease and death.17 For example, the combined results of 6 major randomized controlled studies in patients aged 60–96 years demonstrated that the treatment of hypertension reduced the incidence of all cardiovascular complications by approximately 30%, fatal coronary events by 26%, and fatal stroke by 33%.18 However, treatment still remains challenging in aging patients because of other comorbidities, age-related changes, and problems with compliance and adherence, particularly in those taking multiple medications.17
Calcium channel blockers, such as amlodipine, are an effective treatment option for hypertension because both the risk of cardiovascular events and all-cause mortality are reduced.19–21 Furthermore, calcium channel blockers may have better efficacy for preventing stroke than other classes of antihypertensive agents,13 including in older and elderly hypertensive patients.22 Much of this advantage may be related to their robust blood pressure–lowering effects9,23 and their beneficial effects on blood pressure variability compared with other antihypertensive classes.16
Calcium channel blockers are recommended in several international clinical guidelines as a first-line treatment for hypertension including patients 55 years or older.1,7,24,25 Furthermore, the recent National Institute of Clinical Excellence (NICE) guidelines recommend calcium channel blockers as the first-line agent of choice in all patients aged 55 years or older or of African descent (Figure 1). Amlodipine has been shown to be an effective well-tolerated antihypertensive agent in older patients,26–28 and its efficacy is not affected by age.26
Despite these well-documented benefits, hypertension remains a public health problem and is still frequently undiagnosed, untreated, or inadequately controlled, particularly among older individuals and the elderly.17,29–32 In a recent large multinational study with 142,000 participants (mean age 50.4 years) conducted in 17 countries, 40.8% had hypertension. Of these, less than half (46.5%) were aware of their diagnosis, with blood pressure being controlled in only 32.5% of those being treated.33
As hypertension is still inadequately controlled in most patients, 2 post hoc pooled analyses of clinical studies using similar methodology were conducted to quantify any incremental benefit achieved when titrating hypertensive patients (including older patients, 55 years or older) from amlodipine 5 to 10 mg daily.
MATERIALS AND METHODS
This was an analysis of the safety and efficacy of amlodipine 5 mg titrated to 10 mg daily in patients with mild or moderate hypertension taken from 2 post hoc pooled analyses. Both analyses pooled data from the same patient groups included in 6 randomized controlled or open-label studies [A0531004, A053R0510, A0531085, A0531086, AML-NY-93-002, A0531044 (Pfizer data on file)] to increase the precision around blood pressure estimates (Table 1). Eligible patients were male and female, aged 18 years or older with mild or moderate hypertension (diastolic blood pressure: ≥95 to ≤120 mm Hg; systolic blood pressure: >140 to <200 mm Hg). The 6 studies included in this analysis enrolled patients who mirrored actual clinical practice. Namely, they were a mixture of treatment-naive patients and those who were uncontrolled on prior antihypertensive medication. All patients remained on stable treatment throughout the study.
The first analysis compared a subgroup of patients aged younger than 55 years with patients aged 55 years or older. The second analysis assessed patients of all age groups (mean age, 58.9 years). Although total study durations varied depending on the design, patients received amlodipine at a dose of 5 mg daily for 4–8 weeks and were then allowed to titrate up to 10 mg daily as required for an additional 4–8 weeks.
The efficacy analysis included all patients in the intent-to-treat (ITT) population who received at least 1 dose of amlodipine and were titrated from 5 to 10 mg daily and had both a baseline (while on 5 mg) and follow-up (4–8 weeks after dose titration) blood pressure measurement. The safety analysis included all patients who received a least 1 dose of amlodipine and were titrated from 5 to 10 mg daily.
Study end points
Efficacy end points were the change from baseline in sitting systolic and sitting diastolic blood pressure and the proportion of patients achieving their sitting blood pressure goal (140/90 mm Hg) at follow-up. Baseline was established before titration, that is, after patients had received amlodipine 5 mg daily for 4–8 weeks. The blood pressure goal was also assessed according to the recently revised JNC 8 guidelines of sitting blood pressure goal for persons aged younger than 60 years in general of 140/90 mg Hg and of 150/90 mm Hg for those aged 60 years or older.8
Safety was assessed by measurement of the frequency of treatment-emergent adverse events, treatment-emergent serious adverse events, and adverse events resulting in withdrawal from treatment.
The efficacy results were analyzed using descriptive statistics, single-sample paired t tests, and corresponding confidence intervals. The usual t-distribution confidence interval was applied to mean values. An exact confidence interval based on the binomial distribution was used for proportions.
Age-related pooled analysis
Of 706 patients included in the age-related patient analysis, 253 (35.8%) were aged younger than 55 years and 453 (64.2%) aged 55 years or older (Table 2). The majority (391; 55.4%) were male, with a mean age of 47.2 years for patients younger than 55 years and 65.5 years for patients aged 55 years or older. Baseline (5 mg) mean systolic blood pressure and diastolic blood pressure were 147.4 [standard error (SE) 0.91] and 95.0 (SE 0.52) mm Hg, respectively, in patients aged younger than 55 years and 151.8 (SE 0.69) and 87.8 (SE 0.48) mm Hg, respectively, in patients aged 55 years or older.
Titration of amlodipine 5 to 10 mg daily resulted in a statistically significant decrease in both systolic blood pressure and diastolic blood pressure for both age subgroups. Amlodipine lowered mean blood pressure by (1) younger than 55 years: −12.8 mm Hg (SE = 0.90) for systolic blood pressure and −8.0 mm Hg (SE = 0.55) for diastolic blood pressure and (2) 55 years or older: −12.1 mm Hg (SE = 0.66) for systolic blood pressure and −6.7 mm Hg (SE = 0.39) for diastolic blood pressure (all P < 0.0001; Figure 2). In total, 45.8% and 39.3% of patients aged younger than 55 and 55 years or older, respectively, achieved their blood pressure goals. Applying the new JNC 8 hypertension guidelines (sitting blood pressure goal for age younger than 60 years is 140/90 mg Hg and for age 60 years or older is 150/90 mm Hg)8 to our data, 51.0% of patients in the group of younger than 55 years and 64.2% of patients in the age group of 55 years or older achieved these blood pressure goals.
A total of 239/253 (94.5%) patients younger than 55 years completed the study and 14 (5.5%) discontinued, similarly 419/453 (92.5%) patients of age 55 years or older completed the study and 34 (7.5%) discontinued. Reasons for discontinuation included adverse events [n = 37 (5.2%)]; withdrawal of consent and other reasons [both n = 4 (0.6%)], protocol violation [n = 2 (0.3%)], and insufficient clinical response [n = 1 (0.15%)].
In total, 62 (24.5%) patients aged younger than 55 years experienced 96 adverse events, of which, system organ class general disorders (7.1%), infections (6.3%), gastrointestinal disorders (4.7%), and musculoskeletal disorders (4.3%) were the most common; 9 patients (3.6%) discontinued treatment due to an adverse event (Table 3), with peripheral edema being the reason for withdrawal in 2 or more patients. In all, 136 (30.0%) patients aged 55 years or older experienced 217 adverse events, of which general disorders (10.4%), infections (8.6%), gastrointestinal disorders (4.6%), and musculoskeletal disorders (4.2%) were most common; 14 patients (3.1%) discontinued treatment due to an adverse event (Table 3), with peripheral edema, chest pain, joint swelling, headache, hypoesthesia, and dyspnea all resulting in the discontinuation of treatment in 2 or more patients.
All patients pooled analysis
Given that results were consistent between the 2 age subgroups, data were also pooled to increase the level of precision for the end points. A total of 710 patients (includes 4 additional patients of unspecified age) were included in the ITT analysis (Table 2). The majority were male [394/710 (55.6%)] with a mean age of 58.9 (SD = 10.9) years. At baseline (5 mg), mean systolic blood pressure was 150.3 (SE = 0.56) mm Hg and diastolic blood pressure was 90.4 (SE = 0.38) mm Hg.
Titration of amlodipine from 5 to 10 mg daily in patients not responding to treatment with the 5 mg dose resulted in a statistically significant decrease in blood pressure: systolic blood pressure by −12.4 mm Hg (SE = 0.53) and diastolic blood pressure by −7.2 mm Hg (SE = 0.32) (both P < 0.0001; Figure 3). Overall, 295/710 (41.5%) patients achieved their blood pressure goal. Using the new JNC 8 hypertension guidelines (sitting blood pressure goal for age younger than 60 years is 140/90 mg Hg and for age 60 years or older is 150/90 mm Hg), 59.4% of patients younger than 55 years achieved their blood pressure goals.
A total of 662 (93.2%) patients completed the study and 48 (6.8%) discontinued. Reasons for discontinuation included adverse events [n = 37 (5.2%)] and withdrawal of consent and other reasons [both n = 4 (0.6%)].
In total, 313 adverse events were reported by 198/710 (27.9%) patients (Table 3). The most common adverse events were general disorders [n = 65 (9.2%)], infections [n = 55 (7.7%)], gastrointestinal disorders [n = 33 (4.6%)], and musculoskeletal disorders [n = 30 (4.2%)]. Serious adverse events were reported by 6 (0.6%) patients. Twenty-three (3.2%) patients discontinued treatment due to an adverse event with chest pain, joint swelling, peripheral edema, headache, hypoesthesia, and dyspnea all resulting in the discontinuation of treatment in 2 or more patients.
Hypertension remains a public health concern, despite numerous outcome trials demonstrating the benefits of blood pressure lowering among older individuals with hypertension; high blood pressure is more prevalent, less well controlled, and more severe in this patient population.4 Compared with younger patients with similar blood pressure, older and elderly hypertensive patients have lower cardiac output, higher peripheral resistance, wider pulse pressure, lower intravascular volume, and lower renal blood flow.34 They are also more likely than younger patients to suffer from the complications of hypertension (such as stroke and myocardial infarction) and have multiple comorbidities.17 Older patients are also more prone to have resistant hypertension and thus require multiple drugs to control their blood pressure, with many drug-related adverse effects.17 All these factors should be considered when treating older patients with hypertension.
Many outcome trials in older and elderly patients have been based on the use of thiazide diuretics or β-blockers. These agents may aggravate coexisting diseases, such as hyponatremia, peripheral vascular disease, insulin sensitivity, and weight gain, and are often unsuitable for older and elderly patients.20,35 Short-term studies have shown that calcium channel blockers seem to be most effective in reducing cardiovascular disease outcomes in older hypertensive patients.36 They have the following advantages as antihypertensive agents: maintenance of cerebral, coronary, renal, and peripheral circulations at good levels despite showing a secure antihypertensive effect and an absence of adverse effects on glucose and lipid metabolism.
Calcium channel blockers have performed particularly well in preventing stroke in older hypertensive patients, which is of major interest for both patients and their physicians. A recent meta-analysis found that dihydropyridine calcium channel blockers reduced stroke by 10% compared with other active therapies.22 Much of this advantage may be related to their strong blood pressure–lowering effects, which were evident in both the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) and Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trials, where 4–5 lower brachial artery systolic blood pressure levels were noted in the first few months of therapy compared with angiotensin receptor antagonists or β-blocker-based treatment.9,23
Amlodipine has been shown to be an effective antihypertensive agent in older patients and the elderly.27 Indeed, in a recent large community-based study in the US, amlodipine was actually more effective in elderly patients compared with those aged younger than 65 years.26 Tolerability has been shown to be good or excellent in most patients20,37 and, because amlodipine is slowly absorbed, the tendency for vasodilatory side effects is reduced. It also has low hepatic metabolism (including first-pass metabolism) and a long elimination half-life, which allows effective blood pressure control with once-daily dosing, an important promoter of compliance,38 particularly in older patients who are likely to be taking several medications. In contrast to short-acting calcium channel blockers, trial data suggest that amlodipine may be used in hypertensive patients with concomitant heart failure.39 Available data also suggest a greater capability of calcium channel blockers, such as amlodipine, in comparison to other therapeutic classes to attenuate long- and short-term blood pressure variability.16,40
These 2 post hoc analyses showed that titration of amlodipine from 5 mg to 10 mg daily significantly (P < 0.0001) decreased systolic and diastolic blood pressure in younger and older age groups whose blood pressure did not reach target levels. This incremental change in systolic blood pressure of approximately 12 mm Hg is vital in reducing the potential occurrence of future cardiovascular and cerebrovascular events. Just by titrating the amlodipine dose to 10 mg, blood pressure goals were achieved in approximately 40% of patients aged younger than 55 years or 55 years or older. Amlodipine 10 mg was well tolerated in both analyses with a low incidence of adverse events. Peripheral edema occurred in approximately 7.1% of patients overall, consistent with previous findings.41
The present analysis is subject to several limitations. First, it was a post hoc analysis pooled from 6 studies with differing designs (randomized controlled and open-label), in which there were large differences in sample sizes. When the studies vary in size, the larger studies can have a greater influence on the pooled results. Three of the trials included (accounting for 342 of the 706 participants in the analysis) were open-label and could be subject to types of bias commonly associated with such designs. Finally, it should be noted that the trials used in this analysis may have had differences in characteristics of participants (ie, receiving monotherapy or combination therapy—although any background therapy was kept constant during the assessment period, treated blood pressure or treatment naive, comorbidities, etc.).
These results are similar to another post hoc analysis, where the titration of amlodipine from 5 to 10 mg daily significantly decreased both systolic blood pressure and diastolic blood pressure in Asian patients with mild-to-moderate hypertension.42 Amlodipine 10 mg lowered systolic blood pressure by −13.3 mm Hg (95% CI: −15.5 to −11.0) and diastolic blood pressure by −9.2 mm Hg (95% CI: −10.6 to −7.8) at the final visit (P < 0.0001 for both).
The results also support those of large-scale clinical studies in patients with hypertension where amlodipine uptitrated to 10 mg once daily controlled blood pressure and suppressed cardiovascular events.9,23,43–45 The wealth of studies reporting not only the dangers of sustained hypertension in older patients on the risk of cardiovascular events but also the benefits of uptitration to amlodipine 10 mg in reducing elevated blood pressure highlights the importance of encouraging this strategy in prescribing patterns.
Increasing amlodipine from 5 to 10 mg could also provide an alternative to initiate combination therapy, especially in patients with very high blood pressure and those at greater cardiovascular risk. Indeed, recent guidelines, such as NICE, still advocate the use of monotherapy with a calcium channel blocker in the older patient population (55 years or older) before initiating combination therapy.25 Our results showed that not only will this result in clinically meaningful incremental blood pressure lowering but that a significant portion of the patents will also achieve their blood pressure targets.
Titration of amlodipine from 5 to 10 mg once daily significantly decreased both systolic blood pressure and diastolic blood pressure in patients with hypertension across both age subgroups (younger than 55 years vs. 55 years or older). Blood pressure goals were achieved safely in ∼40% of patients. This is clinically relevant as advancing age is associated with hypertension and an increased risk of nonfatal and fatal cardiovascular events and stroke.
1. Chobanian AV, Bakris GL, Black HR, et al.. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
: the JNC 7 report. JAMA. 2003;289:2560–2572.
2. Lewington S, Clarke R, Qizilbash N, et al.. Age
-specific relevance of usual blood pressure
to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
3. Vasan RS, Larson MG, Leip EP, et al.. Impact of high-normal blood pressure
on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291–1297.
4. Lloyd-Jones DM, Evans JC, Levy D. Hypertension
in adults across the age
spectrum: current outcomes and control in the community. JAMA. 2005;294:466–472.
5. Vasan RS, Beiser A, Seshadri S, et al.. Residual lifetime risk for developing hypertension
in middle-aged women and men: the Framingham Heart Study. JAMA. 2002;287:1003–1010.
6. Wang H, Zhang X, Zhang J, et al.. Factors associated with prevalence, awareness, treatment and control of hypertension
among adults in Southern China: a community-based, cross-sectional survey. PLoS One. 2013;8:e62469.
7. Mancia G, Fagard R, Narkiewicz K, et al.. 2013 ESH/ESC Guidelines for the management of arterial hypertension
: the Task Force for the management of arterial hypertension
of the European Society of Hypertension
(ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281–1357.
8. James PA, Oparil S, Carter BL, et al.. 2014 evidence-based guideline for the management of high blood pressure
in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520.
9. Dahlof B, Sever PS, Poulter NR, et al.. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine
adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure
Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895–906.
10. Ogihara T, Kikuchi K, Matsuoka H, et al.. The Japanese Society of Hypertension
Guidelines for the Management of Hypertension
(JSH 2009). Hypertens Res. 2009;32:3–107.
11. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure
Lowering Treatment Trialists' Collaboration. Lancet. 2000;356:1955–1964.
12. Chobanian AV, Bakris GL, Black HR, et al.. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
13. Law MR, Morris JK, Wald NJ. Use of blood pressure
lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
14. Ogihara T, Nakao K, Fukui T, et al.. Effects of candesartan compared with amlodipine
in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension
15. Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension
. Lancet. 2010;375:938–948.
16. Rothwell PM, Howard SC, Dolan E, et al.. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure
and risk of stroke. Lancet Neurol. 2010;9:469–480.
17. Chaudhry KN, Chavez P, Gasowski J, et al.. Hypertension
in the elderly: some practical considerations. Cleve Clin J Med. 2012;79:694–704.
18. Lever AF, Ramsay LE. Treatment of hypertension
in the elderly. J Hypertens. 1995;13:571–579.
19. Costanzo P, Perrone-Filardi P, Petretta M, et al.. Calcium channel blockers and cardiovascular outcomes: a meta-analysis of 175,634 patients. J Hypertens. 2009;27:1136–1151.
20. Cross BW, Kirby MG, Miller S, et al.. A multicentre study of the safety and efficacy of amlodipine
in mild to moderate hypertension
. Br J Clin Pract. 1993;47:237–240.
21. Takagi H, Umemoto T. Revisiting evidence of blood pressure
-dependent and independent effects of amlodipine
on the risk of stroke. J Clin Hypertens (Greenwich). 2011;13:781–782.
22. Angeli F, Verdecchia P, Reboldi GP, et al.. Calcium channel blockade to prevent stroke in hypertension
: a meta-analysis of 13 studies with 103,793 subjects. Am J Hypertens. 2004;17:817–822.
23. Julius S, Kjeldsen SE, Weber M, et al.. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine
: the VALUE randomised trial. Lancet. 2004;363:2022–2031.
24. Daskalopoulou SS, Khan NA, Quinn RR, et al.. The 2012 Canadian hypertension
education program recommendations for the management of hypertension
: blood pressure
measurement, diagnosis, assessment of risk, and therapy. Can J Cardiol. 2012;28:270–287.
25. National Clinical Guideline Centre. Hypertension
: The clinical management of primary hypertension
in adults. Clinical Guideline 127. Methods, evidence, and recommendations. Commissioned by the National Institute for Health and Clinical Excellence. 2011. Available at: http://www.nice.org.uk/guidance/cg127/resources/cg127-hypertension-full-guideline3
. Accessed February 26, 2014.
26. Kloner RA, Sowers JR, DiBona GF, et al.. Sex- and age
-related antihypertensive effects of amlodipine
. The amlodipine
cardiovascular community trial study group. Am J Cardiol. 1996;77:713–722.
27. Abernethy DR, Gutkowska J, Lambert MD. Amlodipine
in elderly hypertensive patients: pharmacokinetics and pharmacodynamics. J Cardiovasc Pharmacol. 1988;12(Suppl) 7:S67–S71.
28. Payeras AC, Sladek K, Lembo G, et al.. Antihypertensive efficacy and safety of manidipine versus amlodipine
in elderly subjects with isolated systolic hypertension
: MAISH study. Clin Drug Investig. 2007;27:623–632.
29. Duggan S, Aylett MJ, Eccles M, et al.. Defining hypertension
in older people from primary care case notes review. J Hum Hypertens. 1997;11:193–199.
30. 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.
31. Kendall MJ. Hypertension
in the elderly. Basic Res Cardiol. 1998;93(Suppl 2):43–46.
32. Ooi HH, Coleman PL, Duggan J, et al.. Treatment of hypertension
in the elderly. Curr Opin Nephrol Hypertens. 1997;6:504–509.
33. Chow CK, Teo KK, Rangarajan S, et al.. Prevalence, awareness, treatment, and control of hypertension
in rural and urban communities in high-, middle-, and low-income countries. JAMA. 2013;310:959–968.
34. Messerli FH, Sundgaard-Riise K, Ventura HO, et al.. Essential hypertension
in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet. 1983;2:983–986.
35. Ramsay LE, Williams B, Johnston GD, et al.. British Hypertension
Society guidelines for hypertension
management 1999: summary. BMJ. 1999;319:630–635.
36. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419.
37. Varrone J. A study of the efficacy and safety of amlodipine
for the treatment of hypertension
in general practice. Postgrad Med J. 1991;67(Suppl 5):S28–S31.
38. Bittar N. Maintaining long-term control of blood pressure
: the role of improved compliance. Clin Cardiol. 1995;18(6 Suppl 3):III12–III16.
39. Elkayam U. Calcium channel blockers in heart failure. Cardiology. 1998;89(Suppl 1):38–46.
40. Hocht C, Bertera FM, Taira CA. Importance of blood pressure variability
in the assessment of cardiovascular risk and benefits of antihypertensive therapy. Expert Rev Clin Pharmacol. 2010;3:617–621.
41. Weir MR. Incidence of pedal edema formation with dihydropyridine calcium channel blockers: issues and practical significance. J Clin Hypertens (Greenwich). 2003;5:330–335.
42. Kario K, Robbins J, Jeffers BW. Titration of amlodipine
to higher doses: a comparison of Asian and Western experience. Vasc Health Risk Manag. 2013;9:695–701.
43. ALLHAT. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.
44. Omvik P, Thaulow E, Herland OB, et al.. 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.
45. Fujiwara T, Ii Y, Hatsuzawa J, et al.. The Phase III, double-blind, parallel-group controlled study of amlodipine
10 mg once daily in Japanese patients with essential hypertension
who insufficiently responded to amlodipine
5 mg once daily. J Hum Hypertens. 2009;23:521–529.