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Original ORIGINAL Article ARTICLE Korean Circulation J 2005;35:854-859 ISSN 1738-5520 c 2005, The Korean Society of Circulation 고혈압환자에서 Lercanidipine 과 Indapamide 의부가효과에대한무작위교차연구 (Ramdomized Crossover Study) 한림대학교의과대학한강성심병원심장내과학교실, 1 울산대학교의과대학서울아산병원심장내과학교실 2 김민규 1 박우정 1 박종훈 2 A Randomized Crossover Study of the Additive Effect of Lercanidipine and Indapamide in Patients with the Mild to Moderate Hypertension Min-Kyu Kim, MD 1, Woo-Jung Park, MD 1 and Chong-Hun Park, MD, PhD 2 1 Division of Cardiology, Department of Internal Medicine, Hangang Sacred Heart Hospital, University of Hallym, Seoul, 2 Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea ASTRACT ackground and Objectives:There is evidence available from randomized control trials about the additive effects of combination regimens that are mainly based on diuretics and β-blockers or ACE inhibitors. Yet there are some arguments about the effect of the combination of calcium channel blockers (CCs) and diuretics. We aimed to study the blood pressure-lowering effects of lercanidipine, indapamide or a combination therapy on the home blood pressure (HP) and the 24-hour ambulatory blood pressure (AP), and we wanted to examine the agreement with using these two methods. Subjects and Methods:70 patients participated in this randomized open crossover design study. The treatments in each phase were 10 mg lercanidipine (L) and 1 mg indapamide (I), separately and also in combination (L+I). Each patient had their HP checked twice during each phase and the 24h AP was checked in two of the 3 phases. We also measured the agreement between the HP and AP by using a land-altman plot. Results:58 patients (mean age: 49±9 (31-71) years; 37 males and 21 females) completed the study. The blood pressure was significantly reduced during all the active treatments compared with the baseline (L: 160.2±12/.3±9 mmhg, I; 130.5±9.3/86.0±8.1 mmhg, 129.2±12.9/83.9±11.1 mmhg, L+I:124.9±10.9/81.3±8.5 mmhg, p<.000) and the P for the combination therapy was also significantly less than those Ps for both the other monotherapies (L+I vs. L: p<.002, L+I vs. I: p<.01) by measuring the 24h AP. The land-altman plot showed±25 mmhg for the limit of agreement between both measurement methods. Conclusion:CC and diuretics were effective agents for treating hypertensive patients. As a combination therapy, the effects on blood pressure are additive. Poor agreement of the blood pressures with using the two measurement methods was observed. (Korean Circulation J 2005;35:854-859) KEY WORDS:Hypertension;Ambulatory blood pressure monitoring;calcium channel blockers;diuretics, and drug effects. 서 고혈압치료의목적은고혈압으로인한심혈관계의합병 론 증을예방하여삶의질 (QOL) 을높이는데있다. 칼슘채널차단제는지난 20여년동안고혈압, 허혈성심질환, 부정맥및이완기심부전등의심장혈관질환에쓰여왔다. 이전 논문접수일 :2005 년 17월 6일수정논문접수일 :2005 년 8월 24 일심사완료일 :2005 년 10 월 6일교신저자 : 박종훈, 138-736 서울송파구풍납동 388-1 울산대학교의과대학서울아산병원심장내과학교실전화 :(02) 3010-3156 전송 :(02) 486-5918 E-mail:chpark@amc.seoul.kr 854

Min-Kyu Kim, et al:additive Effect of Lercanidipine and Indapamide Combination Therapy 855 의몇몇임상시험에서이뇨제와베타차단제또는안지오텐신전환효소차단제가병용투여되었을때, 단독투여시보다뛰어난강압효과가나타냄을보였다. 그러나 dihydropyridine 계칼슘채널차단제와이뇨제의병용투여시그강압효과의부가성에대해의견이분분하다. 1-6) 본연구는경증및중등증의본태성고혈압환자에대해칼슘채널차단제인 lercanidipine 과이뇨제인 indapamide 을각각단독투여및병용투여시그유용성및부가효가유무를알아보고자하였다. 대상및방법 대상처음외래방문시측정한안정시수축기혈압평균이 140~ 180 mmhg 이거나확장기혈압평균이 90~110 mmhg 인 18~74 세의본태성고혈압환자를대상으로하였다. 중증고혈압, 이차성고혈압, 기립성저혈압, 조절되지않는심부전, 대동맥판막증등의좌심실유출로폐쇄질환, 불안정협심증, 당뇨병이나다른동반질환등이있거나, 최근 1개월이내에심근경색증이나뇌졸증의과거력이있거나, 또는임상시험약투여개시전 1주일이내에항고혈압약물을투약한경우는연구에서제외하였다. 방법무작위교차연구 (randomized open crossover study) 로 4주씩의 3개의기 (phase) 로구성되어있으며, 각기는 lercanidipine 10 mg 단독투여군 (L), indapamide 1 mg 단독투여군 (I), 그리고병용투여군 (L+I) 으로구성되어있다. 대상환자는첫기에는단독약물투여나병용약물투여군에무작위로배정하고, 4주후에단독약물투여군은처음과다른단독약물을투약받거나병용투여를받고, 병용투여군은단독약물을투여받게된다. 시험 8주후에는처음두기에단독약물투여를받은환자는병용약물투약을, 단독약물투약및병용약물투약을받은환자는이전에받지않은단독약물을투약받도록하였다 (Fig. 1). 본연구에서는항고혈압약제의유용성을평가하기위하여 24시간활동혈압감시 7) 와가정혈압측정을시행하였다. 각환자에서시험약물투약후 2주와 4주째에가정혈압을, 투약 4주째에 24시간활동혈압을측정하였다. 가정혈압은손목형전자혈압계 R4(Omron, Japan) 을이용하여 1일 4회- 아침기상직후 ( 임상시험약복용전 ), 복용 4시간후, 복용 10시간후및취침전-측정하여기록하였다. 혈압측정일에흡연이나카페인은섭취하지않도록하면서, 적어도 5분이상앉은자세에서안정을취한후 2분간격으로 2회측정하여그평균치를구하고, 연속측정한혈압치의차이가 5 mmhg 이상일경우연속측정한혈압치가안정될때까지반복측정한다. 24시간활동혈압측정은 spacelabs-90217(spacelabs medical Inc. UK) 를이용하여연구기간중총 2회 ( 단독투여시 1회, 병용투여시 1회 ) 측정하였다. 측정방법은오전 6시에서오후 10시사이의주간혈압은 15분마다측정하고오후 10시부터오전 6시까지의야간혈압은 20분간격으로측정하도록하였으며, 약물투여직전오전 8시에서 10시사이에활동혈압계를부착하고 24시간후제거하였다. 투약은환자의기상시간에따라오전 8시에서 10시사이에이루어지도록교육하였다. 결과분석 24시간활동혈압분석은기존에사용하는표준지표들을기준으로하였다. 8) 자료는평균 ± 표준편차로표시하고, 통계분석은 SPSS 11.0 package 를사용하여분석하였다. 각각의요법에대한혈압변화는 paired t-test 를사용하였고, p<0.05 미만을유의수준으로하였다. 가정혈압과 24시간활동혈압측정의일치도를확인하기위하여 land-altman plot 를이용하였다. 9) 강압효과판정은투여 4주째측정한가정혈압의차이를기초로수축기및확장기혈압각각에대하여판정하고, 양자에대한판정이일치하지않을때는평균혈압으로판정하였다. 하강기준에일치하지않으나혈압이 140/90 mmhg 미만으로하강한경우에도하강으로판정하였다 (Table 1). 결과 0 week Screening test 등록된 70명중동의철회나외래추적이불가했던 12명을제외하고 58명 (83%) 이실험을완료하였으며, 소수에서 Lercanidipine 10 mg Indapamide 1 mg Combination lercanidipine 사용시하지부종을호소하였으나중대한부 4 week 작용은없었다. 각약물투약기별기저특징 (baseline cha- Combination Indapamide 1 mg Lercanidipine 10 mg 8 week Lercanidipine 10 mg Combination Indapamide 1 mg Fig. 1. Study protocol. Table 1. Criteria of blood pressure reduction P Reduced Reducing pattern No change Elevated Systolic -20-19~-10 ±9 10 Diastolic -10 0-9~0-5 ±4 05 Mean -13-12~0-7 ±6 07 P: blood pressure

856 Korean Circulation J 2005;35:854-859 racteristics) 은차이가없었다 (Table 2). 24시간활동혈압변화 Lercanidipine, indapamide 단독투여시측정한활동혈압의다양한지표들에있어양군간의차이는없었다 (24 hour mean P130.5±9.3/86.0±8.1 vs. 129.2±12.9/83.9±11.1, p=ns, awake P 133.7±10.5/88.7±8.6 vs. 133.0±13.4/ 86.2±13.4, p=ns, sleep P 121.1±10.1/79.5±7.6 vs. 119.0±13.6/76.8±10.9, p=ns). 그러나병용투여시측정한활동혈압은단독투여군과비교하여 24시간평균혈압 (L vs. L+I, 130.5±9.3/86.0±8 vs. 124.9±10.9/81.3 ±8.5, p<.001, I vs. L+I, 129.2±12.9/83.9±11.1 vs. 124.9±10.9/81.3±8.5, p<.05) 및주간혈압 (L vs. L+I, 133.7±10.5/88.7±8.6 vs. 128.0±11.9/83.2±9.7, p<.001, I vs. L+I, 133.0±13.4/86.2±13.4 vs. 128.0±11.9/83.2 ±9.7, p<.001) 에있어의미있는감소를보였으며, 야간혈압은 lercanidipine 단독투여군에비하여의미있게감소하였다 (L vs. L+I, 121.1±10.1/79.5±7.6 vs. 116.6±11.4/ 74.9±8.8, p<.05, I vs. L+I 119.0±13.6/76.8±10.9 vs. 116.6±11.4/74.9±8.8, p=ns)(table 3). 단독및병용투여시의시간대별혈압변화는 Fig. 2와같다. 가정혈압변화단독투여및병용투여시각각에서 2주째와 4주째의수 Table 2. aseline characteristics L+I phase L phase I phase Age (yr) 48.5±8.3 46.5±6.9 49.9±9.0 Sex (M: F) 37:21 18:10 17:16 Duration (Mon) 042.5±62.0 035.0±50.3 37.2±51.3 Clinical SP 160.2±12.2 161.8±13.3 157.8±12.1 Clinical DP.3±8.90 102.6±8.90 97.5±8.5 Clinical HR (bpm) 67.4±7.1 66.7±6.4 68.2±7.4 MI (kg/m 2 ) 24.6±2.2 24.3±2.5 25.0±1.8 SP: systolic blood pressure, DP: diastolic blood pressure, HR: heart rate, MI: body mass index, L: lercanidipine, I: indapamide 축기및이완기가정혈압평균은차이는없었다 (L: 132.5 ±12.8/86.7±10.8 mmhg vs. 131.3±11.9/86.4±9.1 mmhg, p=ns, I: 133.4±11.6/88.5±8.4 mmhg vs. 131.9±12.0/ 88.1±9.4 mmhg, p=ns, L+I: 132.0±10.9/87.6±8.7 mmhg vs. 129.8±12.6/86.4±10.2 mmhg, p=ns)(fig. 3). 단지 lercanidipine 단독투여군과 indapamide 단독투여군의이완기혈압의차이 (2주째이완기혈압, 85.5±10.5 mmhg vs. 88.6±8.9 mmhg, p=.007, 평균이완기혈압 85.7±9.5 mmhg vs. 88.0±8.7 mmhg, p=.008) 를제외한각용법들간의평균혈압에차이는없었다. 각시간별혈압의변화는 24시간활동혈압의변화양상과비슷하나, 병용투여및 lercanidipine 투약후 4시간째혈압의감소가 indapamide 투약시에비하여의미있게감소하였다 (L+I vs. I; SP 129.0±10.1 mmhg vs. 133.6±12.7 mmhg, p=.008, DP 85.6±8.7 mmhg vs. 89.0±9.3 mmhg, p=.004, L vs. I; SP 130.2±13.3 mmhg vs. 133.5±12.5 mmhg, p=.156, DP 85.0±9.9 mmhg vs. 88.8±9.4 mmhg, p=.009)(fig. 4). 강압효과단독투여나병용투여시대상환자의 70% 이상에서강압효과가있었으며, 각군간에의미있는차이는없었다 (Table 4). 24시간활동혈압과가정혈압의일치도 (land-altman plot) 비슷한시간대의활동혈압과가정혈압측정치는단독투여나병용투여시모두에서수축기및이완기혈압모두에서두측정치의평균에대한차이의분포가 ±25 mmhg 정도의넓은분포를보인다 (Fig. 5). 고찰 JNC-7 보고서의주요결론중하나는고혈압환자중 2/3 이상은하나의항고혈압약물로혈압을조절할수없 Table 3. 24 hour ambulatory blood pressure monitoring L phase p1 I phase p2 L+I phase p3 24H mean SP 130.5±9.300 0.655 129.2±12.90 0.001 124.9±10.90 0.000 DP 86.0±8.10 0.392 83.9±11.1 0.016 81.3±8.50 0.002 Awake SP 133.7±10.50 0.852 133.0±13.40 0.001 128.0±11.90 0.001 DP 88.7±8.60 0.334 86.2±13.4 0.004 83.2±9.70 0.004 Sleep SP 121.1±10.10 0.491 119.0±13.60 0.061 116.6±11.40 0.005 DP 79.5±7.60 0.264 76.8±10.9 0.157 74.9±8.80 0.018 Lowest night SP 112.0±10.70 0.757 113.0±14.30 0.007 109.2±11.30 0.158 DP 72.4±7.80 0.911 72.1±11.0 0.091 69.5±10.0 0.102 Morning SP 130.9±10.60 0.279 127.5±12.80 0.865 128.5±13.40 0.843 DP 88.6±9.90 0.078 82.7±13.9 0.901 84.0±11.9 0.272 Morning surge 19.3±12.3 0.118 15.5±16.0 0.725 19.4±11.0 0.289 SP: systolic blood pressure, DP: diastolic blood pressure, L: lercanidipine phase, I: indapamide phase, L+I: combination phase, p1: p value between L phase and I phase, p2: p value between I phase and L+I phase, p3: p value between L phase and L+I phase

Min-Kyu Kim, et al:additive Effect of Lercanidipine and Indapamide Combination Therapy 857 150 A 140 90 130 80 120 110 70 60 7 9 13 15 17 19 21 23 1 3 5 (hour) 11 50 7 9 11 13 15 17 19 21 23 1 3 5 (hour) Fig. 2. Average hourly systolic and diastolic mean blood pressure. A: systolic blood pressure. : diastolic blood pressure. Lercanidipine Indapamide Combination Clinic 180 160 140 120 80 60 40 20 0 A 2 Weeks 4 Weeks Mean 105 95 90 85 80 75 Lercanidipine Indapamide Combination Clinic * * 2 Weeks 4 Weeks Mean Fig. 3. Weekly mean home blood pressure change. A: systolic blood pressure. : diastolic blood pressure. There were no significant differences in the systolic and diastolic home blood pressures at the 2 weeks or 4 weeks after medications. ut compared with clinic blood pressure, monoor combination therapies reduce systolic or diastolic blood pressure significantly. There were no significant differences in each therapy except a diastolic pressure between lercanidipine and indapamide therapy at 2 weeks after medication and mean diastolic pressure (p=0.008). 136 A 90 135 134 133 132 p=.008 89 88 87 p=.004 p=.009 131 86 130 85 129 128 127 84 83 126 PRE 4H after 10H after Pre-sleep 82 PRE 4H after 10H after Pre-sleep Fig. 4. Daily home blood pressure change. A: systolic blood pressure. : diastolic blood pressure. There is a significant blood pressure difference between indapamide phase and combination phase 4 hours after medication. Also a diastolic blood pressure difference between lercanidipine phase and indapamide phase is significant. 고, 서로다른계열의두개이상의약물의병용이요구된다는것이다. 그래서제 2기고혈압의경우처음부터 thiazide 계이뇨제를바탕으로한병용요법을추천하였다. 10) 그러나최근까지국내에서항고혈압약제의단독투여시효과에대한보고는있으나, 11)12) 병용투여시의감압효과에대한보고가드물고, 감압효과판정에가정혈압측정이나 24시간활동혈압을이용한경우는더욱드문형편이다. 본연구는경증및중등증의고혈압환자를대상으로칼슘채널차단제인 lercanidipine 과이뇨제인 indapamide 의단독투여시, 의미있게혈압이감소하였고, 24시간활동혈압검사를통하여약물을병용투여시부가적인혈압강하효과가있음을확인하였다.

858 Korean Circulation J 2005;35:854-859 일반적으로혈압측정방법인수은혈압계등을이용한일회성혈압측정은의사의면담이나환자의활동상태등에따라변동이큰것으로알려져있다. 그러나 24시간활동혈압측정은지속적이고연속적인혈압측정이가능하여환자의혈압상태를보다면밀하게관찰할수있다는장점이있다. 13-15) 또한이런혈압수치가좌심실비대, 고혈압성뇌혈관질환, 신장질환, 망막병증및혈관탄력성의변화와보다연관되어있다고보고되고있다. 16) 김등 17) 의연구결과와비슷하게, 본연구에서 24 시간활동혈압자료를보면, 수면시가장낮은혈압 (lowest night blood pressure) 이나기상시혈압상승 (morning surge) 등에차이가없이각각의약물이 24시간지속적으로혈압강하의효과가있다고판단된다. 그러나야간혈압에있어 lercanidipine 이나 indapamide 단독요법에서차이가없으나, lercanidipine 단독요법에비해병용요법에서의미있게낮은야간혈압은 indapamide 와 lercanidipine 의강압효과의부가효과에기인한다고생각된다. 가정혈압측정은 24시간활동혈압측정과같이반복측정이가능하여백의성효과 (whitecoat effect) 등에의한혈압변동요소등을배제하고, 항고혈압약제에대한반응을평가할수있으며, 환자들의순응도를높이는좋은방법이 Table 4. Response rate of blood pressure reduction Reduced Reducing pattern No change L phase 42(72.5%) 7(11.8%) 9(15.7%) I phase 41(70.4%) 6(11.1%) 11(18.5%) L+I phase 46(78.9%) 8(14.0%) 4(7.0%) L: lercanidipine phase, I: indapamide phase 다. 본연구에서는가정혈압은 24시간활동혈압과같이하루내내지속적으로혈압이조절되고있음을확인할수있었다. 또한 indapamide 에비해 lercanidipine 이투약 4시간후특히혈압강하가큰것을관찰할수있었다. 이것은 lercanidipine 의약물역동학과연관되어있어투약초기혈압강하효과가크고이후지속적인강압효과를보인다. 18) Staessen 등 19) 에의한 THOP 연구에서혈압조절에외래에서측정한혈압대신보완적으로가정혈압이나낮시간활동혈압의대용으로사용가능하다고하였다. 본연구는병원밖에서측정되는가정혈압과 24시간활동혈압의일치도를확인하기위해서 land-altman plot 를이용하였다. 기존의검사방법과비교하여새로운검사방법이얼마나정확하게측정하는확인하는방법으로두검사방법간의평균값에대한두검사방법간의차이의분포를보는것으로, 차이의평균분포 (mean±2sd) 가작을수록일치하여새로운검사방법이기존의방법을대치할수있다고할수있다. 그림 5는낮시간양방법간의수축기및이완기혈압의차이의평균분포가 ±25 mmhg 정도관찰되는것을볼수있어대용으로사용이불가함을보여주는것이다. 이것은측정방법에문제일가능성이있다. 우선 24시간활동혈압은평일일상생활시에측정하였고, 가정혈압은하루 4회측정으로집에서휴식하는일요일에측정하게함으로써값의차이를유발하였을수있다. 또한 24시간활동혈압측정시, 처음부착시양방법으로혈압을측정하여값을보정하여야하나이를시행하지않은것등이이런결과를가져왔다고생각된다. 40.00 Difference (AMP-Hone P) SYSTOLIC P 20.00 0.00-20.00-40.00-60.00 Mean+2SD=28.7 Mean=-0.35 Mean -2SD=-29.4 Difference (AMP-Hone P) in DIASTOLIC P 40.00 20.00 0.00-20.00 Mean+2SD=24.3 Mean=0.02 Mean-2SD=-23.9.00 110.00 120.00 130.00 140.00 150.00 160.00 170.00 A Average (APM+Home P) SYSTOLIC P.00 110.00 120.00 130.00 140.00 150.00 160.00 Average (AMP+Hone P) DIASTOLIC P Fig. 5. land-altman plot. A: systolic blood pressure. : diastolic blood pressure. This is a land-altman plot 4 hours after medication. A X- axis is a mean pressure of ambulatory P and home P. A Y-axis is a pressure difference between ambulatory P and home P. This plots show a ±25 mmhg of the limit of agreement for both methods. These two methods are not exchangeable. There is a similar finding in different time period. AMP: ambulatory blood pressure.

Min-Kyu Kim, et al:additive Effect of Lercanidipine and Indapamide Combination Therapy 859 결론본연구는경증및중증도고혈압환자에서 lercanidipine 또는 indapamide 단독요법시, 혈압강하효과가있으며, 병용투여시부가적인혈압강하효과가관찰되었다. 그러나 24 시간활동혈압과가정혈압의측정치에일치하지않았다. 요약 배경및목적 : 이전의몇몇임상시험에서, 이뇨제와베타차단제또는 ACE 저해제를병용투여시, 단독투여시보다뛰어난강압효과를나타냄을보였다. 그러나칼슘채널차단제와이뇨제의병용투여시그강압효과의부가성에는의견이분분하다. 그래서본연구는가정혈압및 24시간활동혈압측정을통하여, 두약제를각각단독투여및병용투여시유효성및부가효과의존재여부알아보고자하였다. 또한두혈압측정방법간의일치도를확인하고자하였다. 방법 : 경증및중등증의본태성고혈압환자에게 lercanidipine 10 mg 1일 1정 (L) 및 Indapamide 1 mg 1일 1정 (I) 를각각 4주간격으로단독요법및병합요법 (L+I) 으로무작위배분하고, 각시기의 2주째와 4주째에혈압을자가측정하도록하였다. 또한이중두시기의 4주째에 24시간활동혈압측정검사 (AMP) 를시행하였다. 자가혈압은 24시간활동혈압과 land-altman plot 을통해타당성을평가하였다. 결과 : 전체 70명중 58 명 (83%, 49±9 세 (31~71), 남성, 37명 ) 에서결과를얻었다. 24시간활동혈압상기저혈압에비해적극적인치료시의미있게혈압이감소하였으며 (ba: seline: 160.2±12/.3±9 mmhg, L: 130.5±9.3/86.0 ±8.1 mmhg, I: 129.2±12.9/83.9±11.1 mmhg, L+I: 124.9±10.9/81.3±8.5 mmhg, p<.000), 또한단독요법군에비해병합요법군에서의미있게낮았다 (L+I vs. L: p<.002, L+I vs. I: p<.01). land-altman plot 상자가혈압과 24시간활동혈압에서일치도의한계가 ±25 mmhg 정도로넓게분포하였다. 결론 : 경증및중등증의본태성고혈압환자에서 Lercanidipine 단독이나 Indapamide 단독요법시 2/3 에서강압효과가관찰되었고, 병용투약시부가적혈압강하효과를확인하였다. 그러나자가가정혈압치와활동혈압치의일치는관찰하지못했다. 중심단어 : 고혈압 ;24 시간활동혈압 ; 칼슘채널차단제및이뇨제 ; 부가효과. 이연구는 LG생명과학의지원에의하여연구되었음. REFERENCES 1) Sever PS, Poulter NR. Calcium antagonists and diuretics as combined therapy. J Hypertens Suppl 1987;5:S123-6. 2) Glasser SP, Chrysant SG, Graves J, Rofman, Koehn DK. Safety and efficacy of amlodipine added to hydrochlorothiazide therapy in essential hypertension. Am J Hypertens 1989;2:154-7. 3) Cappuccino FP, Marknandu ND, Tucker FA, Shore AC, Mac- Gregor GA. A double-blind study of the blood pressure lowering effect of a thiazide diuretic in hypertensive patients already on nifedipine and a beta-blocker. J Hypertens 1987;5:733-8. 4) di Somma S, Liguori V, Petitto M, Cavallotti G, Savonitto S, de Divitiis O. Hemodynamic interactions between diuretics and calcium antagonists in the treatment of hypertensive patients. Cardiovasc Drugs Ther 1990;4:1151-6. 5) Cappuccio FP, Markandu ND, Singer DR, et al. A double-blind crossover study of the effect of concomitant diuretic therapy in hypertensive patients treated with amlodipine. Am J Hypertens 1991;4:297-302. 6) Salvetti A, Magagana A, Innocenti P, et al. The combination of chlorthalidone with nifedipine does not exert an additive antihypertensive effect in essential hypertensives: a crossover multicenter study. J Cardiovasc Pharmacol 1991;17:332-5. 7) Kim CH. Ambulatory blood pressure monitoring. Korean Circ J 1997;27:1218-21. 8) Eguchi K, Kario K, Hoshide Y, et al. Comparison of valsartan and amlodipine on ambulatory and morning blood pressure in hypertensive patients. Am J Hypertens 2004;17:112-7. 9) land JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1:307-10. 10) Chobanian AV, akris GL, lack HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High lood Pressure. Hypertension 2003;42: 1206-52. 11) Park JI, Gwon HC, Kim JK, et al. Dose-dependent effect of benidipine in patients with mild-moderate hypertension. Korean Circ J 2000;30:586-91. 12) Shin EK, Chung WS, Seo HS, et al. Efficacy and safety of amlodipine camsylate (Amodipin TM ) for treatment of essential hypertension. Korean Circ J 2005;35:247-52. 13) Mancia G, ertinieri G, Grassi G, et al. Effects of blood pressure measurement by the doctor on patient's blood pressure and heart rate. Lancet 1983;2:695-8. 14) Mancia G, Ferrari A, Gregorini L, et al. lood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53:96-104. 15) Mancia G, Omboni S, Ravogli A, Parati G, Zanchetti A. Ambulatory blood pressure monitoring in the evaluation of antihypertensive treatment: additional information from a large data base. lood Press 1995;4:148-56. 16) White W. Ambulatory and home blood pressure monitoring. In: Hypertension Primer. 3 rd ed. p.330-4. 17) Kim YH, Lee KS, Jo ST, Park CH. Ambulatory blood pressure change after Lercanidipine treatment in mild to moderate hypertensive patients. J Korean Soc Hypertens 2001;7:20-5. 18) archielli M, Dolfini E, Farina P, et al. Clinical pharmacokinetics of lercanidipine. J Cardiovasc Pharmacol 1997;29(Suppl 2): S1-15. 19) Staessen JA, Celis H, Hond ED, et al. Comparison of conventional and automated blood pressure measurement. lood Press Monit 2002;7:61-2.