Calcium Channel Blockers in Management of Hypertension. Yong-Jin Kim, MD Seoul National University Hospital

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1 Calcium Channel Blockers in Management of Hypertension Yong-Jin Kim, MD Seoul National University Hospital

2 Contents Clinical significance of hypertension CCB: Brief introduction Evidences of CCB s in HT and CAD Review on beyond BP lowering effect Practical usefulness of CCB s

3 Headlines of the St. Louis Post-Dispatch, April 13, 1945

4 FDR s Final Picture (April 11, 1945)

5 FDR s BP recorded April 1944

6 Global Burden of CHD Cause Millions (%) Millions (%) CHD Stroke Other CVD TOTAL CVD All Cause Death WHO:WHF

7 Rank Order of Disability (DALYs) 1999 Disease or Injury 2020 Disease or Injury 1. Acute lower respiratory infections 1. Coronary heart disease 2. HIV/AIDS 2. Unipolar major depression 3. Perinatal conditions 3. Road traffic accidents 4. Diarrhoeal diseases 4. Cerebrovascular disease 5. Unipolar major depression 5. COPD 6. Coronary heart disease 6. Lower respiratory infections 7. Cerebrovascular disease 7. Tuberculosis 8. Malaria 8. War 9. Traffic accidents 9. Diarrhoeal diseases 10. COPD 10. HIV

8 HT: A Risk Factor for CV Disease 50 Coronary disease 45.4 Stroke Peripheral artery disease Heart failure Biennial Age- Adjusted Rate per 1000 Patients Risk ratio Men Women Kannel WB. JAMA. 1996;275: Men 3.8 Women 2.6 Normotensive Men 2.0 Women 3.7 Men 4.0 Hypertensive Women 3.0

9 CV Mortality Risk with BP Increment CV Mortality Risk x 4x 2x 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged 40 to 69 years, starting at blood pressure 115/75 mm Hg Chobanian AV et al. JAMA. 2003;289: Lewington S et al. Lancet. 2002;360:

10 Small Difference Produces Big Impact Meta-analysis of 61 observational studies 1 million adults For every 2 mm Hg decrease in mean SBP 7% reduction in CHD mortality 10% reduction in stroke mortality Lewington S et al. Lancet. 2002;360:

11 Individual Risk vs Proportional Attributable Risk 5% People with low risk level 70% People with average risk level 25% People with high risk level Individual risk of CHD Distribution of cases

12 Treatment of Hypertension β-blocker JNC 1 JNC Chlorothiazide α-blocker CCB ACEI ARB

13 Contents Clinical significance of hypertension CCB: Brief introduction Evidences of CCB s in HT and CAD Review on beyond BP lowering effect Practical usefulness of CCB s

[K + ] 140 mm [Na + ] 10 mm [Ca ++ ] 1 µm 0 mv Electrical Gradient [K +

14 Ion Channels and Ion Gradients Ion channel Cl - OH - Ion Exchangers Ca ++ Na + Ca ++ Ion pump ATP Na + HCO - Cl - 3 Ca ++ [Cl - ] 15 mm - 90 mv [K + ] 140 mm [Na + ] 10 mm [Ca ++ ] 1 µm 0 mv Electrical Gradient [K + ] 4 mm [Na + ] 140 mm Concentration Gradient [Cl - ] 140 mm [Ca ++ ] 2 mm

15 Voltage-Dependent Ca ++ Channels Calcium Binding Sites Ca ++ Ca ++ Ca ++ Ca ++ Extracellular Ca ++ Ca ++ Ca ++ Selectivity filter Ca ++ Phosphorylation Site Ca ++ Activation Gate Intracellular P Inactivation Gate

Excitation-Contraction Coupling α 2 Actin-myosin

on contractile apparatus β VOC δ SR Contraction

channels open at a level of depol. of ~-60 mv.

16 Excitation-Contraction Coupling α 2 Actin-myosin interaction Ca ++ -Troponin relieves inhibition on contractile apparatus β VOC δ SR Contraction Ca ++ -induced Ca ++ release L-type Ca ++ channels open at a level of depol. of ~-60 mv. The entry of small Ca ++ triggers Ca ++ release from SR.

17 Excitation-Contraction Coupling

18 Types of Calcium Channels Channel Blockers Properties Location/Role L type Calcium Large, long-lasting Cardiac & smooth m. antagonists current with neurons; excitationslow activation contraction, excitation-secretion coupling T type Amiloride Tiny, transient SA & Purkinje cell; current pacemaker activity N type Conotoxin Neither L or T Neurons; neurotransmitter release

19 First Observation about CCB in 1964 Developed Tension (g) Developed Tension (g) [Ca ++ ]= 2.4 mm [Ca ++ ]= 0 mm [Ca ++ ]= 2.4 mm [Ca ++ ]= 2.4 mm Verapamil 1 µm Isoproterenol 1µM

20 Classes of L-Type CCB Class I (diphenylalkylamine) Verapamil Isoptin Class II (1,4-dihydropyridines) Amlodipine Felodipine Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine Norvasc, Lotrel Plendil, Lexxel Dynacirc Cardene Adalat, Procardia Nimotop Sular Class III (benzothiazepine) Diltiazem Angizem, Altiazem Class IV (miscellaneous) Bepridil Vascor Class V (T-type blocker) Mibefradil (withdrawn)

21 Pharmacodynamic Effects of CCBs Phenylalkylamine Dihydropyridines Benzothiazepine (Verapamil) (Nifedipine)(Nimodipine) (Diltiazem) Vasodilation peripheral coronary cerebral Heart rate -- SA node AV node Contractility --

22 Classification of CCB s Group First Second generation Third (specificity) generation generation New active principles and/or novel formulations Dihydropyridine Nifedipine Nifedipine Benidipine Amlodipine (artery > cardiac) Nicardipine SR/GITS Isradipine Lacidipine Felodipine ER Manidipine Nicardipine SR Nilvadipine Nimodipine Nisoldipine Nitrendipine Benzothiazepine Diltiazem Diltiazem SR (artery = cardiac) Phenylalkylamine Verapamil Verapamil SR (artery < cardiac) Gallopamil Abbreviations: ER = extended release; GITS = gastrointestinal therapeutic system; SR = sustained release Zanchetti, 1997

23 Contents Clinical significance of hypertension CCB: Brief introduction Evidences of CCB s in HT and CAD Review on beyond BP lowering effect Practical usefulness of CCB s

24 CCB Controversy in 1990 s Circulation 1995

25 Evidences of CCB s in HT, CAD CCB vs Placebo Syst-EUR nitrendipine, Lancet 1997 PREVENT amlodipine, Circulation 2000 ACTION nifedipine GITS, Lancet 2004

26 Syst-EUR Nitrendipine reduces CV events -5% Stroke MI HF All CV events Reduction (%) -15% -25% -35% -30% -29% -31% -45% -42% 4695 Elderly (> 60yr) pts with ISH: SBP>160, DBP<95) Systolic Hypertension in Europe. Staessen et al, Lancet, 1997.

27 Mean Change (mm) PREVENT: Primary QCA Endpoint symptomatic CAD with 3yr f/u Change in Minimum Lumen Diameter (MLD) Primary QCA Endpoint Amlodipine Placebo 30% >30% to 50% >50% All Segments * Values are mean ± SE, adjusted for segment, clinic, and PTCA during baseline angiogram. P=NS for all comparisons of amlodipine versus placebo. Pitt et al. Circulation ;102:

28 PREVENT: Vascular Event or Procedure 30.0 Cumulative Event/ Procedure Rate (%) Placebo (n=408) Amlodipine (n=417) 31% P= Months of Follow-up Pitt et al. Circulation ;102:

29 Evidences of CCB s in HT, CAD CCB vs Active control ABCD nisoldipine vs ACEI, NEJM1998 STOP-2 felodipine or isradipine vs ACEI or diuretic/bb, Lancet 1999 INSIGHT nifedipine GITS vs diuretics, Lancet 2000 ALLHAT amlodipine vs diuretics vs ACEI, JAMA 2002 AASK amlodipine vs BB vs ACEI, JAMA 2002 CONVINCE verapamil vs diuretic/bb, JAMA 2003 CAMELOT amlodipine vs ACEI, JAMA 2004 VALUE amlodipine vs ARB, Lancet 2004

30 Number of Patients International Nifedipine Study enrolled 6321 randomised, eligible for intention-to-treat analysis Long-acting calcium antagonist Nifedipine GITS Diuretic combination: Hydrochlorothiazide & Amiloride ( Active control )

31 International Nifedipine Study 31 Antihypertensive Efficacy Mean Blood Pressure mmhg Nifedipine GITS Hydrochlorothiazide & Amiloride mmhg mmhg Systolic Week 99 mmhg 82 mmhg Diastolic Year 1 Year 2 Year 3 Year 4

32 International Nifedipine Study 32 Sympathetic System Heart Rate 100 Nifedipine GITS Hydrochlorothiazide & Amiloride 80 Beats per Minute Week -4-2/ End Year Year 1 2 Year 3 Year 4

33 International Nifedipine Study 33 Main Clinical Outcome Kaplan Meier Curves Cumulative Proportion Surviving Cumulative Proportion Surviving p = ,200 1,600 2,000 p = ,200 1,600 2,000 Time (Days) Nifedipine GITS Hydrochlorothiazide & Amiloride Myocardial Infarction, Sudden Death, Stroke, Heart Failure, Other Cardiovascular Death (Primary Endpoints) All Cardiovascular Morbidity and All-Cause Mortality (Sum of Primary and Secondary Endpoints)

34 International Nifedipine Study 34 Overview: Individual and Combined Endpoints Relative Risk and 95% Confidence Interval Stroke Myocardial Infarction 0.17 Sudden Death 0.43 Other Cardiovascular Death Heart Failure All Primary Endpoints p All Cardiovascular Morbidity and All-Cause Mortality All Primary and Secondary Endpoints Nifedipine GITS better Hydrochlorothiazide & Amiloride better 1.8

Emergence of New Diseases* % of Patients 6 4 2 0 1.3 International Nifedipine Study 35 2.1 3.0 5.3 Gout 1 Peripheral Vascular Disorder 1 p < 0.01 p < 0.

35 Emergence of New Diseases* % of Patients International Nifedipine Study Gout 1 Peripheral Vascular Disorder 1 p < 0.01 p < 0.01 Nifedipine GITS Hydrochlorothiazide & Amiloride Diabetes 2 p = 0.02 *or Recurrence; 1 Reported by investigator; 2 WHO definition of random glucose measurement >11.0 mmol/l or use of anti-diabetic drugs

36 Randomized Design of ALLHAT High-risk hypertensive patients Consent/ Randomize (42,448) Amlodipine besylate mg (n=9048) Chlorthalidone mg (n=15,255) Doxazosin mg (n=9067)* Lisinopril mg (n=9054) Eligible for lipid-lowering lowering Not eligible for lipid-lowering lowering Consent/Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up p to 8 years). *In January 2000, the National Heart, Lung, and Blood Institute decided d to discontinue the doxazosin arm of the antihypertensive trial and report results. ALLHAT Collaborative Research Group. JAMA ;283: ALLHAT Collaborative Research Group. JAMA ;288:

37 ALLHAT: BP by Treatment Group 150 Chlorthalidone Amlodipine besylate Lisinopril % <140/90 mm Hg 68.2% 66.3% 61.2% 90 mm Hg Systolic BP mm Hg Diastolic BP Years Compared with chlorthalidone: SBP significantly higher in the amlodipine group (0.8 mm Hg) and the lisinopril group (2 mm Hg) at 5 years Years Compared with chlorthalidone: DBP significantly lower in the amlodipine group (0.8 mm Hg) at 5 years ALLHAT Collaborative Research Group. JAMA. 2002;288:

38 ALLHAT: Fatal CHD or Nonfatal MI Cumulative CHD Event Rate Number at Risk: Chlorthalidone Amlodipine Lisinopril , A/C L/C 14, RR (95% CI) 0.98 ( ) 0.99 ( ) Chlorthalidone Amlodipine besylate Lisinopril 13, P Value Years to CHD Event 13, , ALLHAT Collaborative Research Group. JAMA. 2002;288:

39 Rollover from previous therapy (92%) VALUE: Design HT pt with elective e titration to target BP Valsartanbased regimen V 80 mg A 5 mg Amlodipinebased regimen V 160 mg A 10 mg V 160 mg + HCTZ 12.5 mg A 10 mg + HCTZ 12.5 mg V 160 mg + HCTZ 25 mg A 10 mg + HCTZ 25 mg V 160 mg + HCTZ 25 mg + "Free" add-on A 10 mg + HCTZ 25 mg + "Free" add-on Month * 72 Screening Randomisation *Patient visits every 6 months for months Julius S et al. Lancet.. June 2004;363. End of treatment adjustment period

40 VALUE: Primary Composite Endpoint Proportion of Patients With First Event (%) Number at risk Julius et al. Lancet.. June 2004; Valsartan-based regimen Amlodipine besylate -based regimen HR=1.03; 95% CI : P= Time (months) Valsartan Amlodipine besylate

41 VALUE: Fatal and Non-Fatal MI Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine besylate-based based regimen HR=1.19; 95% CI ; 1.38; P= Time (months) Number at risk Valsartan Amlodipine besylate % Julius S et al. Lancet.. June 2004;363.

42 VALUE: Fatal and Non-fatal Stroke Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine besylate-based based regimen HR=1.15; 95% CI ; P=0.08 Number at risk Time (months) Valsartan Amlodipine besylate Julius S et al. Lancet.. June 2004;

43 VALUE: Systolic BP in Study mmhg mmhg Julius S et al. Lancet.. June 2004;363. Sitting SBP by Time and Treatment Group Valsartan (N=7649) Amlodipine besylate (N=7596) 135 Baseline Months (or final visit) Difference in SBP Between Valsartan and Amlodipine besylate Months (or final visit)

44 VALUE: Outcome and SBP Differences Time Interval SBP (months) mm Hg Overall study Study end 1.7 PRIMARY ENDPOINT Odds Ratios and 95% CIs Favours valsartan Favours amlodipine besylate Julius S et al. Lancet.. June 2004;363.

45 VALUE: Outcome and SBP Differences

46 New ESC Guideline: Early Treatment

47 BP-Lowering Treatment Trialists Comparisons of Active Treatments and Control BP Difference (mm Hg) Relative Risk Favors Favors Active Control Blood Pressure Lowering Treatment Trialists Collaboration. Lancet ;362: RR (95% CI) Stroke ACEI vs placebo -5/ 5/ (0.64, 0.81) CA vs placebo -8/ 8/ (0.47, 0.82) Coronary heart disease ACEI vs placebo -5/ 5/ (0.73, 0.88) CA vs placebo Heart failure ACEI vs placebo -8/ 8/-4-5/ 5/ (0.62, 0.99) 0.82 (0.69, 0.98) CA vs placebo -8/ 8/ (0.93, 1.58) Major CV events ACEI vs placebo -5/ 5/ (0.73, 0.83) CA vs placebo -8/ 8/ (0.71, 0.95) CV mortality ACEI vs placebo -5/ 5/ (0.71, 0.89) CA vs placebo -8/ 8/ (0.61, 1.00) Total mortality ACEI vs placebo -5/ 5/ (0.81, 0.96) CA vs placebo -8/ 8/ (0.75, 1.05)

48 Stroke CHD HF BP-Lowering Treatment Trialists Comparisons of Different Active Treatments BP Difference (mm Hg) ACE Inhibitor vs D/BB 2/0 CA vs D/BB 1/0 ACE Inhibitor vs CA 1/1 ACE Inhibitor vs D/BB 2/0 CA vs D/BB 1/0 ACE Inhibitor vs CA 1/1 ACE Inhibitor vs D/BB 2/0 Relative Risk 0.5 Favors 1.0 Favors 2.0 First Listed Second Listed RR (95% CI) 1.09 (1.00, 1.18) 0.93 (0.86, 1.01) 1.12 (1.01, 1.25) 0.98 (0.91, 1.05) 1.01 (0.94, 1.08) 0.96 (0.88, 1.05) 1.07 (0.96, 1.19) CA vs D/BB 1/ (1.21, 1.47) ACE Inhibitor vs CA 1/ (0.73, 0.92) Blood Pressure Lowering Treatment Trialists Collaboration. Lancet ;362:

49 BP-Lowering Treatment Trialists Comparisons of Different Active Treatments BP Difference (mm Hg) Relative Risk RR (95% CI) Major CV events ACEI vs D/BB CA vs D/BB ACEI vs CA CV mortality ACEI vs D/BB CA vs D/BB ACEI vs CA Total mortality ACEI vs D/BB CA vs D/BB ACEI vs CA 2/0 1/0 1/1 2/0 1/0 1/1 2/0 1/0 1/ (0.98, 1.07) 1.04 (0.99, 1.08) 0.97 (0.92, 1.03) 1.03 (0.95, 1.11) 1.05 (0.97, 1.13) 1.03 (0.94, 1.13) 1.00 (0.95, 1.05) 0.99 (0.95, 1.04) 1.04 (0.98, 1.10) Blood Pressure Lowering Treatment Trialists 0.5 Favors 1.0 Favors 2.0 First Listed Second Listed Trialists Collaboration. Lancet ;362:

50 Contents Clinical significance of hypertension CCB: Brief introduction Evidences of CCB s in HT and CAD Review on beyond BP lowering effect Practical usefulness of CCB s

51 HOPE Trial 9,297 pt with CAD or DM plus 1 RF (no CHF, LV dysfxn) 75% Aspirin, 40% beta-blocker, 30% statin Ramipril 10mg/day n=4,645 Placebo n=4,652 Primary Endpoint Composite of cardiac death, MI, or stroke follow-up: 5 years The HOPE investigators. N Engl J Med 2000 ; 342 :

52 HOPE: Primary Endpoint cardiac death, MI, or stroke Primary endpoints (%) RRR = 28% p < Placebo Ramipril days The HOPE investigators. N Engl J Med 2000 ; 342 :

53 HOPE: Events per Patient Group Events per Patient Group (%) RR=22% P< RR=26% P< Placebo RR=20% P< RR=32% P< Ramipril RR=0% P=NS RR=16% P= Primary CV Outcome Death *MI, stroke, or CV death. Yusuf et al. N Engl J Med ;342: MI Stroke Non- CV Death Total Mortality

54 Ambulatory BP in HOPE Trial BP (mm Hg) SBP baseline DBP baseline Svensson et al. Hypertension. 2001;38:e28-e32. e32. SBP year 1 DBP year 1 Ramipril Group (n=20) Night =17/8 mm Hg (P<.001)( 24-h =10/4 mm Hg (P<.03)( Time (hours)

55 EUROPA Trial 12,218 patients with stable angina without CHF 90% Aspirin, 60% beta-blocker, 60% statin Perindopril 8mg/day n=6,110 Placebo n=6,108 Primary Endpoint Composite of cardiac death, MI, or cardiac arrest mean follow-up: 4.2 years Lancet 2003; 362:

EUROPA: Primary Endpoint % CV death, MI or cardiac arrest 14 12 10 8 6 Placebo annual event rate : 2.

56 EUROPA: Primary Endpoint % CV death, MI or cardiac arrest Placebo annual event rate : 2.4% Placebo Perindopril % 12% 14% RRR: 20% p = Years Lancet 2003; 362:

57 CAD Mortality and Usual BP by Age Systolic BP Diastolic BP IHD Mortality (Floating Absolute Risk and 95% CI) years years years years years years years years years years Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet ;360:

58 Stroke Mortality and Usual BP by Age Systolic BP Diastolic BP Stroke Mortality (Floating Absolute Risk and 95% CI) years years years years years years years years Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet ;360:

59 Odds Ratio for CV Events & SBP Difference Odds Ratio (Experimental/Reference) Difference (reference minus experimental) in Systolic BP (mm Hg) Staessen et al. J Hypertens ;21: Recent trials Older trials placebo Older trials active HOPE P<.0001 Recent AASK L vs H ABCD/NT L vs H ALLHAT/Aml Aml ALLHAT/Lis ALLHAT/Lis 65 ALLHAT/Lis Blcks ANBP2 CONVINCE DIABHYCAR ELSA IDNT2 LIFE/ALL LIFE/DM NICOLE PREVENT SCOPE Older ALLHAT/Dox ATMH EWPHE HEP HOPE HOT HOT M vs H INSIGHT MIDAS/NICS/VHAS L vs H MRC MRC2 PART2/SCAT PATS PROGRESS/Per PROGRESSION/Com RCT70-80 RENAAL SHEP STONE STOP 1 STOP2/CCBs STOP2/ACEIs Syst-China Syst-Eur UKPDS C vs A UKPDS L vs H

60 Odds Ratio for CV Events & SBP Difference Odds Ratio (Experimental/Reference) Recent trials Older trials placebo Older trials active EUROPA P< Difference (reference minus experimental) in Systolic BP (mm Hg) Recent AASK L vs H ABCD/NT L vs H ALLHAT/Aml Aml ALLHAT/Lis ALLHAT/Lis 65 ALLHAT/Lis Blcks ANBP2 CONVINCE DIABHYCAR ELSA IDNT2 LIFE/ALL LIFE/DM NICOLE PREVENT SCOPE Fox. Lancet. 2003;362: ; 788; Staessen et al. J Hypertens ;21: Older ALLHAT/Dox ATMH EWPHE HEP HOPE HOT HOT M vs H INSIGHT MIDAS/NICS/VHAS L vs H MRC MRC2 PART2/SCAT PATS PROGRESS/Per PROGRESSION/Com RCT70-80 RENAAL SHEP STONE STOP 1 STOP2/CCBs STOP2/ACEIs Syst-China Syst-Eur UKPDS C vs A UKPDS L vs H

61 Target BP in HT JNC 7, /90-130/80: DM, renal disease ESC guideline, /90-130/80: DM, established CV ds ( stroke, MI, renal ds)

62 BP-Lowering Treatment Trialists 1.50 Stroke CHD A B C D E F G A B C D E F G 1.50 RR of Outcome Event RR of Outcome Event SBP Difference Between (mm Hg) SBP Difference Between (mm Hg) A = CA vs placebo; B = ACE inhibitor vs placebo; C = more intensive vs less intensive blood- pressure- lowering; D = ARB vs control; E = ACE inihibitor vs CA; F = CA vs diuretic or β-blocker; G = ACE inhibitor vs diuretic and β-blocker. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet ;362:

63 BP-Lowering Treatment Trialists 1.50 Heart Failure A B C D E F G RR of Outcome Event SBP Difference Between Groups (mm Hg) A = CA vs placebo; B = ACE inhibitor vs placebo; C = more intensive vs less intensive blood- pressure- lowering; D = ARB vs control; E = ACE inihibitor vs CA; F = CA vs diuretic or β-blocker; G = ACE inhibitor vs diuretic and β-blocker. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet ;362:

64 Regimens based on each of the most commonly used drug classes produce reductions in the risk of major cardiovascular events that appear to be roughly proportional to the size of the blood pressure reductions achieved With the exception of heart failure, the intensity of blood pressure lowering appears to be a more important determinant of outcome than the choice of drug class. BP Lowering Treatment Trialists Collaboration, The Lancet (2003)

65 Target BP lowering in ALLHAT

66 Adequate BP Control First!

67 Adequate BP Control First! source: National health and nutrition examination survey, 2005

68 CVD Survival in Treated HT Untreated BP <140/90 mm Hg Untreated BP 140/90 mm Hg Treated BP at goal <140/90 mm Hg Treated BP not at goal 140/90 mm Hg 1 Survival (%) P=.03 P<.0001 P= Follow-up (Years) Benetos et al. J Hypertens ;21:

69 Contents Clinical significance of hypertension CCB: Brief introduction Evidences of CCB s in HT and CAD Review on beyond BP lowering effect Practical usefulness of CCB s

70 No. of agents to Achieve BP Goal UKPDS (<85 mm Hg, diastolic) MDRD (<92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) RENAAL (<140/90 mm Hg) IDNT ( 135/85 mm Hg) 1 2 Number of BP Medications 3 4 Bakris et al. Am J Kidney Dis ;36: ; 661; Bakris et al. Arch Intern Med. 2003;163: ; 1565; Lewis et al. N Engl J Med ;345:

71 Combination Therapy in Korea >4 drugs drugs 2 drugs Monotherapy Note: * Consider small base number for implementation especially when n<30

72 Effect of CCB for Add-on Therapy 0 No Previous Therapy (n=421) ACEI/ARB (n=117) β-blocker (n=70) Diuretic (n=119) ACE/ARB + diuretic (n=165) β-blocker + diuretic (n=47) SBP mm Hg SBP mm Hg *The DHP CCB was Norvasc (amlodipine besylate). P<.001 vs baseline. McLaughlin et al. Am J Hypertens ;16:123A. Abstract P-237. P

73 Guideline on Combination Therapy Thiazide BB ARB Alpha CCB ACEI ESC guideline 2007

74 Summary CCB: strong evidences in management in HT Benefit of HT drugs: mainly from BP lowering effect Early initiation of HT drug: high risk patients Importance of BP lowering at goal

76 Thank You for Your Attention!

APPENDIX D: PHARMACOTYHERAPY EVIDENCE

Página 1 de 7 APPENDIX D: PHARMACOTYHERAPY EVIDENCE Table D1. Outcome Trials of Antihypertensive Agents Study Drug Regimen N Duration Primary Outcomes Remarks Antihypertensive Therapy vs Placebo SHEP 1991