Calcium Channel Blockers in Management of Hypertension Yong-Jin Kim, MD Seoul National University Hospital
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
Headlines of the St. Louis Post-Dispatch, April 13, 1945
FDR s Final Picture (April 11, 1945)
FDR s BP recorded April 1944
Global Burden of CHD Cause 1990 2020 Millions (%) Millions (%) CHD 6.2 12.4 11.1 16.2 Stroke 4.3 8.5 7.7 11.3 Other CVD 2.6 5.1 6.0 8.8 TOTAL CVD 13.1 26.0 24.8 36.3 All Cause Death 50.4 100 68.3 100 WHO:WHF
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
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 40 30 20 10 0 22.7 Men 2.0 9.5 21.3 Women 2.2 12.4 Kannel WB. JAMA. 1996;275:1571-1576. 6.2 3.3 2.4 Men 3.8 Women 2.6 Normotensive 13.9 9.9 7.3 5.0 6.3 2.0 3.5 2.1 Men 2.0 Women 3.7 Men 4.0 Hypertensive Women 3.0
CV Mortality Risk with BP Increment CV Mortality Risk 8 7 6 5 4 3 2 1 0 8x 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;289:2560-2572. Lewington S et al. Lancet. 2002;360:1903-1913.
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;360:1903-1913.
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
Treatment of Hypertension β-blocker JNC 1 JNC 7 1957 1962 1970 1976 1980 1990 2003 Chlorothiazide α-blocker CCB ACEI ARB
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
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
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 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.
Excitation-Contraction Coupling
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
First Observation about CCB in 1964 Developed Tension (g) Developed Tension (g) 30 20 10 0 30 20 10 0 [Ca ++ ]= 2.4 mm [Ca ++ ]= 0 mm [Ca ++ ]= 2.4 mm [Ca ++ ]= 2.4 mm Verapamil 1 µm Isoproterenol 1µM
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)
Pharmacodynamic Effects of CCBs Phenylalkylamine Dihydropyridines Benzothiazepine (Verapamil) (Nifedipine)(Nimodipine) (Diltiazem) Vasodilation peripheral ++ +++ + + coronary ++ +++ + +++ cerebral + + +++ + Heart rate -- SA node -- -- AV node -- -- Contractility --
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
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
CCB Controversy in 1990 s Circulation 1995
Evidences of CCB s in HT, CAD CCB vs Placebo Syst-EUR nitrendipine, Lancet 1997 PREVENT amlodipine, Circulation 2000 ACTION nifedipine GITS, Lancet 2004
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.
Mean Change (mm) PREVENT: Primary QCA Endpoint 0.15 0.10 0.05 0.00-0.05-0.10-0.15 825 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.. 2000;102:1503-1510. 1510.
PREVENT: Vascular Event or Procedure 30.0 Cumulative Event/ Procedure Rate (%) 25.0 20.0 15.0 10.0 5.0 0.0 Placebo (n=408) Amlodipine (n=417) 31% P=.01 0 6 12 18 24 30 36 Months of Follow-up Pitt et al. Circulation.. 2000;102:1503-1510. 1510.
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
Number of Patients International Nifedipine Study 30 7434 enrolled 6321 randomised, eligible for intention-to-treat analysis 3157 3164 Long-acting calcium antagonist Nifedipine GITS Diuretic combination: Hydrochlorothiazide & Amiloride ( Active control )
International Nifedipine Study 31 Antihypertensive Efficacy Mean Blood Pressure 180 160 173 mmhg Nifedipine GITS Hydrochlorothiazide & Amiloride mmhg 140 120 138 mmhg Systolic 100 80 60 Week 99 mmhg 82 mmhg Diastolic 0 2 4 8 12 18 36 70 87 121 138 173 190 225 242 Year 1 Year 2 Year 3 Year 4
International Nifedipine Study 32 Sympathetic System Heart Rate 100 Nifedipine GITS Hydrochlorothiazide & Amiloride 80 Beats per Minute 60 40 20 Week -4-2/0 0 2 4 8 12 18 36 70 87 121 138 173 190 225 242 End Year Year 1 2 Year 3 Year 4
International Nifedipine Study 33 Main Clinical Outcome Kaplan Meier Curves Cumulative Proportion Surviving Cumulative Proportion Surviving 1.01 1.00 0.99 0.98 0.97 0.96 0.95 0.94 0.93 0.92 0.91 1.04 1.02 1.00 0.98 0.96 0.94 0.92 0.90 0.88 0.86 0.84 p = 0.32 0 400 800 1,200 1,600 2,000 p = 0.54 0 400 800 1,200 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)
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 1.09 0.85 2.17 Heart Failure 0.023 All Primary Endpoints 0.74 0.91 1.11 1.27 p 0.61 0.34 All Cardiovascular Morbidity and All-Cause Mortality All Primary and Secondary Endpoints 0.96 0.62 0.2 0.4 0.6 0.8 Nifedipine GITS better 1.0 1.2 1.4 1.6 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 < 0.01 Nifedipine GITS Hydrochlorothiazide & Amiloride 4.3 5.6 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
Randomized Design of ALLHAT High-risk hypertensive patients Consent/ Randomize (42,448) Amlodipine besylate 2.5-10 mg (n=9048) Chlorthalidone 12.5-25 25 mg (n=15,255) Doxazosin 2-82 8 mg (n=9067)* Lisinopril 10-40 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.. 2000;283:1967-1975. 1975. ALLHAT Collaborative Research Group. JAMA.. 2002;288:2981-2997. 2997.
ALLHAT: BP by Treatment Group 150 Chlorthalidone Amlodipine besylate Lisinopril % <140/90 mm Hg 68.2% 66.3% 61.2% 90 mm Hg 145 140 Systolic BP mm Hg 85 80 Diastolic BP 135 75 130 0 1 2 3 4 5 6 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 70 0 1 2 3 4 5 6 Years Compared with chlorthalidone: DBP significantly lower in the amlodipine group (0.8 mm Hg) at 5 years ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Fatal CHD or Nonfatal MI Cumulative CHD Event Rate Number at Risk: Chlorthalidone Amlodipine Lisinopril.20.16.12.08.04 0 15,255 9048 9054 A/C L/C 14,477 8576 8535 RR (95% CI) 0.98 (0.90-1.07) 0.99 (0.91-1.08) Chlorthalidone Amlodipine besylate Lisinopril 13,820 8218 8123 P Value.65.81 0 1 2 3 4 5 6 7 Years to CHD Event 13,102 7843 7711 11,362 6824 6662 6340 3870 3832 2956 1878 1770 209 215 195 ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
Rollover from previous therapy (92%) VALUE: Design 15245 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 0.5 0 1 2 3 4 6 * 72 Screening Randomisation *Patient visits every 6 months for months 6-72. 6 Julius S et al. Lancet.. June 2004;363. End of treatment adjustment period
VALUE: Primary Composite Endpoint Proportion of Patients With First Event (%) Number at risk 14 12 10 Julius et al. Lancet.. June 2004;363. 8 6 4 2 0 Valsartan-based regimen Amlodipine besylate -based regimen HR=1.03; 95% CI 0.94-1.14: P=0.49 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Valsartan 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3764 1474 Amlodipine besylate 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474
VALUE: Fatal and Non-Fatal MI Proportion of Patients With First Event (%) 7 6 5 4 3 2 1 0 Valsartan-based regimen Amlodipine besylate-based based regimen HR=1.19; 95% CI 1.02-1.38; 1.38; P=0.02 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Number at risk Valsartan 7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520 Amlodipine besylate 7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532 19% Julius S et al. Lancet.. June 2004;363.
VALUE: Fatal and Non-fatal Stroke Proportion of Patients With First Event (%) 6 5 4 3 2 1 0 Valsartan-based regimen Amlodipine besylate-based based regimen HR=1.15; 95% CI 0.98-1.35; P=0.08 Number at risk Time (months) Valsartan 7649 7494 7448 7312 7170 7022 6877 6692 6515 6093 3859 1516 Amlodipine besylate 7596 7499 7455 7334 7195 7055 6918 6744 6587 6163 3846 1532 Julius S et al. Lancet.. June 2004;363. 0 6 12 18 24 30 36 42 48 54 60 66
VALUE: Systolic BP in Study mmhg mmhg 155 150 145 140 Julius S et al. Lancet.. June 2004;363. Sitting SBP by Time and Treatment Group Valsartan (N=7649) Amlodipine besylate (N=7596) 135 Baseline 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 Months (or final visit) 5.0 4.0 3.0 2.0 1.0 0 1.0 Difference in SBP Between Valsartan and Amlodipine besylate 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 Months (or final visit)
VALUE: Outcome and SBP Differences Time Interval SBP (months) mm Hg Overall study 2.2 0 3 3.8 3 6 2.3 6 12 2.0 12 24 24 1.8 24 36 1.6 36 48 1.4 Study end 1.7 PRIMARY ENDPOINT Odds Ratios and 95% CIs 0.5 1.0 2.0 4.0 Favours valsartan Favours amlodipine besylate Julius S et al. Lancet.. June 2004;363.
VALUE: Outcome and SBP Differences
New ESC Guideline: Early Treatment
BP-Lowering Treatment Trialists Comparisons of Active Treatments and Control BP Difference (mm Hg) Relative Risk 0.5 1.0 2.0 Favors Favors Active Control Blood Pressure Lowering Treatment Trialists Collaboration. Lancet.. 2003;362:1527-1535. 1535. RR (95% CI) Stroke ACEI vs placebo -5/ 5/-2 0.72 (0.64, 0.81) CA vs placebo -8/ 8/-4 0.62 (0.47, 0.82) Coronary heart disease ACEI vs placebo -5/ 5/-2 0.80 (0.73, 0.88) CA vs placebo Heart failure ACEI vs placebo -8/ 8/-4-5/ 5/-2 0.78 (0.62, 0.99) 0.82 (0.69, 0.98) CA vs placebo -8/ 8/-4 1.21 (0.93, 1.58) Major CV events ACEI vs placebo -5/ 5/-2 0.78 (0.73, 0.83) CA vs placebo -8/ 8/-4 0.82 (0.71, 0.95) CV mortality ACEI vs placebo -5/ 5/-2 0.80 (0.71, 0.89) CA vs placebo -8/ 8/-4 0.78 (0.61, 1.00) Total mortality ACEI vs placebo -5/ 5/-2 0.88 (0.81, 0.96) CA vs placebo -8/ 8/-4 0.89 (0.75, 1.05)
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 1/0 1.33 (1.21, 1.47) ACE Inhibitor vs CA 1/1 0.82 (0.73, 0.92) Blood Pressure Lowering Treatment Trialists Collaboration. Lancet.. 2003;362:1527-1535. 1535.
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 1/1 1.02 (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.. 2003;362:1527-1535. 1535.
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
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 : 145-53
HOPE: Primary Endpoint cardiac death, MI, or stroke Primary endpoints (%) 20 15 10 5 RRR = 28% p < 0.001 Placebo Ramipril 0 0 500 1000 1500 days The HOPE investigators. N Engl J Med 2000 ; 342 : 145-53
HOPE: Events per Patient Group Events per Patient Group (%) 20 15 10 5 RR=22% P<.001 17.8 14 RR=26% P<.001 8.1 6.1 Placebo RR=20% P<.001 12.3 9.9 RR=32% P<.001 4.9 3.4 Ramipril RR=0% P=NS 4.1 4.3 RR=16% P=.005 12.2 10.4 0 Primary CV Outcome Death *MI, stroke, or CV death. Yusuf et al. N Engl J Med.. 2000;342:145-153. 153. MI Stroke Non- CV Death Total Mortality
Ambulatory BP in HOPE Trial BP (mm Hg) 180 160 140 120 100 80 60 40 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)( 1 3 5 7 9 11 13 15 17 19 21 23 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours)
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: 782-88
EUROPA: Primary Endpoint % CV death, MI or cardiac arrest 14 12 10 8 6 Placebo annual event rate : 2.4% Placebo Perindopril 4 2 0 10% 12% 14% 0 1 2 3 4 5 RRR: 20% p = 0.0003 Years Lancet 2003; 362: 782-88
CAD Mortality and Usual BP by Age Systolic BP Diastolic BP IHD Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 8 4 2 1 0 80-89 89 years 70-79 79 years 60-69 69 years 50-59 59 years 40-49 49 years 256 128 64 32 16 8 4 2 1 0 80-89 89 years 70-79 79 years 60-69 69 years 50-59 59 years 40-49 49 years 120 140 160 180 70 80 90 100 110 Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet.. 2002;360:1903-1913. 1913.
Stroke Mortality and Usual BP by Age Systolic BP Diastolic BP Stroke Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 8 4 2 1 80-89 89 years 70-79 79 years 60-69 69 years 50-59 59 years 256 128 64 32 16 8 4 2 1 80-89 89 years 70-79 79 years 60-69 69 years 50-59 59 years 0 120 140 160 180 0 70 80 90 100 110 Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet.. 2002;360:1903-1913. 1913.
Odds Ratio for CV Events & SBP Difference Odds Ratio (Experimental/Reference) 1.50 1.25 1.00 0.75 0.50 0.25-5 0 5 10 15 20 25 Difference (reference minus experimental) in Systolic BP (mm Hg) Staessen et al. J Hypertens.. 2003;21:1055-1076. 1076. 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
Odds Ratio for CV Events & SBP Difference Odds Ratio (Experimental/Reference) 1.50 1.25 1.00 0.75 0.50 0.25 Recent trials Older trials placebo Older trials active EUROPA P<.0001-5 0 5 10 15 20 25 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;362:782-788; 788; Staessen et al. J Hypertens.. 2003;21:1055-1076. 1076. 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
Target BP in HT JNC 7, 2004-140/90-130/80: DM, renal disease ESC guideline, 2007-140/90-130/80: DM, established CV ds ( stroke, MI, renal ds)
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 1.25 1.00 0.75 0.50 RR of Outcome Event 1.25 1.00 0.75 0.50 0.25-10 -8-6 -4-2 0 2 4 0.25-10 -8-6 -4-2 0 2 4 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.. 2003;362:1527-1535. 1535.
BP-Lowering Treatment Trialists 1.50 Heart Failure A B C D E F G RR of Outcome Event 1.25 1.00 0.75 0.50 0.25-10 -8-6 -4-2 0 2 4 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.. 2003;362:1527-1535. 1535.
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)
Target BP lowering in ALLHAT
Adequate BP Control First!
Adequate BP Control First! source: National health and nutrition examination survey, 2005
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 (%) 0.96 0.92 0.88 0.84 P=.03 P<.0001 P=.001 0.8 1 3 5 7 9 11 13 15 17 19 21 23 25 Follow-up (Years) Benetos et al. J Hypertens.. 2003;21:1635-1640. 1640.
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
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.. 2000;36:646-661; 661; Bakris et al. Arch Intern Med. 2003;163:1555-1565; 1565; Lewis et al. N Engl J Med.. 2001;345:851-860. 860.
Combination Therapy in Korea >4 drugs 8 7 23 19 10 25 7 7 8 19 19 26 14 31 3 drugs 2 drugs 41 44 39 44 42 41 34 Monotherapy 28 31 26 31 33 25 22 Note: * Consider small base number for implementation especially when n<30
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 -10-20 -15.9-15.1-18.1 *The DHP CCB was Norvasc (amlodipine besylate). P<.001 vs baseline. McLaughlin et al. Am J Hypertens.. 2003;16:123A. Abstract P-237. P -19.3-17.3-13.9
Guideline on Combination Therapy Thiazide BB ARB Alpha CCB ACEI ESC guideline 2007
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
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