CCB Reappraisal CCB as the first line for the East-Asians

Transcription

1 CCB Reappraisal CCB as the first line for the East-Asians Park, Chang G, MD, PhD Cardiovascular Center, Guro Hospital, Korea University Medical School

2 일본의국화 ( 國花 ) 는? LOGO

3 일본 ( 日本 ) 의국화 ( 國花 ) 정확히말하면, 日本에는국화 ( 國花 ) 가없다. 황실 ( 皇室 ) 을상징하는꽃으로국화 ( 菊花 ) 가있을뿐. 따라서외국에나가있는日本의대사관정문에도황금색의국화문양 ( 紋様 ) 이있을뿐이다. LOGO

4 벗꽃의원산지는? 왕벚나무는한국제주도원산 LOGO

5 한국의국화 ( 國花 ) LOGO

6 Agenda The evidence on CCBs over the world The evidence on CCBs over the eastern Asian region The mechanisms for the benefit of CCBs

7 Agenda The evidence on CCBs over the world The evidence on CCBs over the eastern Asian region The mechanisms for the benefit of CCBs

8 Regulatory mechanisms of BP and antihypertensive drug classes Stress Na + & K + Activation of SNS and RAS Volume expansion SNS RAS Na + & H2O Peripheral resistance BB ACEI Diu CCB ARB

9 META-ANALYSES OF EARLY TRIALS ON CCBS OVER THE WORLD

10 CCBs vs. diuretics/ -blockers: Fatal and nonfatal stroke Trials Heterogeneity Number of events/patients Old drugs CCBs Odds ratios (95% CIs) Difference (SD) MIDAS/NICS/VHAS 15/ /1353 STOP2/CCBs 237/ /2196 NORDIL 196/ /5410 INSIGHT 74/ /3157 ALLHAT/Amlodipine 675/ /9048 ELSA 14/1157 9/1177 CCBs without CONVINCE p = / / % (4.8) 2p = 0.02 CONVINCE 118/ /8179 All CCBs p = / / % (4.4) 2p = CCBs better Old drugs better Staessen JA, et al. Lancet 2001;37: Staessen JA et al. J Hypertens 2003;21:

11 CCBs vs. diuretics/ -blockers: Fatal and nonfatal MI Trials Heterogeneity Number of events/patients Old drugs CCBs Odds ratios (95% CIs) Difference (SD) MIDAS/NICS/VHAS 16/ /1353 STOP2/CCBs 154/ /2196 NORDIL 157/ /5410 INSIGHT 61/ /3157 ALLHAT/Amlodipine 1362/ /9048 ELSA 17/ /1177 CCBs without CONVINCE p = / / % (3.9) 2p = 0.26 CONVINCE 166/ /8179 All CCBs p = / / % (3.7) 2p = CCBs better Old drugs better Staessen JA, et al. Lancet 2001;37: Staessen JA et al. J Hypertens 2003;21:

12 THE RECENT TRIALS OR ANALYSES ON CCBS OVER THE WORLD ASCOT: vs a -blocker, atenolol ACCOMPLISH: vs a diuretic, HCZ ALLHAT: vs an ACEI, lisinopril VALUE: vs an ARB, valsartan

13 ASCOT-BPLA: Primary and secondary endpoints Primary endpoint Nonfatal MI (including silent MI)+fatal CHD Unadjusted Hazard ratio (95% CI) 0.90 ( ) Secondary endpoint Nonfatal MI(excluding silent MI)+ fatal CHD All coronary events All CV events and procedures Total mortality CV mortality Fatal and nonfatal stroke Fatal and nonfatal heart failure 0.87 ( ) 0.87 ( ) 0.84 ( ) 0.89 ( ) 0.76 ( ) 0.77 ( ) 0.84 ( ) Amlodipine Atenolol Perindopril better Bendrofluathiazide better Dahlöf B et al. Lancet 2005:366;

14 ACCOMPLISH: Primary endpoint and components Risk Ratio (95%) Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death 0.80 ( ) 0.81 ( ) 0.81 ( ) 0.87 ( ) 0.74 ( ) 0.85 ( ) 1.75 ( ) Favors CCB / ACEI Favors ACEI / HCTZ Jamerson K et al. N Engl J Med 2008;359:

15 ALLHAT:Lisinopril vs. Amlodipine Endpoint Relative risk (95% CI) Difference (95% CI) CHD All cause mortality Combined CHD Stroke Combined CVD Hospitalized GI bleeding Heart failure Angina Coronary revascularisation Peripheral arterial disease Lisinopril better % ( 9% to +11%) +5% ( 3% to +13%) +4% ( 3% to +12%) +23% (+8% to +41%) +6% ( 0 to +12%) +20% (+6% to +37%) -13% ( 22% to 4%) +9% ( 0 to +19%) 0 ( 9% to +11%) +19% (+1% to +40%) Amlodipine better P=0.003 P=0.047 P=0.004 P=0.007 P=0.055 P= Leenen FHH, et al. Hypertension 2006;48:

16 ALLHAT: Incidence of MI and fatal CHD Cumulative rate of CHD With CHD at baseline Without CHD at baseline Amlodipine Lisinopril Follow-up time (years) Follow-up time (years) RR(95%Cl) P RR(95%Cl) P lis/aml 1.06( ) 0.69 lis/aml 0.98( ) 0.78 Leenen FHH, et al. Hypertension 2006;48:

17 VALUE: Fatal and nonfatal MI % of patients with 1st event Valsartan Amlodipine 19% Number at risk 1 0 HR = 1.19; 95% CI = ; P = Months Valsartan Amlodipine Julius S et al. Lancet. June 2004;363.

18 Amlodipine vs. ARBs*: Fatal and nonfatal stroke Trials Heterogeneity Number of events / patients Odds ratios ARBs CCBs (95% CIs) Difference (SD) IDNT 30/579 18/567 VALUE 322/ /7596 CASE-J 60/ /2349 All trials p = /10, /10, % (6.2) 2p = * Irbesartan, valsartan, and candesartan CCBs better ARBs better Wang JG et al. Hypertension 2007; 50:

19 Amlodipine vs. ARBs*: Fatal and nonfatal MI Trials Heterogeneity Number of events/patients ARBs CCBs Odds ratios (95% CIs) Difference (SD) IDNT 51/579 33/567 VALUE 369/ /7596 CASE-J 17/ /2349 All trials p = /10, /10, % (6.1) 2p = * Irbesartan, valsartan, and candesartan CCBs better ARBs better Wang JG et al. Hypertension 2007; 50:

20 Agenda The evidence on CCBs over the world The evidence on CCBs over the eastern Asian region The mechanisms for the benefit of CCBs

21 Summary of the evidence on CCBs over the Asian region Syst-China: nitrendipine vs a placebo FEVER: felodipine+hctz vs HCTZ+placebo CASE-J: amlodipine vs candesartan CHIEF: amlodipine+telmisartan vs amlodipine+diuretics

22 Syst-China Systolic Hypertension in China Trial J Hypertens 1998; 16: Arch Intern Med 2000; 160:

23 Syst-China: Fatal and non-fatal endpoints Placebo Active treatment (n=1141) (n=1253) Total mortality CV mortality Stroke mortality All CV events Fatal and non-fatal stroke % Active treatment better Placebo better Liu LS et al. J Hypertens 1998;16:

24 FEVER Felodipine Event Reduction Trial J Hypertens 2005;23:

25 FEVER:Fatal and nonfatal stroke 10 8 HCTZ+placebo HCTZ+felodipine Stroke incidence (%) % Follow-up (years) Liu LS et al. J Hypertens 2005;23:

26 CASE-J:Primary composite CV endpoint % of patients with first event Candesartan: 17.7/1000 p-y Amlodipine: 17.6/1000 p-y Amlodipine Candesartan P=0.969 HR=1.01;95% CI X Months since randomisation Ogihara T et al. Hypertension. 2008;51:393-8.

27 CASE-J:Candesartan vs amlodipine Events Candesartan (n=2354) Amlodipine (n=2349) Hazard ratio (95%CIs) P value CV composite Sudden death Cerebrovascular 134 ( 5.7 % ) 134 ( 5.7 % ) ( 0.5 % ) 15 ( 0.6 % ) ( 2.6 % ) 50 ( 2.1 % ) 0.28 Cardiac 43 ( 1.8 % ) 47 ( 2.0 % ) 0.68 Renal Other vascular 19 ( 0.8 % ) 27 ( 1.1 % ) ( 0.5 % ) 7 ( 0.3 % ) Candesartan better Amlodpine better Ogihara T et al. Hypertension. 2008;51:393-8.

28 Chinese Hypertension Intervention Efficacy (CHIEF):General design Hypertensive patients at high CV risk (n=12,000) Amlodipine 2.5 mg/d +telmisartan 40 mg/d Amlodipine 2.5 mg/d +amiloride 1.25/ HCTZ 12.5 mg/d 0y 1y 2y 3y 4y Primary endpoint: CV death, stroke and MI

29 Clear recommendations If no compelling indications or contraindications, simply start with CLASSIC (Amlodipine), with the possible replacement of or combination with FASHION (ARB/ACEI). The A+A partnership.

30 Agenda The evidence on CCBs over the world The evidence on CCBs over the eastern Asian region The mechanisms for the benefit of CCBs

31 Possible mechanisms for the benefit of CCBs Better central BP control Better 24 h BP control Lesser metabolic side effects Positive synergy with statins Less SBP variability Prevention of thickening of arterial wall

32 O1 IDACO*: Prognosis of various forms of ambulatory hypertension *IDACO; International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome Fan HQ, et al. J Hypertens 2010; Epub.

33 슬라이드 32 O1 In the next 3 slides, I will show you the characteristics of the participants. In 204 men and 223 women, age averaged 44 years. two third of men consumed alcohol and cigarrettes. About 20% of women drank alcohol but none smoked. The prevalence of hypertension was about 25% and only about 10% took antihypertensive drugs. Owner,

34 IDACO: Morning BP surge Bedding Getting up Awake Asleep Awake Morning BP Pre-awakening BP Lowest BP Pre-awakening MS Sleep-through MS 6PM Midnight 6AM Noon Kario K et al. Circulation 2003;107:

35 IDACO: Risk according to the level of morning BP surge Li Y, et al. Hypertension 2010;55:

36 2 VALUE ABPM substudy : Differences in 24 h SBP Valsartan lower Mean SBP difference (mm Hg) mmHg P= n= Hours after drug intake Amlodipine lower Pedersen et al. J Hypertens 2007;25:

37 Augmentation Index (AIx) 1st shoulder 2nd shoulder Augmentation Pressure (AP) Incisura P1 PP AIx = AP / PP Systole Diastole Start of the Wave (msec)

38 ASCOT-CAFE:Peripheral and central pressure 140 Pheripheral SBP: mean =0.7 (-0.4 to 1.7) mm Hg Atenolol Amlodipine SBP (mm Hg) Central SBP: mean =4.3 (3.3 to 5.4) mm Hg Time since randomisation (years) Williams B, et al. Circulation 2006;113:

39 Associations between SBP variability and stroke risk (hazard ratios per 20 mm Hg increase in SBP) p value=0.006 UK and Dutch TIA trials

40 Mean (SD) SBP at baseline and during follow-up in the ALLHAT trial

41 IDACO*: Reading-toreading BP variability 20 All cause NCV mortality CV mortality CV events Cardiac events Stroke 387 Events per 1000 personyears Systolic AVR (mm Hg) *IDACO; International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome Hansen TW, et al. Hypertension. 2010;55:

42 ASCOT:Long-term BP variability Stroke Coronary events Mean of SBP Amlodipine Atenolol HR (95% CI) SD of SBP Percentile Rothwell PM et al. Lancet 2010; 375:

43 ASCOT: Coefficient of variation for SBP Amlodipine Atenolol CV of 3 BP readings on the same occasion (%) Baseline Follow-up (years) Rothwell PM et al. Lancet Neurol 2010; 9:

44 Mean and SD SBP during F/U All large randomised trials of CCBs versus β blockers or ACEIs CCB better CCB better

45 The Relationship Between Visitto-Visit Variability in SBP and All-Cause Mortality in the General Population Findings From NHANES III, 1988 to 1994 Hypertension. 2011;57:

46 All-Cause Mortality over a median of 14 years of follow-up

47 Effects of initiation and increase in dose of CCBs on within-individual variability in BP Amlodipine 5mg Amlodipine 10mg Felodipine 2.5mg Felodipine 5mg Felodipine stop

48 VALUE: Blood pressure DBP (mmhg) Valsartan (N= 7649) Amlodipine (N = 7596) 75 Baseline Difference in SBP (mmhg) Difference between valsartan and amlodipine Incidence of syncope 1.0%/1.7% 59%; P< Follow-up (months) Julius S et al. Lancet. June 2004;363.

49 IMT and CV events Incidence of MI or stroke per 1000 p-y Maximal CCA IMT Maximal ICA IMT Maximal CCA/ICA IMT Quintiles of IMT O Leary DH, et al. N Engl J Med 1999;340:14.

50 Active treatment vs placebo/no treatment on IMT Trial n* Baseline IMT ( m)* Change/y ( m)* Difference ( m/y, 95% CI) All ACEIs 929:1161 Heterogeneity 2 = 18.1 P = BCAPS ELVA All Bs 390:393 44:35 434:428 Heterogeneity 2 = 3.7 P = : :894 8:7 12:-12-6 (-12 to 0.4) p = (-33 to 13) p = 0.41 PREVENT 186: : :-4 All trials 1549:1780 Heterogeneity 2 = 25.9 P = *Control:Active -7 (-12 to -2) p = Favours Favours active treatment control Wang JG, et al. Stroke 2006;37:1933.

51 CCBs vs diuretics/ -blockers Trial n* Baseline IMT ( m)* Change/y ( m)* Difference ( m/y, 95% CI) MIDAS 441: : :40 VHAS 191: :902 16:15 INSIGHT 164: :668 5:-1 ELSA 1012: : :13 All CCBs 1808:1811 Heterogeneity 2 = 2.1 P = (-9 to -1) p = *Old:CCB Favours Favours CCBs old drugs Wang JG et al. Stroke 2006;37:

52 IMT: CCBs vs. ACEIs Trial n* Baseline IMT ( m)* Change/y ( m)* Difference ( m/y, 95% CI) Koshiyama 11:11 : 22:-104 Topouchian 18:21 680:720-80:-40 Pontremoli 16:15 820:840-65:-110 Stanton 34:35 792:763-27:-48 ELVERA 63: :1019 0:-17 All trials 142:145 Heterogeneity 2 = 4.5 P = 0.34 *ACEIs:CCBs -23 (-42 to -4) p = Favours CCBs Favours old drugs Wang JG, et al. Stroke 2006;37:1933.

53 Impact on the risk of development of T2DM based on treatment choice AASK ALLHAT ALPINE ANBP-2 ASCOT CAPPP CHARM DREAM EWPHE FEVER HAPPHY HOPE HOPE-TOO-HOPE INSIGHT INVEST LIFE MRC-E NORDIL PEACE SCOPE SHEP SHEP-2 SOLVD STAR STOP-2 TROPHY VALUE Decreased risk T2DM Neutral Increased risk T2DM ARB 0.57 ( ) p< ACE Inhibitor 0.67 ( ) p< CCB 0.75 ( ) p=0.002 Placebo 0.77 ( ) p=0.009 ß Blocker 0.90 ( ) p=0.30 Diuretic Referent Incoherence= Odds Ratio of Incident Diabetes Adapted from Elliott et al. Lancet.2007;369(9557):201-7

54 ASCOT-BPLA: New-onset diabetes mellitus Cumulativ e events (%) Atenolol thiazide (No. of events = 799) 30% Amlodipine perindopril (No. of events = 567) HR 0.70 (95% ) P < Number at risk Amlodipine perindopril Atenolol thiazide Years Dahlöf B et al. Lancet 2005:366;

55 Clinical trials:new onset diabetes TRIAL (FU>2.5 years) CAPPP/Cap STOP 2/ACEIs ANBP 2/Ena ALLHAT/Lin NORDIL/Dil INSIGHT/Nif ALLHAT/Aml INVEST/Ver ASCOT/Aml LIFE/Los SCOPE/Can New onset diabetes Hazard Ratio (95% CI) P -21%; P= %; P= %; P< %; P< %; P= %; P= %; P= %; P= %; P< %; P< %; P= ACEIs/CCBs -blockers/diuretics Mancia G, et al. J Hypertens 2006;24:3-10.

56 Take Home Message (1) CCBs are more beneficial in stroke prevention compared with diuretics, - blockers, ACEIs and ARBs. LOGO

57 Take Home Message (2) Among various DHP-CCBs, amlodipine has the best evidence in the prevention of MI. Amlodipine is efficacious as diuretics, -blockers, and ACEIs, and more than ARBs.

58 Take Home Message (3) The better outcome of CCB over other class of antihypertensive drugs is largely due to Better 24 h and central BP control Less SBP variability Prevention of thickening of arterial wall LOGO

59 Thanks for your attention! Thank you for attention~!