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Antihypertensiv fixdózisú kombinációk, mint elsővonalbeli szerek?

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1 Antihypertensiv fixdózisú kombinációk, mint elsővonalbeli szerek?
Prof. Dr. Farsang Csaba egyetemi tanár Szent Imre Kórház Belgyógyászat, Kardiometabolikus Centrum, Budapest

2 GYÓGYSZERKOMBINÁCIÓK Főv. Szt. Imre Kórház, Kardiometabolikus Centrum
HYPERTONIÁBAN Farsang Csaba Főv. Szt. Imre Kórház, Kardiometabolikus Centrum DNN, Debrecen 2009 június 3

3 Vérnyomás normalizációs rátája
Monoterápiával csak a betegek mintegy 40 %-ában , Kombinációval a betegek > 80 %-ában normalizálható a vérnyomás:

4 ESH/ESC Guidelines 2007: Monotherapy Combination therapy
Mild BP elevation Low /moderate risk Conventional BP target Marked BP elevation High / very high risk Lower BP target Choose between Monotherapy low dose Two-drug combination at low dose

5 Marked BP elevation: High / very high risk: Lower BP target
actual BP 20/10 mm Hg > target BP High / very high risk: HTN, additional risk factors, DM, MS, established cardiovascular or renal disease Lower BP target nephropaty, DM, MS, High risk pts.

6 Monotherapy versus combination therapy
In high risk hypertensives, goal blood pressure should be achieved more promptly, which favours initial combination therapy and quicker adjustment of doses. 2007 ESH / ESC Guidelines

7 Ratio of observed to expected incremental blood pressure-lowering effects* of adding a drug or doubling the dose 1.5 1.16 ( ) Adding a drug from another class (on average standard doses) Doubling dose of same drug (from standard dose to twice standard) 1.00 ( ) 1.04 ( ) 0.89 ( ) 1.01 ( ) 1.0 of observed to expected additive effects Incremental SBP reduction ratio 0.37 ( ) 0.5 0.23 ( ) 0.19 ( ) 0.20 ( ) 0.22 ( ) 0.0 Thiazide Beta- blocker ACE- inhibitor Calcium channel blocker All classes * The expected incremental effect is the incremental blood pressure reduction of the added (or doubled drug), assuming an additive effect and allowing for the smaller reduction from 1 drug (or dose of 1 drug) given the lower pretreatment blood pressure because of the other Wald DS et al., Am J Med 2009; 122: 290

8 Discontinuation Rate at 9 Months of Initial Antihypertensive Drug
Treatment (data from Italy / The Netherlands / Sweden; n = 49,805) 25.2 23.9 18.2 Discontinuation rate All Initial monotherapy Initial combination therapy Nicotra et al., 2009

9 Requirements for and advantages of drug combinations
Good tolerability for components; Higher efficacy than individual components Additive or potentiation synergism between components; Duration of action should be > 24 hr; It sould be applicable in the majority of hypertensive patients; Prevalence and severity of side effects >;

10 Advantages of the fix combination
Simple uptitration; Easy administration; Components have additive of potentiation synergism enhanced effect in special population: compliance / adherence / persistance of patients is better: -- one tablet / day %, -- two tablets / day %, -- three tablets / day %.

11 Possible combinations between some classes of Antihypertensive drugs
Thiazide diuretics ACE inhibitors β-blockers Angiotensin receptor antagonists Calcium antagonists α- blockers The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled intervention trials

12 ESH / ESC 2007: 810 lehetséges hatóanyag-kombináció
2 x 8 = 16 Pitter J. 2008

13

14 Kiss I és Farsang Cs. (közlés alatt 2009)

15 + MI T2DM LVH Diuretics ARBs ACEIs CCBs Stroke Beta- blockers CV
events LVH Farsang C, Naditch-Brule L, Avogaro A, Östergren JO, Verdecchia P, Maggioni A, van de Borne P, Lins R, Roca-Cusachs A. J.Clin.Hypertens.2009

16 A jövő antihypertensiv kombinációi?
Renin-Angiotenzin- Aldosteron gátlás Kalcium antagonisták Diureticumok Vasodilatator béta-blokkolók ? Alfa-blokkolók I-1 agonisták

17 Melyik kombinációt ? ACEI+CCB (LisonormR) (HAMLET)
ACEI+CCB (LisonormR) (ALFESS) ACEI+CCB vs. ACEI+DIU (ACCOMPLISH) ACEI+CCB vs. BBL+DIU (ASCOT) ACEI + Ndhp-CCB vs. ARB+DIU (STAR, STARLET) ARB+DIU vs. BBL+DIU (LIFE) ARB+DIU vs. CCB+DIU (VALUE)

18 ACEI + CCB

19 ACEI + CCB versus ACEI + DIU

20 Systolic Blood Pressure Over Time
ACCOMPLISH Systolic Blood Pressure Over Time ACEI + HCTZ N=5733 ACEI+CCB N=5713 mm Hg 130mmHg Difference of 0.7 mmHg p<0.05* 129.3 mmHg Month Patients *Mean values are taken at 30 months F/U visit DBP: 71.1 DBP: 72.8 Jamerson K, et al N Engl J Med 2009

21 Kaplan Meier for Primary Endpoint
ACCOMPLISH Kaplan Meier for Primary Endpoint ACEI / HCTZ ACEI / CCB 20% Risk Reduction 650 526 Cumulative event rate p = 0 .0 2 Time to 1st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90) Jamerson K, et al N Engl J Med 2009 21

22 Primary Endpoint and Components
ACCOMPLISH Primary Endpoint and Components Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) 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 0.5 1.0 2.0 0.80 (0.72–0.90) 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 2009 22 22 22

23 Primary and Other Endpoints
ACCOMPLISH Primary and Other Endpoints Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio (95%) Composite CV mortality/morbidity Primary w/o revascularization Hard CV endpoint (CV death, non-fatal MI, non-fatal stroke) All cause mortality 0.80 (0.72–0.90) 0.79 (0.68–0.92) 0.80 (0.68–0.94) 0.90 (0.75–1.08) 0.5 1.0 2.0 Favors CCB / ACEI Favors ACEI / HCTZ Jamerson K, et al N Engl J Med 2009 23 23

24 KÖVETKEZTETÉS ACEi + CCB jobb mint az ACEi + DIU
80 évnél idősebb betegekben (HYVET) Diabeteses betegekben (ADVANCE) az ACEI + DIU jobb, mint a placebo

25 Nagyon idős (>80 év) betegekben
Incidence of Morbidity / Mortality in HYVET All stroke Fatal stroke 8 5 7 -30% 4 6 -39% 5 p = 0.055 p = 0.046 3 4 2 3 5 months 2 1 1 No. of events per 100 patients 7 Heart failure 30 Total mortality Placebo Active treatment (perindopril+ indapamide) 6 5 20 -21% 4 p < -64% p = 0.019 3 10 2 4 months 1 2.3 years 1 2 3 4 1 2 3 4 Follow-up (yr) Follow-up (yr)

26 ACEI + CCB versus BBL + DIU

27 amlodipine ± perindopril
Study design 19,257 hypertensive patients ASCOT-BPLA atenolol ± bendroflumethiazide PROBE design amlodipine ± perindopril BBL + DIU CCB + ACEI

28 Amlodipine  perindopril
Unstable angina % 1.2 Atenolol  thiazide (No. of events 106) 1.0 0.8 Amlodipine  perindopril (No. of events 73) 0.6 0.4 RRR: 32 % HR = 0.68 (0.51­0.92) p = 0.2 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

29 Amlodipine  perindopril
CV mortality % 3.5 Atenolol  thiazide (No. of events 342) 3.0 2.5 2.0 Amlodipine  perindopril (No. of events 263) 1.5 1.0 HR = 0.76 (0.65­0.90) p = RRR: 24 % 0.5 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

30 Fatal and non-fatal heart failure
% 1.8 1.6 Atenolol  thiazide (No. of events 159) 1.4 1.2 Amlodipine perindopril (No. of events 134) 1.0 0.8 0.6 0.4 HR = 0.84 (0.66­1.05) p = RRR: 16 % 0.2 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

31 Fatal and non-fatal stroke
% 5.0 Atenolol  thiazide (No. of events 422) 4.0 3.0 Amlodipine  perindopril (No. of events 327) 2.0 HR = 0.77 (0.66­0.89) p = RRR: 23 % 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

32 Peripheral arterial disease
% 2.5 2.0 Atenolol  thiazide (No. of events = 202) 1.5 1.0 Amlodipine  perindopril (No. of events = 133) RRR: 35 % 0.5 HR = 0.65 (0.52­0.81) p = 0.0 Years 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril Atenolol  thiazide

33 New-onset renal impairment
% 5.0 Atenolol  thiazide (No. of events = 469) 4.0 3.0 Amlodipine  perindopril (No. of events = 403) 2.0 HR = 0.85 (0.75­0.97) p = RRR: 15 % 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

34 New-onset diabetes mellitus
% 10.0 Atenolol  thiazide (No. of events = 799) 8.0 6.0 Amlodipine  perindopril (No. of events = 567) 4.0 2.0 HR = 0.70 (0.63­0.78) p < RRR: 30 % 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

35 KÖVETKEZTETÉS ACEi + CCB jobb mint a BBL + DIU

36 ACEI + ndhpCCB versus ARB + DIU

37 Treatment Period for Main Study
STAR - STARLET Study Design Washout Period Treatment Period for Main Study Follow-up Period STAR STAR-LET T/V 2/180 mg QD or 4/240 mg QD T/V 2/180 mg QD T/V 2/180 mg QD or 4/240 mg QD L/H 50/12.5 mg QD Treatment Period L/H 50/12.5 mg QD or 100/25 mg QD End of Treatment Main Study Subject Screened Subject Randomized Dose Titration as Needed 30 Days 4 Weeks 4 Weeks 48 Weeks 26 weeks Bakris GL et.al. Diabetes Care 2006;29: and Bakris GL et.al J CardioMetabolic Syn, In Press

38 STAR Primary Endpoint 2-Hour OGTT Adjusted# Mean (± SE) Change in Blood Glucose From Baseline T/V L/H 40 35 Baseline 2-Hour OGTT Blood Glucose N Mean (SD) mg/dL T/V (43.9) L/H (45.0) 30 *** *** 25 20 15 *** L / H mg/dL 10 5 T / V -5 -10 -15 -20 12 Weeks 52 Weeks Study End& n = *** P ≤0.001 between treatment groups. & Mean period of follow-up for OGTT for T/V group was 45.5 weeks (range, 6.9–54.3 weeks) and for L/H group was 48.3 weeks (range, 11.7–56.1 weeks). # Adjusted for Baseline and center. Bakris GL et.al. Diabetes Care 2006;29:

39 STAR 2-Hour OGTT Adjusted# Mean (± SE) Change in Blood INSULIN From Baseline 40 T/V L/H 35 30 25 * 20 * 15 * L / H µIU/mL 10 5 T / V -5 -10 -15 -20 12 Weeks 52 Weeks Study End& n = * P ≤0.05 between treatment groups. & Mean period of follow-up for OGTT for T/V group was 45.5 weeks (range, 6.9–54.3 weeks) and for L/H group was 48.3 weeks (range, 11.7–56.1 weeks). # Adjusted for Baseline and center. Bakris GL et.al. Diabetes Care 2006;29:

40 OGTT Results at Baseline and Study End
STAR T/V Baseline (n=108) 220 T/V Study End (n=108) L/H Baseline (n=107) L/H Study End (n=107) 200 180 * Mean Blood Glucose (mg/dL) 160 140 120 100 30 60 90 120 Minutes * P = for comparison of T/V versus L/H OGTT-glucose AUC0-120 [mg/dL/hr] change from Baseline to Study End. Bakris GL et.al. Diabetes Care 2006;29:

41 New Onset of Diabetes (FBG: ≥ 126 mg/dL)
STAR - STARLET New Onset of Diabetes (FBG: ≥ 126 mg/dL) 35 T/V L/H ** 30 * ** 25 20 Percent 15 10 5 Week 12 Week 52 Study End& New onset Diabetes (n) = Total (n) = 6 86 20 93 10 72 20 83 10 91 25 94 * P ≤0.05 between treatment groups, ** P ≤0.01 between treatment groups. & Mean period of follow-up for OGTT for T/V group was 45.5 weeks (range, 6.9–54.3 weeks) and for L/H group was 48.3 weeks (range, 11.7–56.1 weeks). Incidence of new-onset diabetes (post Baseline) was defined as either a fasting blood glucose of ≥126 mg/dL and/or a blood glucose of ≥200 mg/dL following the OGTT (ADA Guidelines), excluding patients meeting one of these criteria at Baseline. Bakris GL et.al. Diabetes Care 2006;29:

42 STAR-LET OGTT Results At Baseline and Study End
Patients Continuing With T/V Patients Switched From L/H to T/V 200 200 L+H 180 180 160 Mean Blood Glucose (mg/dL) 160 Mean Blood Glucose (mg/dL) T+V 140 140 120 120 T/V Continued Baseline (n = 59) L/H Switched to T/V Baseline (n = 50) T/V Continued Study End (n = 59) L/H Switched to T/V Study End (n = 50) 100 100 30 60 90 120 30 60 90 120 Time (Minutes) Time (Minutes) Bakris GL et.al. Diabetes Care 2006;29: and Bakris GL et.al J CardioMetabolic Syn, In Press

43 CH anyagcserét tekintve jobb mint az
KÖVETKEZTETÉS ACEI + NDH-CCB CH anyagcserét tekintve jobb mint az ARB +DIU

44 ARB+DIU versus BBL+DIU?

45 LIFE: Primary Composite Endpoint
2 4 6 8 10 12 14 16 Proportion of patients with first event (%) Composite of CV death, stroke and MI Losartan+HCTZ Atenolol+ HCTZ Slide 16: LIFE: Primary Composite Endpoint The LIFE study was the first time that a combined cardiovascular morbidity and mortality primary endpoint trial in hypertensive patients demonstrated the superiority of an antihypertensive agent, losartan, over an active comparator that is a current standard treatment for hypertension (atenolol).1 The primary endpoint of LIFE was the composite of cardiovascular morbidity and mortality (defined as stroke, MI, and cardiovascular death). By adjusted intention-to-treat analysis (which was the primary analysis approach of this study), losartan was superior to atenolol in reducing the risk of combined cardiovascular morbidity and mortality – a significant 13% relative risk reduction versus atenolol (p=0.021).1 If not adjusted for Framingham risk score and ECG-confirmed LVH at baseline, the outcomes were slightly more favorable, 14.6% (p=0.009).1 No significant differences in CV death and MI versus atenolol were observed.1 The risk reduction in CV events with atenolol was consistent with those in previous studies with beta blocker-based regimens versus placebo, such as the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).12 The superior risk reduction in the primary endpoint (composite of CV death, MI, and stroke) with losartan versus atenolol in the LIFE study suggests an important role for losartan in patients with hypertension beyond the effects of blood-pressure reduction alone. Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009 Number at Risk 6 12 18 24 30 36 42 48 54 60 66 Study Month Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf B et al Lancet 2002;359: 45

46 Proportion of patients with first event (%)
Stroke 1 2 3 4 5 6 7 8 Fatal and nonfatal stroke Atenolol+HCTZ Losartan+HCTZ Proportion of patients with first event (%) Slide 17: LIFE: Stroke Losartan reduced the risk of fatal and nonfatal stroke, a major cause of death and disability, by 25% compared with atenolol. This risk reduction was highly significant (p=0.0010).1 This cerebrovascular protective benefit in patients treated with losartan was greater than has been observed in trials of varying hypertensive patient populations in comparisons of CCB-based therapy with diuretic-based or beta blocker-based therapy.35 The superior risk reduction in stroke with losartan versus atenolol in the LIFE study suggests an important role for losartan in patients with hypertension beyond the effects of blood-pressure reduction alone.1 Adjusted Risk Reduction %, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 6 12 18 24 30 36 42 48 54 60 66 Study Month Number at Risk Losartan Atenolol Dahlöf B et al Lancet 2002;359:

47 KÖVETKEZTETÉS ARB (+DIU) jobb, mint a BBL (+DIU)

48 ARB+DIU versus CCB+DIU?

49 VALUE: Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 Valsartan+HCTZ Amlodipine+HCTZ Proportion of Patients With First Event (%) HR = 1.03; 95% CI = 0.94–1.14; P = 0.49 The primary composite endpoint, a cardiac morbidity or mortality event, occurred in 810 patients in the valsartan group and 789 patients in the amlodipine group (10.6% vs 10.4%, P=0.49).1 There was no significant difference in cardiac morbidity or mortality in these high-risk patients treated with valsartan- or amlodipine-based regimens. The Kaplan-Meier curves separated during the first 6 months, but then started to converge and ultimately overlapped towards the end of the study.1 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Time (months) Number at risk Valsartan 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 Amlodipine 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474 Julius S et al. Lancet. June 2004;363.

50 VALUE: Outcome and SBP Differences at Specific Time Periods: Stroke
Time Interval  SBP STROKE (months) (mmHg) Odds Ratios and 95% CIs Overall study 2.2 0–3 3.8 3–6 2.3 6–12 2.0 12–24 1.8 24–36 1.6 36–48 1.4 The association between the greater decrease in SBP with amlodipine and the decrease in stroke was most pronounced in the first 6 months of the trial. As the difference in SPB between groups decreased, so did the odds ratios: in the last 2 years of the study the odds ratio for stroke was lower than unity.1 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Study end 1.7 0.25 0.5 1.0 2.0 4.0 Favours valsartan Favours amlodipine +HCTZ HCTZ Julius S et al. Lancet. June 2004;363.

51 VALUE: Fatal and Non-fatal Stroke
6 5 4 3 2 1 Valsartan+HCTZ Amlodipine+HCTZ Proportion of Patients With First Event (%) HR = 1.15; 95% CI = 0.98–1.35; P = 0.08 There was a trend towards fewer fatal or non-fatal strokes in the amlodipine group, 322 vs 281 in the valsartan and amlodipine groups, respectively (HR=1.15 [95% CI ], P=0.08).1 The Kaplan-Meier curves separated early in favor of amlodipine, and the slopes subsequently became parallel for the remainder of the study.1 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Time (months) Number at risk Valsartan 7649 7494 7448 7312 7170 7022 6877 6692 6515 6093 3859 1516 Amlodipine 7596 7499 7455 7334 7195 7055 6918 6744 6587 6163 3846 1532 Julius S et al. Lancet. June 2004;363.

52 VALUE: Fatal and Non-Fatal Myocardial Infarction
7 6 5 4 3 2 1 Valsartan+HCTZ Amlodipine+HCTZ Proportion of Patients With First Event (%) HR = 1.19; 95% CI = ; P = 0.02 Of the secondary endpoints, fatal or non-fatal myocardial infarction occurred in 369 patients in the valsartan group and 313 patients in the amlodipine group (HR=1.19 [95% CI 1.02–1.38], P=0.02).1 The Kaplan-Meier curves separated during the first 6 months and remained separated in favor of amlodipine throughout the study. 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Time (months) Number at risk Valsartan 7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520 Amlodipine 7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532 Julius S et al. Lancet. June 2004;363.

53 Proportion of Patients With First Event (%)
VALUE: Heart Failure Hospitalisation for HF or death from HF 9 8 7 6 5 4 3 2 1 Valsartan+HCTZ Amlodipine+HCTZ Proportion of Patients With First Event (%) HR = 0.89; 95% CI = ; P = 0.12 A total of 354 patients in the valsartan group were hospitalised for heart failure, compared to 400 patients in the amlodipine group (HR=0.89 [95% CI ], P=0.12).1 Thus there was a trend towards fewer heart failure hospitalisations in the valsartan group. The Kaplan-Meier curves separated after 36 months and the trend in favor of valsartan that became more pronounced as the study progressed. 1 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Time (months) Number at risk Valsartan 7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513 Amlodipine 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511 Julius S et al. Lancet. June 2004;363.

54 VALUE: Incidence of New-onset Diabetes
23% Risk Reduction With Valsartan 18 16 P < 14 12 New-Onset Diabetes (% of patients in treatment group) 10 16.4% 8 13.1% 6 4 2 VALUE was the first trial to demonstrate a significant decrease in new-onset diabetes with an angiotensin receptor blocker when compared with a calcium channel blocker. Therapy with the valsartan-based regimen reduced the incidence of new-onset diabetes by 23% compared to the amlodipine-based regimen (690 vs 845 patients, P<0.0001).1 As diabetes mellitus is a significant risk factor for cardiovascular outcomes, this significant result provides support for use of valsartan in patients who are at risk for developing diabetes. 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. Valsartan+HCTZ (n = 7649) Amlodipine+HCTZ (n = 7596) Julius S et al. Lancet. June 2004;363.

55 jobb (HF, DM) is és rosszabb is (vérnyomás, stroke, AMI), mint a
KÖVETKEZTETÉS ARB (+DIU) jobb (HF, DM) is és rosszabb is (vérnyomás, stroke, AMI), mint a CCB (+DIU)

56 Advantages of amlodipin és lisinopril combination
Different pharmacodynamic target Similar pharmacokinetics Applicable to the majority of hypertensive patients Cardiovascular protective effects of both components are well documented Additive synergism between the two components (Cappuccio 1993, Naidu 2000, HAMLET)

57 Study results of Capuccio (1993)
Diastolic Systolic P = vs. Lis10 P = vs. Aml5 P = vs. Aml5 * No data P = vs. Lis10 P = vs. Aml5 P = vs. Lis10 P = vs. Aml5 _ X ± S.E.M. Mean responses show clinically significant advantage of A+L combo vs both monotherapies Statistical significance: systolic BP at peak and at trough, diastolic BP at peak Peak (supine) Trough (supine)

58 Study results of Naidu (2000)
Diastolic at trough Systolic at trough _ X ± S.D. Mean responses show clinically significant advantage of A+L combo vs both monotherapies Supine Standing

59 (Lisonorm vs. Lisopress vs. Normodipin)
HAMLET ACEI + CCB versus ACEI monotherapia CCB monotherapia (Lisonorm vs. Lisopress vs. Normodipin)

60 Responderráta a csúcshatás idején
HAMLET Responderráta a csúcshatás idején % szignifikáns *,** * szignifikáns * * ** * * P<0.05 **P<0.01

61 ALFESS vizsgálat ACEI + CCB versus baseline (LisonormR fix comb.)

62 Amlodipint és Lisinoprilt tartalmazó Fix gyógyszerkombináció (Lisonorm) hatásosságának és biztonságosságának vizsgálata ESSentialis hypertoniás betegeken. A cardiovascularis morbiditás és mortalitás meghatározó tényezői külön-külön is a tartósan magas vérnyomás és az emelkedett vércukorszint. A diabetes és a hypertonia együttes előfordulása többszörösére emeli a cardiovascularis események kialakulásának valószínűségét. ALFESS vizsgálat Ugyanezt mondhatjuk el a CV halálozás vonatkozásában is. Nagybetegszámú, hosszútávú utánkövetéses vizsgálatokban igazolták, hogy a hipertónia és a diabetes kontrollja érdemben csökkenti a cardiovascularis rizikót.

63 Vizsgálat nyílt, prospektív, multicentrikus 10 magyarországi centrum
járóbetegként kezelt essentialis hypertoniás betegek bevonásával előzetes Ca-antagonista és/vagy ACE-gátló kezelés nem megfelelő hatékonyságú vérnyomásmérés higanyos mérővel és ABPM-mel A vizsgálatban 29 magyarországi kórházi centrum 583 hypetoniás betege vett részt. A Normodipine hatékonyságát rendelői vérnyomásméréssel és ambuláns vérnyomás monitorozással a systolés és diastolés értékek alapján határozták meg. A vizsgálatot kiegészítették a biztonságosságra, tolerabilitásra, compliance-re és az életminőségre vonatkozó elemzésekkel. Tanulmányozták továbbá a Normodipine mellett alkalmazott ACE-gátló kombinációk hatékonyságát, valamint különös figyelmet fordítottak a hypertonia és ISZB együttes előfordulásakor mért paraméterek változására is. ALFESS

64 Vizsgálat - célkitűzések
Elsődleges cél: Lisonorm hatékonysága kiértékelése 12 hetes kezeléssel a syst. és diast. értékek alapján Másodlagos cél: biztonságosság, tolerabilitás, compliance Harmadlagos cél: Lisonorm hatékonysága kiértékelése ABPM-mel, ill. ABPM vs. hagyományos mérés össszehasonlítása a terápia beállításában A vizsgálatban 29 magyarországi kórházi centrum 583 hypetoniás betege vett részt. A Normodipine hatékonyságát rendelői vérnyomásméréssel és ambuláns vérnyomás monitorozással a systolés és diastolés értékek alapján határozták meg. A vizsgálatot kiegészítették a biztonságosságra, tolerabilitásra, compliance-re és az életminőségre vonatkozó elemzésekkel. Tanulmányozták továbbá a Normodipine mellett alkalmazott ACE-gátló kombinációk hatékonyságát, valamint különös figyelmet fordítottak a hypertonia és ISZB együttes előfordulásakor mért paraméterek változására is. ALFESS

65 Beválasztási kritériumok I.
I. vagy II. fokú primaer hypertonia ( Hgmm és/vagy/ Hgmm) Ha ACEI és/vagy Ca ant. előzetes kezelés nem megfelelően hatásos: ≥139/89 Hgmm szövődménymentes hypertoniában ≥ 130/85 Hgmm diab. nephropathiában ≥ 125/75 Hgmm 1g/nap felletti proteinuriás nephropathiában ALFESS

66 Folyamatábra LISONORM ALFESS 1. tabl 2.tabl* HCTZ*
2.vizit 28.nap 3.vizit 56.nap 4.vizit 74.nap 1.vizit -7-0. nap LISONORM 1. tabl 2.tabl* HCTZ* anamnézis fiz.vizsg RR mérés pulzusszám ABPM vizsg. EKG labor életminőség előző .kezelés Nemkiv. esemény fiz.vizsg. RR mérés pulzusszám ABPM, EKG labor nemkiv. Esemény hatásosság, compliance, tolerabilitás,életminőség RR mérés pulzusszám nemkiv .esemény compliance RR mérés pulzusszám nemkiv .esemény compliance ALFESS * Nem kielégítő hatás esetén

67 Vérnyomás változása ALFESS n:88 p<0.0001 p<0.0001 p<0.0001
155 n:88 129 94 80 ALFESS

68 ABPM eredmények ALFESS Hgmm S S S S: p>0.001 S S S
RRs RRd RRs RRd RRs RRd ALFESS ABPM 24 órás ABPM nappal ABPM éjszakai

69 ABPM eredmények ALFESS 1. vizit 4. vizit p - érték szignifikancia
Syst.diur. index 7.85 8.51 0.4691 NS Diast.diurn. index 12.74 13.34 0.4999 MAP diurn.index 8.45 8.25 0.9659 Syst. h. időindex 57.6 28.25 <0.0001 S Diast. h. időindex 23.77 9.56 MAP h. időindex 25.82 8.46 Syst.hyperbar.imp. 283.4 97.54 Diast.hyperbar.imp. 56.33 18.99 MAP hyperbar.impact 66.42 16.04 ALFESS

70 Dózis % n:88 kiinduláskor hónap hónap ALFESS

71 Leggyakoribb nemkívánatos események
esetszám Lábdagadás 2 Köhögés 5 Szédülés Rossz közérzet 4 Végtagfájdalom összesen 27 Nemkívánatos esemény előfordulása: 8,26% ALFESS

72 Tolerálhatóság ALFESS % megelőző kezelés Lisonorm kezelés
1. vizit vizit vizit vizit ALFESS

73 Megállapítások A Lisonorm® terápiával a célértékeket a betegek többségében el lehetett érni. A Lisonorm® szignifikáns vérnyomáscsökkentő hatása ABPM-mel is igazolható. A Lisonorm® terápia jól tolerálható. KÖVETKEZTETÉS: A Lisonorm® alkalmazható első vonalbeli szerként.

74 Következtetés Az ACEI + CCB kombináció előnye egyéb kombinációkkal
(ACEI+DIU, BBL+DIU, ARB+DIU) szemben a betegek túlnyomó többségében bizonyított.

75 Az antihypertensiv kezelés jövője melyik gyógyszer(kombináció)t
Nem az a lényeg, hogy általában mivel kezdjük az antihypertensiv therapiát, hanem az, hogy melyik gyógyszer(kombináció)t melyik betegnek milyen esetben adjuk

76 Antihypertensive Treatment: Preferred Drug combinations 2007
Modified from ESC Guidelines 2007 SUBCLINICAL ORGAN DAMAGE LVH ACEI / ARB + CA, Asymptomatic atherosclerosis CA + ACEI Microalbuminuria ACEI / ARB + NDHP-CA Renal dysfunction ACEI + ARB, ACEI+CA CONDITION ISH (elderly) diuretics + CA (+ ACEi / ARB) Metabolic syndrome ACEI / ARB + CA Diabetes mellitus ACEI / ARB + CA + Diu Pregnancy methyldopa, CA, BBL Blacks diuretics + CA + ARB Glaucoma BBL + ACEi / ARB ACEI: = ACE inhibitors, ARB = angiotensin receptor antagonists CA = calcium antagonists BB = beta-blockers.

77 Recomendations for the initial treatment of HTN in CKD
BP goals <130/80 mmHg, further reduction (<125/75 mmHg) if proteinuria >1 g/24 hr (ESH/ESC Guidelines 2007, ADA 2006) Maintain BP reduction during the 24 hour Drug combination Salt restriction Consider statins and antiplatelet therapy (if Cr >1.5 mg/dl?)

78 Objectives and intermediate endpoints
Main objective Reduce the rate of GFR decline and the development of ESRD Reduce CV morbidity and mortality Intermediate endpoints Reduction of proteinuria Reduction of UAE

79 Impact of treatment in eGFR
Toto R. Kideny Int 2003

80 Impact of BP reduction in renal outcomes in patients treated with ACEi or ARB
Cases et al Lancet 2005

81 Proteinuria reduction between 1 to 4 months of treatment with ARBs
Comparator PLACEBO Comparator CCB Kunz et al Ann Intern Med 2008.

82 Proteinuria reduction between 1 to 4 months of treatment with ARBs
Comparator ACEi Kunz et al Ann Intern Med 2008.

83 Proteinuria reduction between 5 to 12 months of treatment with ARB/ACEi combo
Comparator ARBs Comparator ACEi Kunz et al Ann Intern Med 2008.

84 Urinary Protein Excretion in ONTARGET albumine/creatinine ratio
 log urine albumine/creatinine ratio New onset MA / proteinuria New onset MA / proteinuria % % HR 31 11.7 11.1 R vs. T R vs. R+T 0.94 ( ) 0.88 ( ) P = 0.1 P = 0.003 10.4 24 21 0.5 0.7 1.0 1.5 Favours 2nd Th Favours 1st Th Mann et al., Lancet 2008

85 Primary Renal Outcome in ONTARGET (Dialysis / Doubling SCr / Death)
Telmisartan and ramipril Telmisartan Ramipril Cumulative incidence rates T vs R p = 0.968 R+T vs R p = 0.037 Years of follow-up Mann JFE et al. Lancet 2008; 372: 547

86 RR of Individual Components of Renal Endpoints in ONTARGET
All deaths Doubling SCr Acute dialysis Chronic dialysis 1.07 ( ) 1.20 ( ) 2.19 ( ) 1.05 ( ) P = 0.11 P = 0.02 P = 0.85 0.2 1.0 5.0 Greater risk with R Greater risk with T + R Mann et al., Lancet 2007; 372: 547

87 TRANSCEND: Kaplan-Meier curve for ESRD or doubling sCr
Mann et al. Ann Intern Med 2009

88 TRANSCEND: Kaplan-Meier curve for ESRD or doubling sCr by baseline UAE
Placebo Telmisartan Telmisartan Placebo Mann et al. Ann Intern Med 2009

89 Studies on regression of proteinuria or albuminuria
Similar results in reduction of UAE are obtained with: ACEi + ARBs Very high doses of ARB ACEi or ARB + antialdosterone drug ARB + DIR (aliskiren)

90 Studies in GFR changes Cases et al Lancet 2005

91 Impact of achieved BP on the GFR decline in diabetic nephropathy
Bakris 2002

92 DETAIL: Changes of GFR during the follow-up
10 Enalapril Telmisartan 5 -5 Glomerular filtration rate (ml/min/1,73 m2) -10 -15 -20 -25 1 2 3 4 5 Year Barnett et al. N Engl J Med 2004

93 Studies in the prevention to develop proteinuria/albuminuria: BENEDICT
Time (months) 10 20 6 12 18 24 30 36 42 48 5 ACEi 35 events No-ACEi 66 events 15 P <0.001 Cumulative incidence of Microalbuminuria (%) Ruggenenti P et al. N Engl J Med 2004; 351:

94 KÖSZÖNÖM FIGYELMÜKET


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