Presentation is loading. Please wait.

Presentation is loading. Please wait.

Pr Roland Asmar Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar 1 How to maximize patient benefit.

Similar presentations


Presentation on theme: "Pr Roland Asmar Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar 1 How to maximize patient benefit."— Presentation transcript:

1 Pr Roland Asmar Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar 1 How to maximize patient benefit

2 Goals of Antihypertensive Treatment ESH/ESC 2007 2 How to maximize patient benefit < 140/90 mmHg < 130/80 mmHg Hypertensive patients Diabetes Patient at high risk

3 USA 53.1 Canada 41.0 Mexico 21.8 Turkey 19.8 Germany 33.6 Spain 38.8 Greece 49.5 England 29.2 Egypt 33.5 South Africa 47.6 Italy 37.5 Worldwide Blood Pressure Control in Treated Hypertensive Patients Kearney et al. J Hypertens 2004; 22: 11 Japan 55.7 China 28.8 Taiwan 18.0 3 How to maximize patient benefit

4 HOT: Need for Combination Therapy Hansson et al., Lancet 1998, 351: 1755-62 4 How to maximize patient benefit

5 % Percentage of Patients with Combination Treatment in Clinical Trials 5How to maximize patient benefit

6 ESH/ESC Guidelines - 2007

7 Pharmacological Rationale for Combination Therapy 7How to maximize patient benefit

8 Rationale for Combination Therapy 8 How to maximize patient benefit Increase EfficacyIncrease Efficacy Synergistic & additive effects on BP Synergistic & additive effects on BP Effects on several patho-physiological mechanisms of HT Effects on several patho-physiological mechanisms of HT Inhibition of the contra-regulation mechanisms Inhibition of the contra-regulation mechanisms Decrease Side effectsDecrease Side effects Inhibition of the contra-regulation Inhibition of the contra-regulation Low doseDecrease dose-dependent side effects Low doseDecrease dose-dependent side effects

9 Advantages of Combination Therapy Efficacy 9How to maximize patient benefit

10 Sympathetic nervous system Renin-angiotensin system Total body sodium Sympathetic nervous system Renin-angiotensin system Total body sodium Patient A Patient B Patient C Rationale of Combination Therapy Waeber B. 2004 Pathogenetic Mechanisms in Hypertension

11 11How to maximize patient benefit

12 Titration vs. Combination Diastolic BP Frishman WH et al,Arch Intern Med 1994;154:1461 12 How to maximize patient benefit

13 Efficacy: Up-titration vs Combination Change in SBP (mm Hg) T40T80T40 HCT12.5 V80 V160 V80 HCT12.5 Ol20Ol40 Ol20 O20 HCT12.5 13How to maximize patient benefit

14 Value of combination treatment: analysis of 354 randomised placebo controlled trials Law MR BMJ 2003 14 How to maximize patient benefit

15 Advantages of Combination Therapy Side Effects 15How to maximize patient benefit

16 HCTZ dose (mg/d) ARB dose (mg/d) 0 6.25 12.5 25 0 37.5 100 300 Adjusted mean  from baseline at 8 weeks (mEq/L) Effect of ARB and HCTZ on Serum Potassium Kochar M, et al. Am J Hypertens. 1999;12:797 16How to maximize patient benefit

17 BMJ 2003;326:1427 Drug related symptoms: comparison between monotherapy & combination 50 trials testing drugs of two different categories separately and in combination, 17 How to maximize patient benefit

18 Advantages of Combination Therapy Convenience 18How to maximize patient benefit

19 Fixed-dose Combination Therapy Increases Compliance to Treatment Dezii CM. Manag Care 2000; 9 : s2 Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs two separate pills of lisinopril and HCTZ100 95 95 90 90 85 85 80 80 75 75 70 70 65 65 60 60 55 55 50 50 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Persistence (%) 68.7 57.8 18.8% Lisinopril/HCTZ (1 pill) Lisinopril and HCTZ (2 pills)

20 Advantages of Combination Therapy Equal efficacy? 20How to maximize patient benefit

21 Blood pressure control with ARBs and in Fixed Dose Combination ® ProtocolEndpoints Primary endpoint ■ Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints Changes from: ■ Baseline in DBP during the last 6 hours of dosing interval ■ Baseline in pulse pressure during the last 6 hours of dosing interval ■ Baseline in the 24-hour mean SBP and DBP n=294n=297n=160 Neutel JM, et al. Hypertens Res 2005;28:555

22 ABPM Comparison of Telmisartan HCTZ & Losartan HCTZ Parallel Group Comparison after 6 weeks Therapy Neutel et al. Hypertens Res. 2005;28:555 Time after dosing (h) -6 2 6 10 14 18 22 -10 -12 -14 -8 -16 -8 2 6 10 14 18 22 -16 -20 -24 Change from baseline (mmHg) Telmisartan 80mg + HCTZ 12.5mg Losartan 50mg + HCTZ 12.5mg -12 Telmisartan 40mg + HCTZ 12.5mg Systolic BP Diastolic BP 22 How to maximize patient benefit

23 ® ProtocolEndpoints Study of telMisartan On Obese/overweight Type2 diabetics with Hypertension Primary endpoint ■ Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints ■ Changes in other ABPM-derived parameters ■ Changes in trough cuff SBP and DBP ■ Metabolic blood markers (e.g.cholesterol) ■ Urine markers (e.g. proteinuria) Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28

24 SBP change from baseline (mmHg) ***p < 0.001 T + H vs V + H 24-hour and last 6-hour mean SBP *** Sharma et al. Hypertension 2005;46:898 Telmisartan + HCTZ vsValsartan + HCTZ Powerful 24 hr SBP reductions 24 How to maximize patient benefit

25 Fogari & al Current Therapeutic Research; 2008; 69 Telmisartan 80mg/HCTZ 12.5 mg vs Olmesartan 20mg/HCTZ12.5 mg Systolic BP Diastolic BP 25

26 n=497 n=503 A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension ProtocolEndpoints Primary endpoint ■ Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints Changes from: ■ Baseline in DBP during the last 6 hours of dosing interval ■ Baseline in pulse pressure during the last 6 hours of dosing interval ■ Baseline in the 24-hour mean SBP and DBP ® Neldam S, et al. AJGC 2006;15:151-60.

27 How to maximize patient benefit Neldam S, et al. AJGC 2006;15:151-60. 27

28 Telmisartan in combination HCTZ 25 mg How to maximize patient benefit28

29 Change in clinic trough BP from baseline after 8 weeks therapy Comparison of Telmisartan HCTZ & Valsartan HCTZ White et al. J Hypertens Suppl. 2003;21:S9-15. Telmisartan-HCTZ 80/25mg (n=467) Valsartan-HCTZ 160/25mg (n=479) Placebo (n=120) -25 -20 -15 -10 -5 0 Systolic BP Diastolic BP -2.8 (-4.6, -1.0) p<0.004 Change from baseline (mmHg) -1.8 (-3.0, - 0.6) p<0.02 29 How to maximize patient benefit

30 Comparison of Telmisartan HCTZ & Valsartan HCTZ Change in clinic trough BP from baseline after 8 weeks therapy White W & al BP Monitoring 2008, 13:21 30

31 AIIA + CCB 31How to maximize patient benefit

32 Composed end-point comparing a fixed combination of a CCB +ACEI vs a thiazide+ACEI Jamerson K et al. NEJM; 2008; 359:2417 Time for events Incidence of eventos HR: 0,80; IC 95%: 0,72 – 0,90 ACCOMPLISH Trial 32 How to maximize patient benefit

33 ASCOT - Summary of all end points The area of the blue square is proportional to the amount of statistical information Amlodipine  perindopril better Atenolol  thiazide better 0.500.70 1.001.45 Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + strok e 2.00 Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) 33 How to maximize patient benefit

34 Chemical structures N N CO 2 H CI N N N NH N N COOH C OH CH 3 H3CH3C N N N NH O N N N N N N O CO 2 H N N N NH N N OCH 2 CH 3 N N N NH COOH Candesartan (active form) Losartan (active form) ValsartanIrbesartanOlmesartan (active form) Telmisartan N N N N CH 3 O OH Telmisartan and other angiotensin II antagonists 34How to maximize patient benefit

35 Kakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6. Dissociation Half-Lives of ARB ’ s from Human AT 1 Receptors 0 50 100150200 250 Losartan Telmisartan Olmesartan Candesartan Valsartan EXP3174 202-226 min 151-184 min 121-149 min 60-83 min 73-91 min 60-77 min 95% CI Dissociation half-life (min) 35 How to maximize patient benefit

36 Peroxisome Proliferator-Activated Receptor Gamma (PPAR  ) interaction Selective Nuclear Hormone Receptor Modulation Rosiglitazone Pioglitazone PPAR  Full Agonists Insulin Sensitivity NO Weight Gain NO Oedema Insulin Sensitivity Weight Gain Oedema Telmisartan Selective Modulation Selective Peroxisome Proliferator-Activated Receptor Gamma Modulators (SPPARMS) 36How to maximize patient benefit

37 150 100 50 0 Fold Activation Full Agonists Partial Agonist Difference between Thiazolodinediones & ARBs in the Interaction with PPAR  Receptor rosiglitazonepioglitazonetelmisartanirbesartaneprosartan Benson et al. Hypertension. 2004;43:993 37 How to maximize patient benefit

38 Telmisartan was the only ARB that activated PPAR  at concentrations (1-5  mol/l) attained in plasma with conventional oral dosing Benson et al. Hypertension. 2004;43:993. Activation of PPAR  by ARB’s Fold Activation 0 5 10 15 20 25 TelmisartanCandesartanOlmesartanEXP 3174 IrbesartanValsartanEprosartan 38 How to maximize patient benefit

39 -10 0 -20 -30 FPG Change from baseline (%) P<0.05 FPIHOMA IRHbA 1c P<0.06 P<0.05 Effects of Telmisartan & Losartan in Patients with metabolic syndrome Vitale et al. Cardiovasc Diabetol. 2005;15:6. Telmisartan (n=20) Losartan (n=20) 39 How to maximize patient benefit

40 FPGTGHOMA IRHbA 1c FPIAdiponectin -16 -14 -12 -10 -8 -6 -4 -2 0 -60 -40 -20 0 20 40 60 80 100 120 % change from baseline * p<0.05 & ** p<0.01 vs amlodipine * ** * * n.s. Negro et al. JRAA 2006:243-6. Effects of Telmisartan and Amlodipine on Metabolic Parameters in Type 2 Diabetic Hypertensives Telmisartan Amlodipine 40 How to maximize patient benefit

41 Effects of telmisartan on fat distribution in individuals with metabolic syndrome Shimabukuro, J Hypertens 2007;25:841 50 100 150 200 TelmisartanAmlodipine VFA cm² 300 250 +10% p=0.046 -12% p=0.008 90 92 94 96 TelmisartanAmlodipine Waist circumference (cm) 100 98 +3% -5% Baseline24 wks treatment Change in the Visceral Fat Area (VFA) Change in waist circumference 41How to maximize patient benefit

42 Comparative Cardio-Metabolic Studies with Telmisartan TrialPatients NDuration (weeks) Comparator Agent(s) BP differential Improved Insulin Sensitivity Improved Lipid Profile Anti-oxidant/ Inflammatory Action Derosa 2004aHT, T2DM11952Eprosartan/PlaceboNo (P yes) NoYes- Derosa 2004b HT, T2DM 116 52Nifedipine GITS No Yes- Vitale 2005 HT, MS40 12 LosartanYes? Yes -- Miura 2005 HT, T2DM18 12Candesartan/Valsartan No Yes Koulouris 2005 NT, T2DM 4012 Ramipril No Yes Honjo 2005 HT, T2DM 3812 Candesartan - Yes -- Benndorf 2006 HT 376Nisoldipine No? Yes -- Negro 2006aHT, T2DM4016 AmlodipineNo Yes - Negro 2006bHT, obese,IR4626 IrbesaratnNo Yes - Bahadir 2007HT, MS4210 LosartanNo? Yes?No - Derosa 2007HT, T2DM18852 IrbesartanNo Yes Sharma 2007HT, obese84010 Valsartan HCTZYes No - 42How to maximize patient benefit

43 Conclusions Use of more than one agent is necessary to achieve target BP in the majority of patients. Use of more than one agent is necessary to achieve target BP in the majority of patients. Combination therapy is related with a higher BP reduction and CV protection Combination therapy is related with a higher BP reduction and CV protection Fixed combinations of two drugs can simplify treatment schedule and improve compliance and tolerability. Fixed combinations of two drugs can simplify treatment schedule and improve compliance and tolerability. A combination of two drugs should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high A combination of two drugs should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high Are all the combination therapies equipotent Are all the combination therapies equipotent

44 Backup 44 How to maximize patient benefit

45 Combination Therapy Study / DrugsBPMo- Mort STOP 2Old/Recent≡≡ BACRIARB + HCTZ / ACEI + Verap ≡NA INVESTBB + HCTZ / Verap + ACEI ≡≡ EXFORGEARB + CCB / ACEI + HCTZ ≡ ou ≥NA ASCOTBB + HCTZ / ACEI + CCB ≡≡ ou ≥ LIFEBB + HCTZ / ARB + HCTZ ≡≥ ACCOMPLISHACEI + HCTZ / ACEI + CCB ≡≥ ONTARGETACEI + ARB / ACEI ≥≡ Side effects ++ 45 How to maximize patient benefit

46 The HOT Study: CV Risk Reduction in Diabetics Hansson L, et al. Lancet 1998;351:1755–62. 0 5 10 15 20 25 major CV events/1000 patient.y p < 0.005 for trend (n = 1501) < 90 mmHg 85 mmHg < 85 mmHg 83 mmHg Target Achieved < 80 mmHg 81 mmHg 46How to maximize patient benefit

47 Management of BP for adults- JNC VII BP classification SBP* mmHg DBP mmHg mmHg Lifestyle modification Initial drug therapy Without compelling indication With compelling indications Normal<120 and <80 Encourage Prehypertension 120 – 139 or 80 – 89 Yes No antihypertensive drug indicated. Drug(s) for compelling indications. ‡ Stage 1 Hypertension 140 – 159 or 90 – 99 Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 2 Hypertension >160 or >100 Yes Two-drug combination for most † (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡ Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. 47How to maximize patient benefit

48 Adverse Events: HCTZ 25 mg vs ARB + HCTZ 25 mg HCTZ ARB + HCTZ Potassium Insulin Glucose Lipids Uric Acid Adverse events Impotence 48How to maximize patient benefit

49 Effect of Telmisartan HCTZ 25 mg Change in clinic trough BP from baseline after 8 weeks therapy Neldam & al J Clin Hypertens 2008; 10:612 49

50 INVEST: Primary Composite Endpoint by Treatment Group Cumulative % Time, mo 11267 11309 No. at Risk CAS NCAS 10921 10991 10716 10785 10512 10536 10008 10048 6612 6604 1568 1563 35 33 393 390 3738 3706 974 960 06121824364854426030 Calcium Antagonist Strategy (CAS) (Verap + ACEI) Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ) Log-Rank P=.57 RR = 0.98 (0.90 – 1.06) Pepine CJ, et al. JAMA. 2003;290:2805

51 ONTARGET – Combination ACEI + ARB vs ACE The ONTARGET Investigators N EJM 2008;358:1547 51 How to maximize patient benefit


Download ppt "Pr Roland Asmar Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar 1 How to maximize patient benefit."

Similar presentations


Ads by Google