New European Guidelines and The Role of Low-dose Combinations

1. New European Guidelines and The Role of Low-dose Combinations Bernard Waeber Lausanne, Switzerland

2. Goals of treatment -BP < 140/90 mmHg in all hypertensive patients < 130/80 mmHg in hypertensive patients with diabetes or renal disease -Control of all cardiovascular risk factors ESH - ESC Guidelines, J Hypertens 2003

3. Patient 1 Patient 2 Patient 3 Sympathetic nervous system Renin-angiotensin system Total body sodium

4. Dose titration

5. Therapeutic effect 100 80 Toxic effect Critical dose 60 Percent maximum effect 40 Optimal dose 20 0 0 1 10 100 1000 10000 Dose arbitrary units

6. N° of trials : 20 59 15 96 10 62 Percentage of patients with AE 5 96 44 0 -5 Half standard dose Standard dose Twice standard dose Calcium antagonists AT1-receptor blockers -blockers ACE inhibitors Thiazides Law et al, BMJ 2003

7. Sequential monotherapy

8. Percentage of patients with normal blood pressure Drug A Drug B Drugs C % 0 20 40 60 80 100

9. BP control rate during antihypertensive monotherapy Achieved BP: <140/90 mmHg 80 60 39 % 40 20 0 During monotherapy (diuretic, b-blocker, ACE inhibitor or Ca antagonist) Dickerson et al, Lancet, 1999

10. Sequential monotherapy and dose ranging strategy:yes,but… ! -blood pressure normalization in only a fraction of hypertensive patients -each drug class cannot be given to each patient -dose-dependent side-effects for most antihypertensive agents -time consuming approach possible discouragement of the patient and … of the doctor!

11. Combination therapy

12. Percentage of patients with normal blood pressure Drug A Drug B Drugs A + B % 0 20 40 60 80 100

13. Combination therapy: rationale -Combination of drugs lowering blood pressure by different mechanisms  antihypertensive efficacy  -Complementary actions of drugs from different classes prevention of counter-balancing mechanisms antihypertensive efficacy  -Lower doses generally needed when two drugs are combined incidence of side-effects 

14. Effects of two different drugs on BP separately and in combination (119 randomized placebo controlled trials) "First" drug alone "Second" drug alone Combination 0 -5 -10 -5 Placebo-subtracted BP response. mmHg Systolic Diastolic Law et al, BMJ 2003

15. Percent of ALLHAT participants who achieved their goal blood pressure (SBP/DBP < 140/90 mmHg) 100 80 60 40 20 0 % Controlled (<140/90 mmHg) Percent On 1 drug On 2 drugs On 3 drugs On >4 drugs 0 6 12 24 36 48 60 Cushman et al, J Clin Hypertens, 2002

16. A multifactorial trial design to assess combination therapy in hypertension 512 patients with esential hypertension 3 x 4 factorial trialdouble-blind treatment HCTZ mg/d Bisoprolol mg/d 0 6.25 25 0 2.5 10 40 0 2.5 10 40 0 2.5 10 40 4 weeks Frishman et al, Arch Intern Med, 1994

17. Response rate in sitting diastolic blood pressure (<90 mmHg) HCTZ 0 mg HCTZ 6.25 mg HCTZ 25 mg 90 80 70 60 50 40 30 20 10 0 Responses rate (%) Bisoprolol 0 mg Bisoprolol 2.5 mg Bisoprolol 10 mg Bisoprolol 40 mg Frishman et al, Arch Intern Med, 1994

18. Mean change from baseline in serum potassium HCTZ mg/d Bisoprolol mg/d ∆ Potassium concentrationmmol/l 0 6.25 25 0 2.5 10 40 0 2.5 10 40 0 2.5 10 40 -0.04 +0.17 +0.07 +0.12 -0.5 +0.03 -0.01 -0.12 -0.36 -0.28 -0.07 -0.23 Frishman et al, Arch Intern Med, 1994

19. Low-dose combination therapy as first line treatment of mild-to-moderate hypertension: the efficacy and safety of bisoprolol/HCTZ (LODOZ) versus amlodipine, enalapril, and placebo 323 hypertensive patients bisoprolol/HCTZ (2.5/6.25  10/6.25 mg q.d.) amlodipine (2.5  10 mg q.d.) enalapril (5 mg q.d.  20 mg b.i.d.) placebo Treatment : 18 weeks Neutel et al, CVR and R, 1996

20. Control rate at the end of the trial (DBP ≤ 90 mmHg) p<0.001 p<0.01 77 56 44 % 21 Bisoprolol/HCTZ Amlodipine Enalapril Placebo (n=77) (n=82) (n=84) (n=78) Neutel et al, CVR and R, 1996

21. Bisoprolol/HCTZ Enalapril Amlodipine Placebo Overall 17 33 38 58 discontinuations (%) Patients with 29 34 27 27 at least 1 AE (%) Neutel et al, CVR and R, 1996

22. Biological parameters at baseline and 12 weeks of treatment Baseline 12-week Biso/HCTZ 7 6 5 4 3 2 1 0 mmol/l Cholesterol LDL Cholesterol HDL Cholesterol Triglycerides Glucose Potassium Benetos et al, J Hypertens, 2002

23. Comparison of bisoprolol and low dose hydrochlorothiazide combination with losartan, alone or in combination with hydrochlorothiazide, in the treatment of hypertension : A double blind, randomized, placebo controlled trial 75 hypertensive patients Bisoprolol/HCTZ Losartan Placebo 2.5 mg/6.25 mg 50 mg 5 mg/6.25 mg 100 mg Placebo 10 mg/6.25 mg 50 mg/12.5 mg Placebo ABPM 2 weeks * * * * * * 2 weeks 2 weeks ABPM * if DBP > 90 mmHg Maintenance phase 6 weeks Papademetriou et al, CVR and R, 1998

24. Mean change from baseline in sitting DBP and SBP Treatment Groups Bis/HCTZ Los:Los/HCTZ Placebo 5 0 -5 -10 -15 -20 mmHg * * #* Diastolic #* Systolic # p < 0.05 vs Los/HCTZ * p < 0.05 vs Placebo Papademetriou et al, CVR and R, 1998

25. Mean change from baseline in 24 hr average diastolic and systolic ABPM Treatment Groups 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 Bis/HCTZ Los:Los/HCTZ Placebo mmHg * * #* Diastolic * Systolic # p < 0.05 vs Los/HCTZ * p < 0.05 vs Placebo Papademetriou et al, CVR and R, 1998

26. Self-reported erectile dysfunction in prospective, randomized trials Enalapril(n=102) Bisoprolol/HCTZ(n=333) Amlodipine(n=103) Placebo(n=190) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 % Prisant et al, J Clin Hypertens, 1999

27. Advantages of fixed low-dose combinations Fixed low-dose combination Early normalization of blood pressure Turbulences associated with adjustments in antihypertensive therapy  Motivation of patients to adhere to lifelong treatment  Costs 

28. Advantages of fixed versus liberal combinations of two antihypertensive drugs Fixed Liberal Simplicity of treatment + - Compliance + - Efficacy + + Tolerability +* - Price + - Flexibility - + Risk of administering + -contraindicated drug * lower doses generally used in fixed-dose combinations

29. Pharmacological treatment of hypertension Consider : Blood pressure level before treatment Absence or presence of TOD and risk factors Choose between : Single agent at low dose Two-drug combination at low dose If goal BP not achieved : Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose If goal BP not achieved : Two-three drug combination Two-three drug combination 2003 European Society of Hypertension - European Society of Cardiology Guidelines for the Management of Arterial Hypertension, J Hypertens, 2003

30. Algorithm for treatment of hypertension Lifestyle modifications Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease) Initial drug choices Hypertension without compelling indications Hypertension with compelling indications Stage 1 hypertension(SBP 140-159 or DBP 90-99 mmHg) Thiazide-type diuretics for most May consider ACE inhibitor, ARB, -blocker, CCB, or combination Stage 2 hypertension(SBP ≥160 mmHg or DBP ≥100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or -blocker or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed Not at goal BP Optimize dosages or add additional drugs until goal BP is achieved Consider consultation with hypertension specialist The JNC VII Report, 2003

31. Normalization of BP Good tolerability Simple drug regimen Satisfaction Day-to-day compliance  Long-term compliance 