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New European Guidelines and The Role of Low-dose Combinations Bernard Waeber Lausanne, Switzerland 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 Patient 1 Patient 2 Sympathetic nervous system Renin-angiotensin system Total body sodium Patient 3 Dose titration Therapeutic effect Percent maximum effect 100 80 Toxic effect Critical dose 60 40 Optimal dose 20 0 0 1 10 100 Dose arbitrary units 1000 10000 Percentage of patients with AE N° of trials : 20 15 59 96 10 62 5 96 44 0 -5 -blockers ACE inhibitors Thiazides Half standard dose Standard dose Twice standard dose Calcium antagonists AT1-receptor blockers Law et al, BMJ 2003 Sequential monotherapy Percentage of patients with normal blood pressure Drug A Drug B Drugs C 0 20 40 60 80 100 % BP control rate during antihypertensive monotherapy Achieved BP: 80 60 <140/90 mmHg 39 % 40 20 0 During monotherapy (diuretic, -blocker, ACE inhibitor or Ca antagonist) Dickerson et al, Lancet, 1999 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! Combination therapy Percentage of patients with normal blood pressure Drug A Drug B Drugs A + B 0 20 40 60 80 100 % 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 Effects of two different drugs on BP separately and in combination Placebo-subtracted BP response. mmHg (119 randomized placebo controlled trials) 0 "First" drug alone "Second" drug alone Combination -5 -10 -5 Systolic Diastolic Law et al, BMJ 2003 Percent of ALLHAT participants who achieved their goal blood pressure (SBP/DBP < 140/90 mmHg) 100 Percent 80 % Controlled (<140/90 mmHg) 60 On 1 drug 40 On 2 drugs 20 On 3 drugs On >4 drugs 0 0 6 12 24 36 48 60 Cushman et al, J Clin Hypertens, 2002 A multifactorial trial design to assess combination therapy in hypertension 512 patients with esential hypertension 0 6.25 25 Frishman et al, Arch Intern Med, 1994 Bisoprolol mg/d 0 2.5 10 40 0 2.5 10 40 0 2.5 10 40 4 weeks HCTZ mg/d 3 x 4 factorial trial double-blind treatment Responses rate (%) Response rate in sitting diastolic blood pressure (<90 mmHg) 90 80 70 60 50 40 30 20 10 0 HCTZ 0 mg HCTZ 6.25 mg HCTZ 25 mg Bisoprolol 0 mg Bisoprolol 2.5 mg Bisoprolol 10 mg Bisoprolol 40 mg Frishman et al, Arch Intern Med, 1994 Mean change from baseline in serum potassium HCTZ mg/d Bisoprolol mg/d ∆ Potassium concentration mmol/l 0 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 6.25 25 Frishman et al, Arch Intern Med, 1994 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 Control rate at the end of the trial (DBP ≤ 90 mmHg) p<0.001 p<0.01 77 56 % 44 21 Bisoprolol/HCTZ Amlodipine (n=77) (n=82) Enalapril (n=84) Placebo (n=78) Neutel et al, CVR and R, 1996 Bisoprolol/HCTZ Enalapril Amlodipine Placebo Overall discontinuations (%) 17 33 38 58 Patients with at least 1 AE (%) 29 34 27 27 Neutel et al, CVR and R, 1996 Biological parameters at baseline and 12 weeks of treatment Baseline 12-week Biso/HCTZ 7 6 mmol/l 5 4 3 2 1 0 Cholesterol LDL HDL Triglycerides Cholesterol Cholesterol Glucose Potassium Benetos et al, J Hypertens, 2002 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 ABPM Bisoprolol/HCTZ 2.5 mg/6.25 mg * 5 mg/6.25 mg * 10 mg/6.25 mg Losartan 50 mg * 100 mg * 50 mg/12.5 mg Placebo * 2 weeks Placebo * 2 weeks Placebo 2 weeks ABPM * if DBP > 90 mmHg Maintenance phase 6 weeks Papademetriou et al, CVR and R, 1998 Mean change from baseline in sitting DBP and SBP Treatment Groups 5 Bis/HCTZ Los:Los/HCTZ Placebo mmHg 0 -5 * -10 -15 * #* #* -20 # p < 0.05 vs Los/HCTZ * p < 0.05 vs Placebo Diastolic Systolic Papademetriou et al, CVR and R, 1998 Mean change from baseline in 24 hr average diastolic and systolic ABPM mmHg Treatment Groups 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 Bis/HCTZ Los:Los/HCTZ Placebo * * #* # p < 0.05 vs Los/HCTZ * p < 0.05 vs Placebo * Diastolic Systolic Papademetriou et al, CVR and R, 1998 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 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 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 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 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) Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) Drug(s) for the compelling indications Thiazide-type diuretics for most 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or -blocker or CCB) Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed May consider ACE inhibitor, ARB, blocker, CCB, or combination 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 Normalization of BP Good tolerability Simple drug regimen Satisfaction Day-to-day compliance Long-term compliance