L’hypertension artérielle en 2018 Place des béta bloquants Pr Xavier Girerd Fondation de Recherche de l’Hypertension Artérielle Unité de Prévention des Maladies Cardiovasculaires Groupe Hospitalier Universitaire Pitié-Salpêtrière Sorbonne Université Paris, France Marrakech, 28 avril 2018 1

La prise en charge de l’HTA Bien mesurer la PA éviter les erreurs Bien choisir les médicaments Efficacité et tolérance Bien suivre l’hypertendu Observance, objectif tensionnel 2

Bien mesurer la pression artérielle

de la Pression Artérielle La mesure électronique de la pression artérielle (PA) doit être privilégiée dans le cadre du diagnostic et du suivi des hypertendus au cabinet médical et en ambulatoire Recommandation SFHTA 2011 Automesure Tensionelle (AMT) Mesure Ambulatoire de la Pression Artérielle (MAPA) Mesure automatique sans surveillance

Position assise au calme et après repos de 3 minutes Mesure automatique en consultation (Unattented BPM) OMRON 907 (SPRINT study) Position assise au calme et après repos de 3 minutes Mesure 1 en présence du professionnel de santé Mesure 2 et 3 sans présence du professionnel de santé 2 minutes entre chaque mesure Myers et col. J Hypertension 2009, 27:280–286

Pourcentage des hypertendus traités ayant une pseudo-resistance, une HTA masquée ou une concordance entre la mesure de consultation à 2 minutes ou 8 minutes et l’automesure Villeneuve F Ann Cardio Angeio 2012

http://www.comitehta.org

Correspondance des seuils de PAS/PAD selon la méthode de mesure USA - BP Guidelines Hypertension - 2017

Le suivi avec automesure et télétransmission chez l’hypertendu traité Baisse de la PAS en consultation après 1 an 1,7 : nbre d’antihypertenseurs

Le suivi avec automesure et télétransmission chez l’hypertendu traité selon les caractéristiques cliniques

Bien choisir les médicaments

L’efficacité des traitements de l’hypertension artérielle Hypertension non traitée Evaluation en MAPA Pression Systolique Pression Diastolique ARA 21 -13,3 (-7,9 à -17,7) -7,8 (-5,0 à -9,2) IEC1 -12,9 (-11,4 à -14,4) -7,7(-6,5 à -8,9) CA1 -11,8 (-6,1 à -15,9) -8,1(-3,7 à -12,5) BB1 - 11,2 (-8,7 à -13,7) - 8,5 (-4,5 à -12,5) Diurétique thiazidique (HCTZ 12,5 mg/j)1 - 6,5 (-5,3 à -7,7) - 4,5 (-3,1 à -6,0) 1 - J Am Coll Cardiol 2011;57:590–600 1

médicaments/ordonnance FLAHS 2017 Utilisation des anti-hypertenseurs en 2017 Analyse de l’utilisation des classes pharmacologiques sur les ordonnances (37%) (30%) (35%) (27%) (23%) (% des patients traités) (5%) (3%) (<1%) (2%) 1,7±0,8 médicaments/ordonnance Enquête FLAHS 2017- French League Against Hypertension Survey Analyse pour 1334 hypertendus traités www.comitehta.org 13 13

Utilisation des antihypertenseurs en France entre 2002 et 2017 FLAHS 2002 2007 2012 2017 Utilisation des antihypertenseurs en France entre 2002 et 2017 selon les enquêtes FLAHS Répartition des familles pharmacologiques selon le total des prescriptions % Enquête FLAHS French League Against Hypertension Survey Population hypertendus traités de 35 ans et plus www.comitehta.org X Girerd 36ème JHTA décembre 2017

Usage des anti-hypertenseurs en 2017 Utilisation des bêta-bloquants FLAHS 2017 Usage des anti-hypertenseurs en 2017 Utilisation des bêta-bloquants 35,5% des ordonnances 24,3% des prescriptions Enquête FLAHS 2017- French League Against Hypertension Survey Analyse pour 1334 hypertendus traités en France métropolitaine www.comitehta.org 15 15

LIFE : Blood Pressure Reductions 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Atenolol 145.4 mmHg * Systolic Losartan 144.1 mmHg mmHg Atenolol 102.4 mmHg Mean Arterial Losartan 102.2 mmHg Losartan 81.3 mmHg Diastolic Atenolol 80.9 mmHg Slide 19: LIIFE: Comparable Blood Pressure Reductions Both losartan and atenolol substantially reduced systolic and diastolic blood pressures (-30.2/16.6 mmHg with losartan; -29.1/16.8 with atenolol).1 The target blood pressure of <140/90 mmHg was achieved by 49 % of patients treated with losartan and 46% of patients treated with atenolol.1 When adjusting for these minor differences in BP lowering, the significant reduction in risk of the combined primary endpoint of cardiovascular morbidity and mortality was not affected in any appreciable manner.1 6 12 18 24 30 36 42 48 54 Study Month Dahlöf B et al Lancet 2002;359:995-1003.

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 Atenolol Slide 16: LIIFE: Primary Composite Endpoint For the first time ever a combined cardiovascular morbidity and mortality primary endpoint trial in hypertensive patients has 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 LIIFE 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 vs. atenolol (p=0.021).1 The primary result was even stronger, 14.6% (p=0.009), if not adjusted for Framingham risk score and ECG-LVH at baseline.1 No significant differences in CV death and MI vs. atenolol were observed.1 The risk reduction in CV events with atenolol was consistent with those in previous studies with beta blocker-based regimens vs. 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 vs. atenolol in the LIIFE 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 Study Month 6 12 18 24 30 36 42 48 54 60 66 Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf B et al Lancet 2002;359:995-1003.

ASCOT study – pronostic value for central SBP

Pourquoi utiliser des β-bloquants dans l’HTA ? CONTRE Recommandations Plus protecteur que le placebo HTA avec pathologie cardiaque associée Moins protecteur que d’autres antiHTA pour la prévention des AVC après 60 ans (atenolol) Profil patient HTA adrénergique HTA avant 60 ans HTA avec pathologie cardiaque HTA systolique HTA métabolique (risque diabétogène associé aux diurétiques) Facilité d’utlisation Efficacité aux dosages faibles Choix de médicaments au sein de la classe Pas d’ECG (en général) Pas de surveillance biologique Moins de trouble de l’érection que les diurétiques Bradycardie (<50 bat/min) Asthme sévère Mechanism of action of -blockers Binding of -blockers to -receptors does not in itself evoke a cellular response. Instead, most -blockers counter the effect of the adrenergic neutrotransmitter, noradrenaline, and the hormone, adrenaline, by preventing them from binding to their receptors. X Girerd 2018

Étude THOMS problèmes d’érection après 2 ans de suivi Placebo BB DIU IEC ICa AB Sans problème d’érection au début de l’étude 8% 9% 17%* 10% 8% 6% Avec problème d’érection au début de l’étude 46% 31% 36% 50% 45% 0%* *p<0,05 vs. placebo Hypertension 1997; 29 :8-14

Beta1 and Beta2 Selectivity Ratios 100 75 50 25 ICI 118,551 B1/B2 Selectivity Ratios Propranolol Metoprolol Atenolol Betaxolol Bisoprolol 1 / 2 5 20 35 300 Wellstein et al Eur Heart J 1987

Pharmacokinetics of selected β-blockers Criteria Bisoprolol Atenolol Metoprolol Carvedilol Nebivolol* Plasma elimination half-life (h) 10–12 6–9 3–4 6–7 8/27 Absorption (%) > 90 40-60 85 >95 First-pass effect (%) < 10 – 25-50 60–75 88/4 Bioavailability (%) 90 50 50-75 25 12/96 Protein binding (%) 35 3 12 98 Active metabolites  (+) +++ Balanced clearance + * Nebivolol shows complicated pharmacokinetics: Extensive first-pass effect by hepatic metabolism (isoenzyme CYP450 2D6);CYP2D6 genetic polymorphisms leading to poor and fast (>90% of the European population) metabolizers CYP2D6 quickly metabolizes nebivolol to active metabolites (1-antagonistic activity similar to that of unchanged nebivolol) large interindividual variations of plasma concentrations (between poor and fast metabolisers) Since the 1-antagonistic activities of unchanged drug and active metabolites are similar, the antihypertensive activity obviously is not different between poor (unchanged drug) and fast (active metabolites) metabolizers. Bioavailability: 96% in poor metabolisers, 12% in fast (>90% of Europeans) metabolisers Elimination half-life: 27h in poor metabolisers, 8h in fast metabolisers Plasma elimination half-life is sufficiently long for a once-a-day administration only for bisoprolol and nebivolol. Atenolol does not provide sufficient 24 hour efficacy and should be administerd twice a day. For metoprolol, an extended-release formulation (metoprolol succinate CR/XL) with 24 hour efficacy is usually used. Carvedilol has to be administered twice per day. Extended-release capsules for once-a-day administration are now available in the USA. A high bioavailability, the result of a high absorption and a low first pass-effect, provides the basis for a small intra- and interindividual variability of pharmacokinetics for bisoprolol. Protein binding is low for bisoprolol, atenolol and metoprolol, representing the basis for kinetics being insensitive to drug-drug interactions and pathophysiological changes. Balanced clearance, the basis for kinetics being almost insensitive to renal or hepatic insufficiency, is demonstrated only for bisoprolol. References: Borchard U. β-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. 2011 PMPH-USA, Ltd. Hoffmann JG, Maisch B. Beta-Blocker bei kardiovaskulären Erkrangungen. UNI-MED Verlag AG, 2002 Moen MD, Wagstaff AJ. Nebivolol. A review of ist use in the management of hypertension and chronic heart failure. Drugs 2006;66:1389–1409 Borchard U. β-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. 2011 PMPH *Nebivolol demonstrates complicated pharmacokinetics

Evalution de l‘effet sur la PA par MAPA Bisoprolol vs. Atenolol SBP Bisoprolol (n=107) 10-20 mg Atenolol (n=96) 50-100 mg -5 Mean Change in Systolic Blood Pressure (mmHg) -10 -15 Figure above depicts systolic blood pressure (SBP) data (ABPM) Bisoprolol 10–20 mg was compared with atenolol 50–100 mg in 606 (659-53 protocol violators) hypertensive patients (DBP 95–115 mmHg) in a double-blind, parallel group study using casual (office) BP readings and 24-h ambulatory blood pressure monitoring (ABPM; 203 patients). If after 4 or 6 weeks of treatment with 10 mg bisoprolol or 50 mg atenolol DBP was >90 mmHg, the dosages were doubled for the remainder of the study (total active treatment phase of 8 weeks). 53% of the patients randomized to bisoprolol compared with 64% of the patients randomized to atenolol required dose escalation. Casual office readings demonstrated that the two drugs significantly decreased trough SBP and DBP to a similar extent. The response rate (DBP≤90 mmHg or a reduction ≥10 mmHg) was greater in patients treated with bisoprolol compared with atenolol (70% vs 62%, p=0.04). However, by 24-h ABPM, bisoprolol showed a 33% greater reduction in whole-day average DBP than did atenolol (11.60.7 mmHg vs 8.70.8 mmHg, p<0.01). Significant treatment differences in SBP (p<0.05) and DBP (p<0.01) were also noted for bisoprolol compared with atenolol during the time period 06:00 a.m. to noon (43% and 49% regarding SBP and DBP) and over the last 4 hours of the dosing interval (06:00 am to 10:00 am). As the rapid early morning rise in BP corresponds to an increased frequency of cardiovascular events (myocardial infarction, stroke), these findings may have important clinical implications. During nighttime the two agents produced effective but similar decreases in BP. Reference Neutel JM, Smith DHG, Ram CVS, et al. Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents. Am J Med 1993;94:181–7 -20 10 am 4 pm 10 pm 4 am 10 am Time of Day Dose Intake Casual office readings response rates (DBP≤90 mmHg or reduction ≥10 mmHg): bisoprolol 70% vs atenolol 62%, p=0.04 Neutel JM et al. Am J Med 1993;94:181–187

High Blood Pressure Clinical Practice Guideline The overall goal of treatment should be reduction in BP, in the context of underlying CVD risk. Five drug classes have been shown, in high-quality RCTs, to prevent CVD as compared with placebo (diuretics, ACE inhibitors, ARBs, CCBs, and beta blockers) (14, 15). 14. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. 15. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs--overview and meta-analyses. J Hypertens. 2015;33:1321-41. Whelton PK, et al. 2017

High Blood Pressure Clinical Practice Guideline In contrast, some meta-analyses have suggested that beta blockers may be less effective, especially for stroke prevention in older adults, but interpretation is hampered by inclusion of RCTs that used beta blockers that are now considered to be inferior for prevention of CVD (16, 17). 16. Zhang Y, Sun N, Jiang X, et al. Comparative efficacy of β-blockers on mortality and cardiovascular outcomes in patients with hypertension: a systematic review and network meta-analysis. J Am Soc. Hypertens. 2017;11:394401. 17. Larochelle P, Tobe SW, Lacourciere Y. β-Blockers in hypertension: studies and meta-analyses over the years. Can J Cardiol. 2014;30:S16-22. Whelton PK, et al. 2017

Calcium channel blocker Associer deux antihypertenseurs est plus efficace sur la baisse de la PA qu’augmenter les doses des monothérapies Mean (95% CI) ratio of observed to expected incremental BP-lowering effects of adding a drug or doubling the dose according to the class of drug Adding a drug from another class (on average standard doses) Doubling dose of same drug (from standard dose to twice standard) Beta blocker ACE inhibitor Calcium channel blocker Thiazide Incremental SBP reduction ratio of observed to expected additive effects 1.4 1.2 1.0 0.8 0.6 0.4 0.2 All Classes 1.04 (0.88–1.20) 1.00 (0.76–1.24) 1.16 (0.93–1.39) 0.89 (0.69–1.09) 1.01 (0.90–1.12) 0.19 (0.08–0.30) 0.23 (0.12–0.34) 0.20 (0.14–0.26) 0.37 (0.29–0.45) 0.22 (0.19–0.25) The recent meta-analysis published by Wald et al.1 has shown that combining two drugs from different classes increases BP reduction much more than doubling the dose of a single agent Guidelines recommend that different agents can be combined2,3 if: They have different and complementary mechanisms of action The antihypertensive effect of the combination is greater than either component They have a favourable tolerability profile that minimises individual side effects 1. Wald et al. Am J Med 2009;122:290–300 2. Mancia et al. J Hypertens 2007;25:1105–87 3. Mancia et al. J Hypertens 2009;27:2121–58 Wald et al. Am J Med 2009;122:290–300