9/17/2015. Reference: Ruschitzka F. J Hypertens 2011;29(Suppl 1):S9-14.

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4 Reference: Ruschitzka F. J Hypertens 2011;29(Suppl 1):S

Slide notes: Large trials such as ALLHAT, LIFE and ASCOT show that the majority of patients with hypertension will require multiple therapies to meet target blood pressure (BP) levels.

5 Slide notes: Large trials such as ALLHAT, LIFE and ASCOT show that the majority of patients with hypertension will require multiple therapies to meet target blood pressure (BP) levels. 1-3 For example, nearly 80% of patients in the ASCOT-BPLA were taking two or more medications by the end of the study. 3 The JNC 7 guidelines state that most hypertensive patients will require two or more drugs to achieve BP control 4 and the 2007 ESH/ESC hypertension guidelines also emphasise the need for treatment with multiple antihypertensive agents to attain BP goals. 5 A retrospective analysis of patients with newly diagnosed hypertension suggests that excessive reliance on monotherapy was the single most important factor contributing to the low rate (33%) of control in that study. 6 A study estimated the numbers of medications that hypertensive patients may require to meet a BP of 140/90 mmhg using data from the Health Survey for England in over 13,000 patients. 7 In the model, 53.9% of hypertensive men aged years in the UK and 50.2% of women require two or three drugs to achieve target BP. Patients under 35 years require at least three drugs to achieve target levels as their pre-treatment BP is higher to be eligible for treatment. However, greater prescribing levels and complexity are associated with lower levels of compliance. 8 Therefore, strategies are required to reduce the prescribing complexity in treating hypertension. References: 1. ALLHAT Collaborative Research Group. JAMA 2002;288: Dahlöf B et al. Lancet 2002;359: Dahlöf B et al. Lancet 2005;366: Chobanian A et al. JNC 7 guidelines. Hypertension 2003;42: Mancia G, Grassi G. ESH/ESC guidelines. Ther Adv Cardiovasc Dis 2008;2: Spranger C et al. Am J Med 2004;117: Marshall T. J Hum Hypertens 2005;19: Choudhry N et al. Arch Intern Med 2011;171:

Slide notes: Satisfactory BP response is rarely reached with monotherapy due to the heterogeneity of the hypertensive population. This results in an extremely wideranging BP response in individuals.

6 Slide notes: Satisfactory BP response is rarely reached with monotherapy due to the heterogeneity of the hypertensive population. This results in an extremely wideranging BP response in individuals. Initial falls in BP from monotherapy are also opposed by reflex responses in counter-regulatory mechanisms that are activated following BP reduction. 1 Combining selected classes of antihypertensive therapy with different modes of action produces improved efficacy and increases BP control. A meta-analysis of 354 randomised, double-blind, placebo-controlled trials of the major classes of antihypertensive monotherapies shows that, on average, the first and second drugs given alone lower BP by 7.0/4.1 and 8.1/4.6 mmhg, respectively, compared with 14.6/8.6 mmhg when given together. 2 References: 1. Sever P, Messerli FH. Eur Heart J 2011;32: Law M et al. BMJ 2003;326:

7 Slide notes: Forest plot comparing odds ratios (and corresponding 95% confidence intervals [CIs]) of nonfatal cardiovascular (CV) outcomes as a whole, coronary heart disease, or cerebrovascular events associated with an initial combination of blood pressurelowering agents, with respect to initial monotherapy. Data show the estimates obtained by fitting a conditional logistic model and adjusted for the number of blood pressure-lowering drug classes used during follow-up and the concomitant use of drugs for the treatment of heart failure, coronary heart disease, diabetes mellitus and other CV disease. Reference: Corrao G et al. Hypertension 2011;58:

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10 Slide notes: Combined inhibition of angiotensin converting enzyme (ACE) and neprilysin (NEP) blocks the vasoconstrictive, sodium retaining, pro-hypertrophic and pro-fibrotic effects of angiotensin 2 and enhances the vasodilatory, sodium excretory, antihypertrophic and antifibrotic effects of the atrium (ANP) and brain (BNP) natriuretic peptides. The increased risk for angio-oedema is due to a rise in plasma bradykinin concentration. Source: Figure reproduced with permission from Laurent S et al. Lancet 2012;380:

11 Slide notes: Kaplan-Meier curves for the key outcomes of the valsartan / sacubitril (LCZ 696) study in heart failure, comparing LCZ 696 and enalapril. Shown are estimates of the probability of the primary composite endpoint (death from cardiovascular causes or first hospitalisation for heart failure) panel A; death from cardiovascular causes panel B; first hospitalisation for heart failure panel C; and death from any cause panel D. LCZ 696 was superior to enalapril in reducing the risks of death and hospitalisation for heart failure. Reference: McMurray JJ et al. N Engl J Med 2014;371:

12 Slide notes: The three trials evaluated LCZ 696 in patients with hypertension or heart failure. Ruilope LM et al (Lancet 2010;375: ) compared LCZ mg vs valsartan 320 mg over 8 weeks in patients with mild-to-moderate hypertension. Kario K et al (Hypertension 2014;63: ) compared LCZ mg versus placebo over 8 weeks in Asian patients with hypertension. The PARAMOUNT trial (Solomon SD et al. Lancet 2012;380: ) compared LCZ mg twice daily versus valsartan 160 mg twice daily over 12 weeks in patients with heart failure. Reference: Bavishi C et al. Eur Heart J 2015;36: doi / eurheartj/ehv

Reference: Bavishi C et al. Eur Heart J 2015;36:1967-73. doi 10.

13 Reference: Bavishi C et al. Eur Heart J 2015;36: doi / eurheartj/ehv 142, based on clinical trials.gov and International Standard Randomised Controlled Trials Number (ISRCTN) Register. 12

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15 Reference: Steckelings UM et al. Curr Opin Nephrol Hypertens 2012;21:

16 Slide notes: Compound 21 is a specific, selective agonist for the angiotensin AT-2 receptor (AT-2R). Stimulation of AT-2R has no antihypertensive effect but promotes tissue protection in animal models. Reference: Steckelings UM et al. Curr Opin Nephrol Hypertens 2012;21:

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18 Slide notes: LCI 699 is an experimental, orally-administered aldosterone synthase inhibitor. Its clinical efficacy was shown in an initial small-scale study in 14 patients with primary aldosteronism who received an increasing amount of LCI 699 (initially 0.5 mg, then 1.0 mg). Mean baseline systolic BP was 151 mmhg (+/- 17) and diastolic 91 (+/- 12) mmhg. The table shows the results after 8 or 29 days. Reference: Amar L et al. Hypertension 2010;56:

19 Reference: Schumacher CD et al. J Hypertens 2013;31:

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21 Slide notes: Chemical structures of endothelin receptor antagonists in clinical use bosentan, ambrisentan and macitentan (Act is an active metabolite of macitentan) as well as some experimental compounds under development: SLV306 is a combined neprilysin (NEP) / endothelin-converting enzyme (ECE) inhibitor; KC12615 is its active metabolite. Reference: Maguire JJ, Davenport AP. Br J Pharmacol 2014;171:

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23 Slide notes: This slide illustrates the nitric oxide-guanylate cyclase-cyclic GMP pathway, which plays a pivotal role in vasodilation and blood pressure lowering. It is the target of various drugs, such as NO donors (e.g. nitroglycerin), direct stimulants of soluble guanylate cyclase such as riociguat and phosphodiesterase-5 inhibitors. This system is the target of new antihypertensive drug development. Reference: Garnock-Jones KP. Drugs 2014;74:

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25 Slide notes: Various classes of drugs are currently under development as agents to de-stiffen arteries in patients with different pathologies, such as hypertension or diabetes. Drugs that lower blood pressure may have an intrinsic ability to de-stiffen arteries, but the classes shown in this slide have additional, non-antihypertensive, mechanisms whereby they contribute to arterial de-stiffening. Reference: Boutouyrie P et al. Drugs 2011;71:

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Disclosure of Relationships

Disclosure of Relationships Over the past 12 months Dr Ruilope has served as Consultant and Speakers Bureau member of Astra-Zeneca, Bayer, Daiichi-Sankyo, Menarini, Novartis, Otsuka, Pfizer, Relypsa, Servier