New updates on Hypertension and Heart Failure 2015 Yiu Kai Hang

New updates on Hypertension and Heart Failure 2015 Yiu Kai Hang MD, MBBS, MRCP, FHKCP, FHKAM, FRCP (Edin) Clinical Associate Professor Cardiology Division, Department of Medicine, HKU Honorary Consultant, QMH Honorary Consultant, HK Sanatorium Hospital

New updates on Hypertension

Guidelines for Hypertension Management 2003 JNC 7 2014 2014 JNC8 2013 2012 2013 ESH/ESC 2013 AHA/ACC/DCD 2013 CHEP 2012KDIGO 2011 2010 2011 NICE 2009 2010 Chinese Guideline for HT 2009ESH/ESC

What is the target?

Revisit the JNC 7 guidelines Blood pressure goal: <140/90 mmhg for most patients <130/80 mmhg for patients with DM/CKD

JNC8: BP goal for elderly patients Age, mmhg All cause mortality Heart failure Stroke CHD 60,<150 (HYVET) (SHEP,HYVET) (Syst-eur,SHEP, HYVET) (Syst-eur,SHEP) BP goal 80,<150 60-79,<150 (HYVET) (Syst-eur,SHEP) - - - - - - 65,<140 (JATOS VALISH) (JATOS VALISH) (JATOS VALISH) (JATOS VALISH) :agree; :disagree - :N/A Note: # HYVET was stopped early because of a 21% reduction in mortality in the active treatment group. If the study had not been stopped early, the reduction in fatal or non fatal stroke may have been significant by the end of the trial. ; *EWPHE: an 11% reduction in non fatal cerebrovascular events at one year (p <0.05) and a 32% non significant decrease (p = 0.16) in cerebrovascular mortality at the end of the trial In elderly 60,lower the SBP to<150mmhg is associated with statistically significant improvement in CCV outcome BP goal for elderly patients: < 150/90 mmhg

JNC 8: BP goal for patients with CKD Age,mmHg GFR ESRD CCV event Mortality BP goal <70 (CKD subgroup) <130/80 vs <140/90 (AASK MDRD REIN-2) (AASK MDRD REIN-2) (AASK) (AASK) <70 (proteinurea subgroup) <130/80 vs <140/90 (AASK* MDRD # ) (AASK REIN-2) :agree; :disagree - :N/A Note: # MDRD:proteinurea>3g/24hr group ; *AASK:proteinurea>300mg/d group vs <300mg/d group In adults <70 years with CKD, the evidence is insufficient to determine if there is a benefit in mortality or CCV outcomes with antihypertensive drug therapy to a goal <130/80mmHg compared with <140/90mmHg BP goal for patients with CKD: < 140/90 mmhg

JNC 8: BP goal for diabetes Age, mmhg All-cause mortality DM related endpoints Heart failure stroke CHD Diabetes <150 (Syst-Eur UKPDS SHEP) (UKPDS) _ (Syst-Eur UKPDS) (SHEP) BP goal Diabetes <120 vs <140 50years with diabetes <80 vs <90 _ (ACCORD) (ACCORD) _ (ACCORD) (HOT) (ACCORD) (HOT) diabetes* <80 vs <90 (ABCD hypertension) (HOT UKPDS) :agree; :disagree - :N/A Note: *diabetes subgroup:sbp:130-139mmhg or DBP:80-89mmHg or hypertensive patients In absence of RCTs addressed whether treatment to an SBP goal < 140 mm Hg compared with <150mmHg improves health outcomes in adults with diabetes and hypertension, the panel recommends BP goal for patients with DM: < 140/90 mmhg

JNC 8: more lenient systolic blood pressure goal Treat to 150/90 in patients aged over 60 and 140/90 for everybody else.

Which drug?

Revisit the JNC 7 guidelines Preferred initial therapy: Thiazide-type diuretics

JNC 8: no preference among initial drugs General population CKD presented Diuretics is no longer the single best initial drug. New guideline recommends: No preference among the 4 initial drugs: thiazide diuretic, ACEI, ARB and CCB. For black patients: CCB or diuretics should be recommended. For CKD patients: ARB or ACEI should be included to improve kidney outcome.

Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults With Hypertension

Single or combination therapy?

Revisit the JNC 7 guidelines Strategy to dose: Optimize the first agent before adding the second agent

JNC8: If goal BP is not reached within 1 month, adjust the treatment regimen until goal is reached The main objective of hypertension treatment is to attain and maintain BP goals! If BP goal is not achieved within 1 month: Increase dose of initial drug Start combination therapy Either separate of single pill Destination is important and not the journey!

2013 AHA/ACC/CDC: initiation of combination therapy in patients at stage 2 hypertension SBP>160mmHg or DBP>100mmHg (stage 2 hypertension),two drugs preferred lifestyle modification and thiazide and ACEI /ARB or CCB or consider ACEI and CCB Recheck and review readings in 2-4 weeks* NO Thiazide for most patients or ACEI ARB CCB or combo If currently on BP med(s), titrate and/or add drug from different class BP at goal? YES Recheck and review readings in 2-4 weeks* BP at goal? No Optimize dosage or add medications Address adherence, advise on selfmonitoring, and request readings from home and other settings Consider secondary causes Yes observation Consider referral to HTN specialist Go AS, et al. Hypertension. 2013 Nov 15.

Why combination? There is a need for multiple agents to achieve target SBP goals Trial (SBP achieved) ASCOT-BPLA (136.9 mmhg) ALLHAT (138 mmhg) IDNT (138 mmhg) RENAAL (141 mmhg) UKPDS (144 mmhg) ABCD (132 mmhg) MDRD (132 mmhg) HOT (138 mmhg) AASK (128 mmhg) Bakris et al. Am J Med 2004;116(5A):30S 8; Dahlöf et al. Lancet 2005;366:895 906 1 2 3 4 Number of medications

SBP<140mmHg patients(%) Most patients cannot achieve their BP goal with monotherapy A randomized, parallel, cross-over designed study to evaluate proportion of patient who achieve SBP < 140 mmhg with different monotherapy Efficacy in elderly patients whose BP is un-controlled 100% 80% 60% 40% 20% 17% 18% 23% 27% 0% β-blocker ACEI Diuretics CCB Morgan TO, et al. AJH. 2001;14:241-247.

Blood Pressure has Multiple Regulatory Pathways Hypertension: a multi-factorial disease Patient 1 Patient 2 Patient 3 Sympathetic nervous system Renin-angiotensin system Total body sodium B. Waeber, March 2007

Initial SPC vs. Sequential Add-on Sequential add-on A A+D Initial combination A/D Sympathetic nervous system b-blockers Renin-angiotensin system/vasoconstriction Total body sodium BP = SV x HR x TPR Salt reduction, CCB, diuretics More effective More sustainable Fewer side effects Better compliance ACE-I, ARB, DRI,

Which combination?

Which combination preferred? Recommendation from ESH/ESC 2013 guidelines: possible but less well tested combination useful combination with some limitation preferred combinations not recommended combination

ESH/ESC 2013 guidelines: Drug to be preferred in specific conditions Condition drug ARB CCB Diuretic ACEI BB Asymptomatic organ damage LVH Asymptomatic atherosclerosis Microalbuminuria Renal dysfunction Clinical CV events Previous stroke Previous myocardial infarction Angina pectoris Heart failure Aortic aneurysm Atrial fibrillation, prevention Atrial fibrillation, ventricular rate control # ESRD/proteinuria Peripheral artery disease Other ISH (elderly) Metabolic syndrome Diabetes mellitus Pregnancy Methyldopa Blacks

Which combination preferred? Recommendation from NICE 2011 guidelines: <55 years 55 years or black patients at any age Step 1 ACEI / ARB CCB Step 2 ACEI / ARB + CCB Step 3 ACEI / ARB + CCB + diuretic Step 4 Add further diuretic therapy, α-blocker, or β-blocker. Consider seeking specialist advice National Institute for Health and Clinical Excellence (NICE) (2011) Hypertension: Hypertension: Clinical management of primary hypertension in adults London: NICE. Available from www.nice.org.uk/cg127

Low-dose CCB ARB therapy is efficacious in getting patients to BP goal (<140/90 mmhg) Patients achieving BP goal (%) 70 60 50 40 30 20 10 * N=137 0 CCB ARB CCB + ARB *p<0.05 vs CCB and ARB alone Andreadis et al. J Hum Hypertens 2005;19:491 6

Significantly smoother BP variation and higher trough-to-peak ratio with low-dose CCB ARB BP (mmhg) variability 150 148 146 144 142 140 138 136 134 132 130 8:00 AM 0.935 10:00 12:00 AM PM *p<0.05 vs CCB and ARB alone Values in boxes represent trough-to-peak ratio Andreadis et al. J Hum Hypertens 2005;19:491 6 CCBs ARBs CCB + ARB 2:00 PM 4:00 PM 0.950* 0.936 6:00 PM 8:00 PM 10:00 PM 12:00 AM 2:00 AM 4:00 AM Variability in blood pressure itself has detrimental effects Fluctuating BP signals high risk 6:00 AM

Safety profile of different ARBs ARB LVH HF MI/CAD High Risk HT DN IGT Losartan LIFE ELITE OPTIMAL RENAAL Valsartan VaHeFT VALIANT VALUE MARVAL NAVIGATOR Irbesartan IDNT/IRMA Candesartan CHARM CALM Telmisartan ONTARGET/TR ASCEND* Omesartan ROADMAP VaHeFT Valsartan Heart Failure Trial /VALIANT Valsartan in Acute Myocardial Infarction Trial CHARM Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity OPTIMAL Optimal Trial In Myocardial Infarction with Angiotensin II Antagonist Losartan/ RENAAL Reduction of Endpoints in NIDDM with Ang II Antagonist Losartan MARVAL Microalbuminuria Reduction with Valsartan trial IDNT and IRMA Irbesartan Diabetic Nephropathy Trial & IRbesartan microalbuminuric DM in HT CALM Candesartan And Lisinopril Microalbumiuria ONTARGET The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial Telmisartan Randomised Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease* NAVIGATOR - Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research

Amlodipine/Valsartan has superior BP-lowering efficacy compared with monotherapies 0 Amlodipine 10 mg Valsartan 160 mg Amlodipine/Valsartan 10/160 mg 5 10 15 20 17.8 16.5 25 N=42 Change from baseline in systolic BP (mmhg) 23.5 * *p<0.001 vs monotherapies Mild-to-moderate HTN = DBP >95 and <110 mmhg Fogari et al. J Hypertens 2006;24(Suppl 4):S34

Amlodipine/Valsartan: appropriate BP reductions across all grades of hypertension Mean change in mean sitting SBP from baseline (mmhg) 0 10 Mild HTN 1 (DBP 95 100 mmhg SBP 140 160 mmhg) n=69 Moderate HTN 1 (DBP 100 110 mmhg SBP 160 180 mmhg) n=140 Stage 2 HTN 2 (DBP 110 mmhg <120 mmhg) n=64 Systolic BP 180 mmhg 2 n=15 20 30 40 20 30 36 50 Dose: 10/160 mg Dose: 5 10/160 mg 43 DBP reduction (mmhg) 17 18 29 26 1 Poldermans et al. Clin Ther 2007;29(2):279-289. 2 Data from Poldermans et al. J Hypertens 2006;24(Suppl 4):S20 (poster)

Oedema CCB dilates arteries Veins remain constricted ARB dilates arteries and veins Capillary overload forces fluid into surrounding tissue Reduces CCB-induced peripheral oedema Single mode of action of the CCB Dual mode of action of the CCB ARB

Amlodipine/Valsartan reduces the incidence of amlodipine-associated peripheral oedema Peripheral oedema (%) 10 8.7 8 6 * 5.4 4 3 2 2.1 0 Placebo (n=337) Valsartan (n=921) Amlodipine (n=460) Amlodipine/Valsartan (n=1,437) *p=0.0138 vs amlodipine Novartis data on file

Amlodipine/Valsartan prevents recurrence of atrial fibrillation more effectively than atenolol/valsartan during a 1-year follow-up Patients with at least one symptomatic or non-symptomatic ECG-documented episode of atrial fibrillation (% incidence) 40 30 33 N=220 20 * 13 10 0 Amlodipine/Valsartan Amlodipine/atenolol 10/160 mg 10/100 mg *p<0.01 vs amlodipine/atenolol Titration to maximum dose of amlodipine Mugellini et al. J Hypertens 2006;24(Suppl 4):S5

Single pill or free combination?

Single-pill combination vs free combination Single pill Free Simplicity of treatment + Compliance + Efficacy + + Tolerability +* Price + Flexibility +** ++ *Lower doses generally used in single-pill combinations **An increasing number of single-pill combinations are becoming available with a range of doses + = potential advantage Burnier, et al. Am J Hypertens 2006;19:1190 6; Neutel. Hypertension. Companion to Brenner & Rector s The Kidney. 2 nd ed. Philadelphia: Elsevier Saunders, 2005. p. 522 9

Meta-Analysis of SPC vs Free Combination of Antihypertensive Agents Compliance Ratio Systolic BP ASCOT Study 21% 4.1 mmhg Adverse Events Diastolic BP 20%! Gupta AK, et al. Hypertension 2010;55:399-407. Gupta AK, et al. Hypertension 2010;55:399-407. 3.1 mmhg

BP respondent rate (%) Valsartan/amlodipine single-pill combination significantly increase respondent rate compared with free combination 100 90 80 70 60 50 40 30 20 10 0 SPC:valsartan/amlodipine Free combination:arb+ccb 81 days observation: 66.0% 0 1 2 3 4 5 6 month 90 days observation: 54.0% P=0.04 The study included 812 patients: 414 on valsartan-based SPCs (209 on valsartan/amlodipine and 205 on valsartan/hctz) and 398 on ARB-based FCs (200 on ARB + CCB and 198 on ARB + HCTZ). BP target:<140/90mmhg(dm or CKD patients <130/80mmHg) Chang J, et al. Curr Med Res Opin. 2010 Sep;26(9):2203-12

EXCITE: prospective, multinational, non-interventional, real-world study Amlodipine/valsartan OR Amlodipine/valsartan/HCT Visit 1 Baseline Optional Visit 2 13 weeks Observational period of 26 weeks ± 8 weeks Visit 3 26 weeks End of study Khan et al. Ther Adv Cardiovasc Dis. 2014 Apr;8(2):45-55

EXCITE: data analyzed from >9700 patients with hypertension pooled from 13 countries Kuwait Bahrain Lebanon Qatar UAE South Korea Taiwan Hong Kong Oman Pakistan Philippines Egypt Indonesia Patients from Saudi Arabia were excluded from this analysis due to non-compliance with the study protocol. Safety data from this country are the subject of a separate report. Adil Hospital Lahore, Lahore, Pakistan. Real-life effectiveness, safety, and tolerability of amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide single-pill combination in patients with hypertension from Pakistan. Ther Adv Cardiovasc Dis. 2014 Apr;8(2):45-55

Change in mean sitting BP (mmhg) EXCITE: significant BP reductions from baseline across all treatment dosages in the AML/VAL group AML/VAL dose (mg) Overall 5/80 5/160 10/160 5/320 10/320 (n=8264) (n=1428) (n=4839) (n=1941) (n=28) (n=24) BL mssbp/msdbp (mmhg) 160.9/97.1 155.0/92.6 160.4/97.5 166.5/99.4 161.8/96.4 169.1/103.3 0 5 10 15 13.7 13.5 20 16.6 16.8 18.2 25 21.0 30 26.1 35 31.0 30.7 31.0 40 35.5 39.2 45 95% CI (LL,UL) Overall 5/80 5/160 10/160 5/320 10/320 mssbp 31.42, 30.67 27.05, 25.16 31.14, 30.26 36.30, 34.61 36.89, 25.11 45.66, 32.67 msdbp 16.79, 16.34 14.28, 13.14 17.03, 16.48 18.65, 17.68 17.94, 9.13 25.21, 16.88 Khan et al. Ther Adv Cardiovasc Dis. 2014 Apr;8(2):45-55

Change in mean sitting BP (mmhg) EXCITE: incremental BP reductions with AML/VAL across prior antihypertensive monotherapy classes Prior antihypertensive monotherapy BL mssbp/msdbp (mmhg) 0 5 Overall ACEi ARB CCB Beta-blocker Diuretic (n=2575) (n=653) (n=581) (n=781) (n=546) (n=14) 158.7/96.5 160.0/97.0 158.3/96.2 157.3/95.8 159.6/97.0 162.9/102.9 10 15 20 25 16.2 16.6 15.5 15.8 17.2 19.3 30 35 29.9 31.2 28.6 28.7 31.3 30.7 40 95% CI (LL,UL) Overall ACEi ARB CCB Beta-blocker Diuretic mssbp 30.50, 29.26 32.45, 29.95 29.84, 27.36 29.86, 27.63 32.68, 29.87 37.04, 24.38 msdbp 16.61, 15.87 17.28, 15.86 16.29, 14.65 16.50, 15.19 17.97, 16.34 23.38, 15.19 Post-hoc analysis. Baseline defined as prior to start of AML/VAL. End of study defined as Visit 3 (Week 26). Included only patients who did not take any antihypertensive medication during the observational period, in addition to AML/VAL, and did not switch to AML/VAL/HCT. No additional treatment prior to study entry was received. Khan et al. Ther Adv Cardiovasc Dis. 2014 Apr;8(2):45-55

EXCITE: Target BP achievement BP target achieved AML/VAL N= 8603 n (%) AML/VAL/HCT N=1191 n (%) Total N=9794 n (%) Therapeutic goal SBP<140 mmhg and DBP <90 mmhg 5822 (69.9) 832 (70.9) 6654 (70.0) SBP response SBP <140 mmhg or a reduction of 20 mmhg from baseline DBP response DBP <90 mmhg or a reduction of 10 mmhg from baseline 7305 (89.5) 1058 (91.0) 8363 (89.7) 6876 (91.8) 965 (91.4) 7841 (91.8)

Summary of the updated hypertension guidelines Loosened SBP target <140 for general; <150 for elderly Simplified drug regimen The initial drug chosen broaden to diuretics, CCB, ACEI and ARB. Initiation of combined therapy: SBP>160 and/or DBP>100 (stage 2 hypertension) mild elevation of BP (stage 1 hypertension) in presence of multiple risk factors, organ damages, DM, CKD or associated CV risk Emerging role of single-pilled combination

New updates on Heart Failure

Definitions of Heart Failure Heart failure is the pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure. Eugene Braunwald

Annual Incidence of New Cases of HF Framingham Heart Study

NORMAL

SYSTOLIC HEART FAILURE

Ivabradine Ivabradine acts by reducing the heart rate via specific inhibition of the funny channel, a mechanism different from beta blockers and calcium channel blockers Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium

Aim To assess the effect of ivabradine on outcomes in heart failure patients on recommended background therapies with heart rates 75 bpm in the SHIFT trial Bö hm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com

Baseline characteristics Ivabradine Placebo n=2052 n=2098 Mean age, years 60 60 Male, % 77 77 BMI, kg/m 2 28 28 Mean HF duration, years 3.4 3.4 HF ischemic cause, % 66 65 NYHA class III, % 50 51 NYHA class IV, % 2 2 Mean LVEF, % 28.7 28.5 Mean HR, bpm 84.3 84.6 Bö hm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com

Baseline background treatment Ivabradine n=2052 Placebo n=2098 β-blockers, % 87 88 At least half target dose 55 56 At target dose 26 26 ACE inhibitors/arbs, % 90 90 Diuretics (excludes AAs), % 85 83 Aldosterone antagonists, % 63 61 Bö hm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com

Patients with primary composite end point (%) Effect of ivabradine on primary outcome CV death or hospitalization for HF Hazard ratio=0.76 40 P<0.0001 Placebo 30 20 Ivabradine 10 0 0 6 12 18 24 30 Time (months) Bö hm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com

Effect of ivabradine on major outcomes Hazard ratio 95% CI P Primary composite end point Cardiovascular mortality Hospitalization for worsening HF Death from HF All-cause mortality All-cause hospitalization Any cardiovascular hospitalization 0.76 0.68-0.85 0.83 0.71-0.97 0.70 0.61-0.80 0.61 0.46-0.81 0.83 0.72-0.96 0.82 0.75-0.90 0.79 0.71-0.88 <0.0001 0.0166 <0.0001 0.0006 0.0109 <0.0001 <0.0001 0.20 0.40 0.60 0.80 1.00 1.20 Favors ivabradine Favors placebo Bö hm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com

Summary of the updated heart failure guidelines Use of ivabradine in patients with impaired LVEF <35% and heart rate >70 bpm on optimal medical therapy Expand indication of device therapy (CRT/ICD) The use of LVAD implemented

Guidelines are trying to help

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