Συμπεράσματα από τις νέες μελέτες για την αρτηριακή υπέρταση (SPRINT,PATHAY 2,HOPE 3)

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1 Συμπεράσματα από τις νέες μελέτες για την αρτηριακή υπέρταση (SPRINT,PATHAY 2,HOPE 3) Χάρης Γράσσος MD,FESC,PhD,EHS Διευθυντής Καρδιολόγος Γ.Ν.Α ΚΑΤ Visiting Professor University of Bolton U.K

2 New England Journal of Medicine Promissing to change everything to know about Hypertension

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4 Primary Outcome and Primary Hypothesis Primary outcome CVD composite: first occurrence of Myocardial infarction (MI) Acute coronary syndrome (non-mi ACS) Stroke Acute decompensated heart failure (HF) Cardiovascular disease death Primary hypothesis* CVD composite event rate lower in intensive compared to standard treatment *Estimated power of 88.7% to detect a 20% difference - based on recruitment of 9,250 participants, 4-6 years of follow-up and loss to follow-up of 2%/year.

5 1.8 vs vs 2.8

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7 ACHIEVED SBP/DBP VALUES (mmhg) IN SPRINT 1 YEAR FINAL. STANDARD INTENSIVE 136.2/ / / /67.2 BP difference 13 mm Hg: Stroke reduction p: NS MI and no MI ACS p: NS 3861

8 BP Reductions as Small as 2 mmhg Reduce the Risk of CV Events by Up to 10% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 2 mmhg decrease in mean SBP 7% reduction in risk of IHD mortality 10% reduction in risk of stroke mortality Prospective Studies Collaboration. Lancet. 2002;360:

9 SPRINT Primary Outcome and its Components Event Rates and Hazard Ratios Intensive Standard No. of Events Rate, %/year No. of Events Rate, %/year HR (95% CI) P value Primary Outcome (0.64, 0.89) <0.001 All MI (0.64, 1.09) 0.19 Non-MI ACS (0.64, 1.55) 0.99 All Stroke (0.63, 1.25) 0.50 All HF (0.45, 0.84) CVD Death (0.38, 0.85) 0.005

10 Participants with CKD at Baseline Renal Disease Outcomes Intensive Standard Events %/yr Events %/yr HR (95% CI) P Primary CKD outcome (0.42, 1.87) % reduction in (0.36, 2.07) 0.75 egfr * Dialysis (0.19, 1.54) 0.27 Kidney transplant Secondary CKD Outcome Incident albuminuria** (0.48, 1.07) 0.11 Participants without CKD at Baseline Secondary CKD outcomes 30% reduction in egfr* (2.44, 5.10) <.0001 Incident albuminuria** (0.63, 1.04) 0.10 *Confirmed on a second occasion 90 days apart **Doubling of urinary albumin/creatinine ratio from <10 to >10 mg/g

11 Is it possible that in SPRINT patients randomized to lower BP target were 1) originally healthier? 2) more carefully followed? Should GLs recommend to start drug treatment in the high normal BP range in both middle age and elderly pts? In SPRINT entry BP 139.7/78.1mmHg but patients were treated!

12 Office Blood Pressure Measurement

13 Unattended Automatic office BP Measurement 5min alone in the room-sbp/dbp fell by 15.7/8.0mmHg for unattended automatic office BP compared to regular OBP. The limit for hypertension of 140/90mmHg,according to office BP corresponded to 125/82mmHg for unattended automatic OBP Filipovsky Blood Pressure 2016

14 ROME 2016 ESC

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17 High-risk+Age 50ys+SBP 130mmHg Consider SBP 120mmHG Guided by AOBP measurements

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19 SPRINT TRIAL No Nnnon s Yes

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22 Influence in Hyp Guidelines in EU???? NO SPRINT TRIAL SPRINT TRIAL

23 The Pathway Project Single vs Combination diuretic in patients with low-renin HTN Optimal therapy of RH Monotherapy vs. Combination for initial treatment

24 Therapeutic Strategies in Patients with Resistant Hypertension

25 A Double blinded, Placebo-Controlled, Crossover Study Williams, Bryan, et al. "Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial." The Lancet 2015;386:

26 A Double blinded, Placebo-Controlled, Cross-over Study Comparison of: Spironolactone, mg/daily with Placebo Doxazocin, 4-8 mg/daily Bisoprolol, 5-10 mg/daily

27 PATHWAY-2: Study Design Inclusion criteria: Patients aged years Seated clinic SBP 140 mmhg (or 135 mmhg for patients with diabetes) Home SBP (18 readings over 4 days) 130 mmhg despite treatment for 3 months with maximally tolerated doses of 3 drugs From 12 secondary and 2 primary care sites in the UK

28 PATHWAY-2: Primary endpoints Difference in average home systolic BP (HSBP) between: Spironolactone and placebo Spironolactone and average of the other 2 active drugs (doxazosin and bisoprolol) Spironolactone and each of the other 2 active drugs

29 PATHWAY-2: Secondary endpoints Clinic BP responses to randomized treatments BP control rates with each treatment (HSBP <135 mmhg) Whether baseline plasma renin concentrations, whilst on treatment with A+C+D, predicted the best drug for individual patients Safety and adverse events during each treatment cycle

30 PATHWAY-2: Primary Outcome

31 There was an inverse and linear relationship between renin and BP response to spironolactone

32 Only six of 285 (2%) patients exposed to spironolactone developed a serum potassium on a single occasion greater than 6 0 mmol/l, with a maximum of 6 5 mmol/l

33 Limitations of the study Short duration of treatment (3 months) Exclusion of patients with egfr <45 ml/min (no data) Inclusion of predominantly white Caucasians (unclear whether the results are applicable to other ethnic groups) Absence of washout periods Absence of data for morbidity and mortality outcomes (BP lowering as a powerful surrogate for clinical benefit in this highrisk group of patients)

34 PATHWAY-2 Only 15 of 285 patients assessed on spironolactone failed to achieve a HSBP <150 mmhg, equivalent to a CSBP 160 mmhg, the usual eligibility criterion for denervation - Spironolactone was clearly the most effective treatment for RH and thus should influence future treatment guidelines and clinical practice globally - Patients should not be defined as RH unless their BP remains uncontrolled on spironolactone!!!

35 Spironolactone 25-50mg daily: Conclusions Is the most effective drug treatment for RH Controls BP in almost 60% of patients with RH and is 3-times as likely to be more effective than doxazocin or bisoprolol

36 The Heart Outcomes Prevention Evaluation (HOPE) 3 Trial Eva Lonn, Jackie Bosch, Salim Yusuf For the HOPE-3 Investigators Population Health Research Institute, (PHRI) McMaster University and Hamilton Health Sciences, Hamilton, Canada Unrestricted grants from the Canadian Institutes of Health Research and AstraZeneca

37 Unique Aspects of HOPE-3 BP lowering trial with wide range of BP entry criteria Cholesterol lowering treatment based on risk opposed to baseline LDL or HDL measurement Diverse population

38 HOPE-3 Baseline characteristics

39 Cumulative Hazard Rates CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure HR (95% CI) = 0.95 ( ) P-value = 0.51 Placebo Candesartan + HCTZ No. at Risk Cand + HCTZ Placebo Years

40 Prespecified Subgroups: By Thirds of SBP CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF Cutoffs SBP Mean Diff Placebo Event Rate% HR (95% CI) P Trend ( ) ( ) > ( ) Candesartan + HCTZ Better Placebo Better

41 BP Lowering Arm: Conclusions Fixed dose combination of Candesartan 16 mg + HCTZ 12.5 mg/day reduced BP by 6.0/3.0 mmhg, but did not reduce CV events CV events were significantly reduced in the highest third of SBP SBP >143.5 mmhg, mean 154 mmhg Results were neutral in the middle third, and trended towards harm in the lowest third of SBP Treatment increased lightheadedness, but not syncope or renal dysfunction

42 Cholesterol Lowering Arm Results Jackie Bosch

43 Cholesterol Lowering: Outcomes Outcome Rosuvastatin N (%) Placebo N (%) HR (95% CI) p Co-Primary (3.7) 304 (4.8) 0.76 ( ) Co-Primary (4.4) 363 (5.7) 0.75 ( ) Secondary 1 306(4.8) 393 (6.2) 0.77 ( ) CV Death 154 (2.4) 171 (2.7) 0.89 ( ) 0.31 MI 45 (0.7) 69 (1.1) 0.65 ( ) 0.02 Stroke 70 (1.1) 99 (1.6) 0.70 ( ) 0.02 CV Hosp. 281 (4.4) 369 (5.8) 0.75 ( )

44 Cumulative Hazard Rates CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure HR (95% CI) = 0.75 ( ) P-value = Placebo Rosuvastatin Rosuva Placebo Years

45 HOPE-3 & Other Studies of LDL Lowering and CVD

46 Cholesterol Lowering: Conclusions Rosuvastatin 10mg/day reduced: LDL-C by 34.6 mg/dl (0.9 mmol/l; i.e. 27% in LDL-C) CVD by 25% Consistent benefits regardless of: LDL-C SBP Risk CRP Ethnicity Excess in muscle pain/weakness (reversible) and perhaps cataract surgery No excess in rhabdomyolysis, myopathy or new diabetes

47 Combined BP & Cholesterol Lowering vs Double Placebo Salim Yusuf

48 Unique Aspects of BP & Chol Lowering First formal testing of polypill concept on clinical events Demonstrates that the concept is valid in people with elevated BP; in others there is no benefit

49 Cumulative Hazard Rates CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure Double Placebo Combination HR (95% CI) = 0.72 ( ) P-value = Combination Rosuvastatin Candesartan/HCTZ Double Placebo Years

50 RRR RRR RRR of Combination and Each Intervention vs Double Placebo Co-Primary 2 50% 40% 30% 28% Overall 26% 20% 10% 6% 50% 40% 30% 20% 40% 0% Combo Highest Third of SBP 24% 20% Rosuva Only 50% 40% 30% 20% Cand + HCTZ Only Lower Two Thirds of SBP 19% 31% 10% 10% Cand + HCTZ Only 0% Combo Rosuva Only Cand+HCTZ Only 0% Combo Rosuva Only -8%

51 Clinical Implications Statins beneficial in intermediate-risk individuals without CVD BP lowering benefits only those with elevated BP Combined BP & cholesterol lowering: Leads to a 40% risk reduction in hypertensives (benefits from both BP lowering and statin) In others, 30% RRR from statin alone Pragmatic strategy: No Lipid or BP entry criteria or targets No Dose titration Infrequent safety monitoring Strategy used in HOPE-3 is simple, safe and effective and widely applicable

52 Ευχαριστώ!!!