e di infarto miocardico nell’ipertensione arteriosa Come ridurre il rischio di ictus e di infarto miocardico nell’ipertensione arteriosa Paolo Verdecchia, F.E.S.C., F.A.C.C. Hospital of Assisi. Department of Medicine Via Valentin Müller, 1 06081 - Assisi PG e-mail: verdec@tin.it

DISCLOSURE INFORMATION Paolo Verdecchia Negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Boehringer-Ingelheim, Bayer, BMS-Pfizer-Daiichi-Sankyo

sia di infarto miocardico In epidemiologia, più bassa è la PA, più basso è il rischio sia di infarto miocardico sia di ictus cerebrale

Systolic blood pressure Diastolic blood pressure BP and Mortality from Coronary Artery Disease The lower, the better Meta-analysis from 61 studies, 1 million individuals and 120 000 deaths Systolic blood pressure Diastolic blood pressure Age at risk (year) Age at risk (year) 256 256 80-89 80-89 128 Ischaemic heart disease mortality (floating absolute risk and 95% CI) 128 70-79 70-79 64 60-69 64 60-69 32 50-59 32 50-59 16 40-49 16 40-49 8 8 4 4 2 2 1 1 120 140 160 180 70 80 90 100 110 Usual systolic blood pressure (mmHg) Usual diastolic blood pressure (mmHg) Lancet 2002; 360:1903-13 4

Systolic blood pressure Diastolic blood pressure BP and Mortality from Stroke The lower, the better Meta-analysis from 61 studies, 1 million individuals and 120 000 deaths Systolic blood pressure Diastolic blood pressure Age at risk (year) Age at risk (year) 256 256 80-89 80-89 128 128 70-79 70-79 64 64 Stroke mortality (floating absolute risk and 95% CI) 60-69 60-69 32 32 50-59 50-59 16 16 8 8 4 4 2 2 1 1 120 140 160 180 70 80 90 100 110 Usual systolic blood pressure (mmHg) Usual diastolic blood pressure (mmHg) Lancet 2002; 360:1903-13 5

...ed è vera anche la ‘reverse epidemiology’: Quanto più scende la pressione arteriosa, tanto più diminuisce il rischio di eventi cardiovascolari....

The greater the BP reduction, the greater the expected benefit The degree of BP Reduction is a Major Determinant of the Benefit. A meta-regression analysis The greater the BP reduction, the greater the expected benefit (reduced risk of events) Staessen J et al. Hypert Res 2005

Effects of Antihypertensive Treatment on CV Complications -60 -50 -40 -30 -20 -10 CHF Stroke LVH CV deaths CHD -60 -50 -40 -30 -20 -10 CHF Stroke LVH CV deaths CHD - 16% - 21% - 16% - 21% - 35% - 38% - 35% - 38% - 52% - 52% Combined results of 17 randomized, placebo-controlled 3- to 5-year trials. BP decreased by 10-12/5-6 mmHg on active treatment vs placebo Moser M et al. J Am Coll Cardiol 1996; 27: 1214-8

fanno differenza tra infarto e ictus? No Le linee-guida fanno differenza tra infarto e ictus? No 2016 European Guidelines on CVD Prevention in Clinical Practice. Eur Heart J 2018;37:2315-81

In alcune ‘specifiche condizioni’ sono preferibili alcuni tipi di farmaci... 2016 European Guidelines on CVD Prevention in Clinical Practice. Eur Heart J 2018;37:2315-81

Eppure c’è evidenza che i farmaci antiipertensivi non sono tutti uguali nel proteggere dall’IMA e dall’ictus….

della cardiopatia coronarica A parità di abbassamento pressorio, gli ACE-inibitori sono più efficaci del Calcio-antagonisti per la prevenzione della cardiopatia coronarica Verdecchia P, et al Hypertension 2005

per la prevenzione dell’ictus cerebrale A parità di abbassamento pressorio, i Calcio-antagonisti sono più efficaci degli ACE-inibitori per la prevenzione dell’ictus cerebrale Verdecchia P, et al Hypertension 2005

E questo è vero anche per quanto riguarda lo scompenso cardiaco ccongestizio…

Angiotensin Receptor Blockers ACE Inhibitors or Angiotensin Receptor Blockers Calcium Channel Blockers 5.0 3.0 MIDAS VHAS DREAM 2.2 INSIGHT 2 1.8 1.6 ALLHAT/CCB-D 1.4 Odds Ratio for Congestive Heart Failure ALLHAT/ACE-D CONVINCE IDNT/CCB-PLB 1.2 SHELL UKPDS39 NORDIL CAPPP TRANSCEND INVEST LIFE 1 ANBP2 STOP2/CCB-BB HOPE IDNT/ARB-PLB SYST-EUR .8 PART-2 ASCOT DIABHYCAR STOP2/ACE-BB Camelot/ACE-PLB ACTION PEACE .6 RENAAL FEVER EUROPA Camelot/CCB-PLB .4 SYST-China STONE .2 NICS PREVENT -5 -2.5 2.5 5 7.5 10 -5 -2.5 2.5 5 7.5 10 Systolic Blood Pressure Difference Between Randomized groups (mmHg) Verdecchia P et al. Eur Heart J. 2009 Mar;30(6):679-88.

I sartani sono più efficaci degli ACE-inibitori nella prevenzione dell’ictus cerebrale

The risk of stroke is 8% lower with angiotensin receptor blockers than with ACE-Inhibitors Publication Year OR (95% CI) Events, ARBs Events, ACEi Study ARB vs. ACEI ELITE 1997 1.41 (0.31, 6.33) 4/352 3/370 ELITE-II 2000 1.64 (0.77, 3.48) 18/1578 11/1574 OPTIMAAL 2002 1.06 (0.83, 1.35) 140/2744 132/2733 DETAIL 2004 1.09 (0.34, 3.47) 6/120 6/130 VALIANT/Val 2006 0.85 (0.69, 1.04) 180/4909 211/4909 ONTARGET/Tel 2008 0.91 (0.79, 1.05) 369/8542 405/8576 Fixed Effect Model (I2 = 0.0%, p = 0.478) 0.93 (0.84, 1.03) 717/18245 768/18292 Random Effect Model 0.93 (0.84, 1.03) ARB+ACEI vs. ACEI VALIANT/Val+Cap 2006 0.87 (0.71, 1.06) 183/4885 211/4909 ONTARGET/Tel+Ram 2008 0.93 (0.80, 1.07) 373/8502 405/8576 Fixed Effect Model (I2 = 0.0%, p = 0.602) 0.91 (0.81, 1.02) 556/13387 616/13485 Random Effect Model 0.91 (0.81, 1.02) Overall Estimate Fixed Effect Model (I2 = 0.0%, p = 0.670) 0.92 (0.85, 0.99) 1273/31632 1384/31777 Random Effect Model 0.92 (0.85, 0.99) Heterogeneity between groups: p = 0.714 Reboldi P, Mancia G. Verdecchia P, et al. J Hypertens 2008 26:1282–1289 0.5 1 2 Favors 1st Listed Favors 2nd Listed

A parità di riduzione pressoria, l’ictus cerebrale viene prevenuto molto più che l’infarto miocardico… Il caso del diabete mellito…

Relative Risk of Stroke Relative Risk of Acute Myocardial Infarction 3.00 3.00 ABCD/HYP 2.75 2.75 2.50 2.50 2.25 2.25 ATLANTIS/1.25 2.00 ABCD/Norm 2.00 IDNT/ARB-CCB 1.75 1.75 ABCD/HYP IDNT/ARB-CCB 1.50 1.50 STOP2/CCB-BB-Diab DETAIL ABCD-N More vs Less 1.25 ACTION-Diab 1.25 STOP2/ACE-CCB-Diab ALLHAT/ACE-CCB-Diab UKPDS39 ABCD/Norm UKPDS39 ABCD-H More vs Less ALLHAT/ACE-D-Diab DETAIL CAPPP-Diab DIABHYCAR IDNT/ARB-PLB INVEST-Diab ATLANTIS/5 1.00 ADVANCE ABCD-H More vs Less 1.00 ADVANCE STOP2/ACE-BB-Diab RENAAL IDNT/ARB-PLB Relative Risk of Stroke ALLHAT/CCB-D-Diab INSIGHT-Diab Relative Risk of Acute Myocardial Infarction ASCOT-Diab ACTION-Diab EUROPA-Diab LIFE-Diab JMIC-B-Diab ACCORD BP MOSES-Diab STOP2/CCB-BB-Diab INVEST-Diab LIFE-Diab HOT-DM More vs Less DIABHYCAR HOPE-Diab UKPDS 38 ASCOT-Diab FACET EUROPA-Diab 0.75 SHEP-Diab 0.75 RENAAL HOPE-Diab PROGRESS-Diab STOP2/ACE-BB-Diab HOT-DM More vs Less IDNT/CCB-PLB JMIC-B-Diab UKPDS 38 ACCORD BP IDNT/CCB-PLB STOP2/ACE-CCB-Diab 0.50 0.50 FACET CAPPP-Diab SYST-EUR-Diab ABCD-N More vs Less 0.25 0.25 -4 -2 2 4 6 8 10 -4 -2 2 4 6 8 10 Reboldi GP, Verdecchia P, Angeli F et al, Journal of Hypertension, 2011 Diastolic BP difference between randomised groups, mmHg

SPRINT

SPRINT: Primary Outcome Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89) Standard (319 events) Intensive (243 events) Median follow-up = 3.26 years Number Needed to Treat (NNT) to prevent a primary outcome = 61

Come porre lo studio SPRINT nel contesto degli altri studi di confronto tra target pressori diversi?

Verdecchia P et al. Hypertension 2016; 68: 642-53

Verdecchia P et al. Hypertension 2016; 68: 642-53

Circulation Research 2017;120:27-29

Grazie per la vostra attenzione

Knot at 20 mmHg 1.20 (1.06-1.35) p=0.0032 Knot at -34 mmHg 1.05 (0.91-1.21) p=0.5124 Knot at -21 mmHg 1.09 (0.96-1.25) p=0.2021 Knot at 10 mmHg 1.04 (0.97-1.12) p=0.2887 Knot at -7 mmHg Reference Knot at -6 mmHg Reference Wald Chi-Square DF p-value Nonlinear 5.7432 1 0.0166 Wald Chi-Square DF p-value Nonlinear 3.6899 1 0.0547 Knot at 20 mmHg 1.42 (1.23-1.63) p<0.0001 Knot at 10 mmHg 1.18 (1.12-1.23) p<0.0001 Knot at -34 mmHg 0.84 (0.71-0.99) p=0.0456 Knot at -7 mmHg Reference Knot at -21 mmHg 0.79 (0.67-0.93) p=0.0049 Knot at -6 mmHg Reference Wald Chi-Square DF p-value Nonlinear 2.5093 1 0.1132 Wald Chi-Square DF p-value Nonlinear 1.0419 1 0.3074 Conclusions. In patients with CAD and initially free from CHF, a BP reduction from baseline over the examined BP range had little effect on the risk of MI and predicted a lower risk of stroke. An increase in SBP from baseline increased the risk of stroke and MI. A treatment-induced BP reduction over the explored range was safe in these patients. Verdecchia P et al. Hypertension. 2015;65:108-14

Il risultato non cambia anche considerando i valori pressori ‘assoluti’.....