GOING BEYOND HYPERTENSION CONTROL

Transcription

1 From bench to practice: hypertension control GOING BEYOND HYPERTENSION CONTROL Prof. Dr. Maria DOROBANTU, FESC,FACC CAROL DAVILA UNIVERSITY OF MEDICINE OF BUCHAREST EMERGENCY HOSPITAL OF BUCHAREST, CARDIOLOGY

2 Declaration of conflict of interest I have nothing to declare.

3 Natural History of Cardiovascular Disease LVH > IM thickness Lacunar infarcts Microalbuminuria MI, Angina Stroke CHF Renal Failure Periferal Artery Disease HT Non-fatal recurrent events Arteriosclerosis Arterial remodeling Hypertension Diabetes Dyslipidemia Central Obesity HT HT HT HT CRF Dialysis Dementia Genes Life style Death

4 High-Normal Blood Pressure and CVD Risk: Framingham Study Men High normal /85-89 mm Hg Normal /80-84 mm Hg Optimal <120/80 mm Hg Prehypertension Women P< P< Cumulative Incidence (%) 14 Time (years) Time (years) Vasan et al. N Engl J Med. 2001;345:

5 Cardiovascular Mortality Risk Cardiovascular Mortality Risk Increases as Blood Pressure Rises * 8 8x x 3 2 2x /75 135/85 155/95 175/105 Systolic/Diastolic Blood Pressure (mm Hg) * Measurements taken in individuals aged years, beginning with a blood pressure of 115/75 mm Hg. Lewington S, et al. Lancet. 2002;360: ; Chobanian AV, et al. JAMA. 2003;289:

6 What are the goals of therapy? <140/90 for patients without diabetes or renal disease (JNC 7) Most patients who achieve their systolic goal will also achieve their diastolic goal <130/80 for patients with diabetes or renal disease (JNC 7)

7 2007 ESH/ESC Guidelines BP Targets (mmhg) by Treatment General hypertensive population < 140/90 (and lower values, if tolerated) High risk patients (CAD/cerebrovasc. disease/ diabetes/renal dysfunction) < 130/80 EHJ 2007;28:

8 What is the Benefit?

9 Evidence History MRC-1985 HAPPHY-1987 EWPHE-1991 STOP-1991 SHEP STONE-1996 SYS-EUR-1997 SYS-CHINA HOT-1998 UKPDS CAPPP-1999 STOP HOPE MICRO-HOPE INSIGHT NORDIL CALM INDT IRMA RENAAL PROGRESS LIFE-2002 SCOPE 2002 ALLHAT 2002

10 Heart Failure Reduction > 50% Stroke Incidence Reduction 35-40% Myocardial Infarction Reduction 20-25%

11 Tight BP Control - Open Questions The lower the better?

12 Benefit of more active versus less active treatment Zanchetti et al. J Hypertens 27:923, 2009

13 The blood presure target in the CAD patients will probably be challenged in the future guidelines.

14 Can we further decrease residual risk and how?

15 Bottom blood pressure or bottom cardiovascular risk? How far can cardiovascular risk be reduced? In high-risk patients there is a 'ceiling effect' for treatment benefits In elderly hypertensive patients, hypertensive patients with diabetes and particularly patients with previous cardiovascular disease quite rarely could incidence of major cardiovascular events be reduced below a bottom level of 12-14% in 5 years, and remained within the high-risk range (above the conventional threshold of 10% in 5 years) despite extensive use of concomitant therapies. Zanchetti E, J Hypertens Aug;27(8):

16 Arterial hypertension = the main modifiable CV risk factor IHD, HF Diabetes Cerebrovascular disease Dyslipidemia Peripheral arterial disease Smoking Obesity Chronic kidney disease

17 Can we further decrease residual risk and how?

18 Although control of blood pressure (BP) is a primary goal of therapy, evidence from several clinical trials suggests that certain antihypertensive agents provide clinical benefits independent of their effect on BP. On the contrary, other agents have side effects for certain categories that limit their use, despite good BP control.

19 Is there benefit beyond decrease of BP values to targets? Are there beneficial class effects? Nephroprotection Cardioprotection Prevention of diabetes Are there specific benefits for individual drugs?

20 Relation between odds ratios (ORs) for congestive heart failure and differences in achieved systolic blood pressure between randomized groups. Verdecchia P et al. Eur Heart J 2009;30:

21 RAAS is influencing all blood pressure regulation systems ACEI

22 Effects of Angiotensin II Pressor effect Proinflammatory Oxidative stress Salt retention Insulin resistance Through PI3 kinase and downstream Akt pathway Reduction in NO production within endothelium Increases vasoconstriction Increases TGF-b production and hepatic fibrosis

23 HOPE, QUIET, EUROPA, PEACE: Primary outcomes % Patients HOPE 22% Risk reduction RR 0.78 ( ) P = Placebo Time (years) Ramipril 10 mg EUROPA 20% Risk reduction RR 0.80 ( ) P = Time (years) Placebo 5 Perindopril 8 mg % Patients PEACE 4% Risk reduction HR 0.96 ( ) P = 0.43 Placebo Time (years) Trandolapril 4 mg % Risk increase RR 1.04 ( ) P = QUIET Quinapril 20 mg Placebo 2 3 Time (years) HOPE Study Investigators. N Engl J Med. 2000;342: EUROPA Investigators. Lancet. 2003;362: PEACE Trial Investigators. N Engl J Med. 2004;351: Pitt B et al. Am J Cardiol. 2001;87:

24 How to differentiate ACEi? Pharmacokinetics - Chemical structures (SH group) - Prodrugs - Oral or tissue availability - Lipid solubility - Binding affinity - Metabolism - actives metabolites, hepatic route, renal excretion Pharmacodynamics - Potency - Binding affinity and characteristics - Regional blood flow - Angiotensine effects, bradykinin, prostaglandines, free radical scavengers Clinical outcomes demonstrations Dzau & al Cardiovascular drugs and therapy 2002,16;

25 Properties of ACE inhibitors based on pharmacology and clinical trial evidence Category I II III Lowers Blood Pressure Lowers Proteinuria Captopril Benazepril Enalapril Lisinopril Trandolapril Fosinopril Cilazepril Ramipril Perindopril Quinapril Lowers Blood Pressure Lowers Proteinuria Reduces Mortality in CHF / post MI Reduces Nephropathy Progression Benazepril Captopril Enalapril Lisinopril Ramipril From S.Yusuf slide presented at AHA 2004 Trandolapril Perindopril Lowers BP Lowers Proteinuria Reduces Mortality in CHF / post MI Reduces Nephropathy Progression Tissue Selectivity Bioavailability Once Daily Dosing Ramipril Trandolapril Perindopril

26 (arbitrary units/mg protein) (pmol/min/mg protein) ecnos activity and expression in HUVECs incubated for 72 h with serum of EUROPA patients receiving perindopril with or without ICATIBANT in the incubation medium ecnos EXPRESSION Baseline ICATIBANT Without With Baseline PERTINENT ecnos ACTIVITY ICATIBANT Without With n = 87 Perindopril n = 43 Perindopril n = 20 0 n = 87 Perindopril n = 43 Perindopril n = 20

27 Angiotensin II Bradykini n Angiotensin II Bradykinin Angiotensin II Bradykinin Normal vascular tone Vasoconstriction Vasodilation Angiotensin II Bradykinin/NO Normal patient CAD patient CAD patient treated with Perindopril

28 ALLHAT Study Design Doxazosin n=9,062 Discontinued early at 3.3 yrs Randomized n=42,418 Chlorthalidone n=15,255 Amlodipine n=9,048 Lisinopril n=9,054 YEAR 1 n=13,854 2,235 (16.1%) stopped drug n=8,215 1,357 (16.5%) stopped drug n=8,158 1,842 (22.6%) stopped drug YEAR 5 n=6,210 1,873 (30.2%) stopped drug n=3,769 1,052 (27.9%) stopped drug n=3,605 1,399 (38.8%) stopped drug Intent-to- Treat Analysis n=15, (2.2%) lost to follow-up 80 (0.5%) refused follow-up n=9, (2.2%) lost to follow-up 58 (0.6%) refused follow-up n=9, (2.4%) lost to follow-up 58 (0.6%) refused follow-up ALLHAT Research Group. JAMA. 2002;288:

29 ALLHAT CHD Death and Nonfatal MI TOTAL Age <65 Age 65 Men Women Black Nonblack Diabetic Nondiabeti c Relative Risk Favors (95% CI) amlodipine 0.98 ( ) 0.99 ( ) 0.97 ( ) 0.98 ( ) 0.99 ( ) 1.01 ( ) 0.97 ( ) 0.99 ( ) 0.97 ( ) Favors chlorthalidone ALLHAT Research Group. JAMA. 2002;288: Copyright 2002, American Medical Association. Relative Risk (95% CI) 0.99 ( ) 0.95 ( ) 1.01 ( ) 0.94 ( ) 1.06 ( ) 1.10 ( ) 0.94 ( ) 1.00 ( ) 0.99 ( ) Favors lisinopril Favors chlorthalidone

30 Pleiotropic effects of BP-lowering agents ACEIs/ARBs Fibrinolysis Mononuclear cell migration Collagen matrix formation Endothelial function Plaque stability CCBs NO BPlowering AHTN agents agents MMP activity Cholesterol deposition in membrane Arterial compliance Both Oxidative stress Platelet aggregation Inflammation VSMC proliferation MMP = matrix metalloproteinase Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-A8. Wassman S and Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-H9. Mason RP et al. Arterioscler Thromb Vasc Biol. 2003;23:

31 Strippoli G et al., BMJ, 2004; 329: 828 EFFECT OF ARBs ON PROGRESSION OF CKD Study ARB (n) Control (n) RR (95%IC) Doubling of creatinine Parving, Lewis, Brenner, TOTAL Final stage CKD Parving, Lewis, Brenner, TOTAL NA 0.71 (0.57;0.90) 0.84 (0.70;1.01) 0.79 (0.67;0.93) NA 0.80 (0.61;1.04) 0.77 (0.64;0.93) 0.78 (0.67;0.91) Fav. ARB Fav. control

32 Inhibition of RAAS and Prevention of Diabetes Complications: Nephropathy In 1993, Lewis et al. published the first large study of the use of ACE inhibitors in patients with type 1 diabetes with nephropathy (Lewis et al. NEJM 329:1456, 1993 Decreased proteinuria Decreased time to dialysis ACE inhibitors and ARBs have demonstrated improvement in renal function when used in patients with type 1 or type 2 diabetes with hypertension or microalbuminuria ACE inhibitors and ARBs have also been associated with decreased albuminuria

33 LIFE Study Design Assessed for eligibility n=10,780 Randomized n=9,222 Ineligible (n=1,558) failed protocol criteria (n=1,343) unwilling to participate (n=215) Excluded for irregularities (n=29) Losartan n=4,605 Atenolol n=4,588 4,605 available for intention-to-treat analyses 44 withdrew consent 57 vital status only 4 lost to follow-up 4,588 available for intention-to-treat analyses 34 withdrew consent 50 vital status only 8 lost to follow-up Dahlof B, et al. Lancet. 2002;359:

34 LIFE Study Summary Losartan-based compared with atenolol-based antihypertensive therapy was associated with: A reduction in the combined primary endpoint of cardiovascular death, stroke or MI (-13%) fewer strokes (-25%) similar blood pressure reduction Losartan reduced the rate of new-onset diabetes (-25%) In the diabetic subgroup, losartan reduced the rate of: combined endpoint of cardiovascular death, stroke and MI (-25%) all-cause mortality (-39%) Dahlof B, et al. Lancet. 2002;359: Lindholm LH, et al. Lancet. 2002;359:

35 Inhibition of RAAS and Prevention of Diabetes Complications: Retinopathy Not as well studied as nephropathy Benefits harder to study and suggest that therapy needs to begin earlier Evidence for RAAS in the retina Diabetic Retinopathy Candesartan Trials Programme with primary and secondary prevention component Benefit on prevention but not progression Lancet 372f:1394, 2008

36 Enalapril/Losartan Effect on Retinopathy Mauer et al. N Engl J Med 361: 40, 2009

37 BENEFITS BEYOND BP CONTROL - Regression of LVH 1 - Cardiovascular protection 2 - Decrease of kidney vessels resistance 4 - Increase in kidney blood flow 4 - Metabolic neutrality 4,5 1. Cuspidi et al 2002 (CATCH); 2. Reboldi G & al J Hypertens Lindholm et al (ALPINE, Hypertens 2003 ; 4. Guido Grassi et al (CROSS)

38 Considerations for individualization of anti-hypertensive therapy Indication Initial Therapy Second line Rx Notes/Cautions DM with nephropathy ACE-i or ARB addition thiazide, * - blockers, LA-CCB, ACE/ARB combo DM without nephropathy ACE-i or ARB or thiazide Combo1st line Rx or * -blockers, LA-CCB *Cardioselective -blockers If CR >150 mmol/l use loop diuretic for volume control Angina -blockers + strongly consider ACE-i LA-CCB Avoid short acting nifedipine Prior MI -blockers + ACE-i Combine additional Rx CHF -blockers + ACE-i + spironolactone (ARB if ACE-i intolerant ) Hydralazine /ISDN: thiazide or loop diuretics as additive therapy Avoid non DHP-CCB (diltiazem, verapamil) Prior CVA or TIA ACE-i/diuretic combination BP reduction recurrent events Renal Disease ACE-i/diuretic as additive Rx ARB if ACE-i intolerant Combo other agents Avoid ACE-i if bilateral Renal artery stenosis LVH ACE-I, ARBs, DHP- CCB, thiazide, - blockers < 55 yr Avoid hydralazine and minoxidil

39 MESSAGES TO TAKE HOME Some Antihypertensive drug classes (RAAS blockers and CCBs) have known good effects independent of BP control These effects have impact on surrogate endpoints The impact on hard endpoints is proven for some agents only (especially ACEIs) New trials and new guidelines are needed to better clarify role of treatment beyond BP control.

40 Thank you!