Progress and Promise in RAAS Blockade

Transcription

1 Progress and Promise in RAAS Blockade

2 Overview Scope of the problem Critical role of RAAS modulation: Mechanisms and insights RAAS blockade: Focus on ACEI Beyond current strategies: Focus on angiotensin receptors Emerging mechanisms in glucose metabolism Combining ACEI and ARB therapy: The next step? Guidelines and practical application

3 CVD is the #1 cause of death in the US Men Women Deaths (thousands) CVD Cancer Accidents CLRD Diabetes CVD Cancer CLRD Alzheimer's Diabetes CLRD = chronic lower respiratory disease CVD = cardiovascular disease Rosamond W et al. Circulation. 2007;115:e

4 1 in 3 adults have 1 or more types of CVD Prevalence (millions) HTN CHD Stroke HF AF Estimated direct and indirect costs = $431.8 billion annually AF = atrial fibrillation, CHD = coronary heart disease HTN = hypertension Rosamond W et al. Circulation. 2007;115:e

5 Relation of BP and age to IHD risk Meta-analysis of 61 observational studies, 12.7 million person-years IHD mortality (absolute risk) DBP Office diastolic BP (mm Hg) SBP Office systolic BP (mm Hg) Age at risk (years): BP = blood pressure, IHD = ischemic heart disease Lewington S et al. Lancet. 2002;360:

6 Both night-time and daytime BP are prognostically important: Rationale for 24-hour BP control N = 7458 enrolled in 6 studies; median follow-up 9.6 years Daytime Night-time Mortality per 1000 person-years Total Non-CV CV SBP (mm Hg) Boggia J et al. Lancet. 2007;370:

7 HTN and the company it keeps HTN* is associated with: 69% of all first myocardial infarctions 74% of cases of HF/ ~2- to 3-fold risk for HF 77% of all first strokes 277,000+ US deaths annually Estimated US costs: $66.4 billion annually *BP >140/90 mm Hg Rosamond W et al. Circulation. 2007;115:e

8 HTN commonly clusters with other risk factors Kaiser Permanente Northwest database; N = 57,573 aged 35 years with HTN and no CVD HTN + 2 other risk factors 14 HTN + 3 other risk factors 3 44 HTN only HTN + 1 other risk factor 39 Other risk factors: Obesity,* hyperlipidemia, and diabetes *BMI 30 kg/m 2 Weycker D et al. Am J Hypertens. 2007;20:

9 INTERHEART: Exponential rise in CVD with added risk factors Odds ratio for first MI* (99% CI) Smk (1) DM (2) HTN (3) 26-fold 3-fold ApoB/ A1 ratio (4) All 4 All 4 + Obes All 4 + Ps All 9 risk factors *Plotted on a doubling scale DM = diabetes mellitus, Obes = obesity Ps = psychosocial factors, Smk = smoking Yusuf S et al. Lancet. 2004;364:

10 Critical Role of RAAS Modulation: Mechanisms and Insights

11 CV and renal continuum: RAAS as a mediator of pathophysiology Atherothrombosis & progressive CVD Tissue injury (MI, stroke, renal insufficiency, PAD) Early tissue dysfunction Pathological remodeling Oxidative & mechanical stress inflammation RAAS Target organ damage Vasoconstriction/Na/H 2 O retention (High BP) End-organ failure (CHF, ESRD) Risk factors Death ESRD = end-stage renal disease Adapted from Dzau V et al. Circulation. 2006;114:

12 RAAS overview: Key targets Angiotensinogen (1-14) Tissue RAAS Renin Cathepsin D Tonins Bradykinin Angiotensin I (1-10) Substance P Chymase Negative feedback via AT 1 -R ACE Angiotensin II (1-8) EP ACE2 AMP-B AMP-N Aldosterone ACE KININASE II Angiotensin (1-7) Angiotensin IV (3-8) Inactive peptides AT 1 -R AT 2 -R AT 1-7 -R AT 4 -R mas receptor Stimulation Inhibition Alternative pathways Adapted from Staessen JA et al. Lancet. 2006;368:

13 Ang II is central to the development of atherosclerosis Oxidative stress Inflammation NAD(P)H oxidase activity Reactive oxygen species LDL peroxidation, LOX-1 Nitric oxide Vasoconstriction PAI-1 activation Platelet aggregation Endothelial dysfunction Ang II Vascular permeability Leucocyte infiltration Signaling pathways (NFκB) Inflammatory mediators VSMC proliferation Matrix deposition MMP activation Tissue remodeling Adapted from Schmieder R et al. Lancet. 2007;369:

14 RAAS modulation: ACEI and ARB pathways Bradykinin/NO Vasodilation Tissue protection ANGIOTENSIN I Chymase tpa Cathepsin Inactive fragments ACEI ANGIOTENSIN II Angiotensin II escape ARB NO = nitric oxide AT 1 RECEPTOR Vasoconstriction Na/H 2 O retention Sympathetic activation Cell growth Mediates apoptosis AT 2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Anti-proliferation Adapted from Dzau V. J Hypertens. 2005;23(suppl I):S9-17.

15 ACEI and ARB improve renal endothelial function N = 93 with HTN and T2DM; Telmisartan 40/80 mg day or ramipril 5/10 mg/day 0-20 ACEI ARB RPF response to L-NMMA (ml/min) * Baseline 9 weeks treatment *P < 0.001, P = vs baseline RPF = renal plasma flow Schmieder RE et al. Diabetes Care. 2007;30:

16 Comparative AT 1 -receptor binding affinity of ARBs AT 1 receptor dissociation half-life (min) Losartan* Valsartan Candesartan Olmesartan Telmisartan Kakuta H et al. Int J Clin Pharmacol Res. 2005;25:41 6.

17 Comparative plasma half-life of ARBs Plasma elimination half-life (hours) Range Eprosartan Losartan* Valsartan Candesartan Olmesartan Irbesartan Telmisartan *Active metabolite EXP3174 Goebel M et al. Expert Rev Cardiovasc Ther. 2006;4:

18 Emerging potential of bifunctional ARBs Bifunctional ARBs Activation Blockade PPARγ pathways Ang II pathways Dyslipidemia Insulin resistance Cell inflammation Cell proliferation BP Oxidative stress Adapted from Pravenec M, Kurtz TW. Hypertension. 2007;49:

19 ARBs exhibit only partial PPAR agonist activity PC12W cells, a rat pheochromocytoma cell line Luciferase activity (x-fold induction over vehicle-treated cells) EC50 0 Pioglitazone: 0.2 µmol/l Telmisartan: 5.02 µmol/l Irbesartan: µmol/l Losartan: >50 µmol/l µmol/l Schupp M et al. Circulation. 2004;109:

20 PPARγ activation by different ARBs Fold activation Candesartan Telmisartan Olmesartan Eprosartan Irbesartan 0 Valsartan Losartan (5 µmol/l) Pravenec M, Kurtz TW. Hypertension. 2007;49:

21 PPARγ activation with ARBs: Summary Less potent than thiazolidinediones Partial vs full agonism Distinctive gene expression profile Effect is independent of AT 1 R Appears to be correlated with ARB lipophilicity Telmisartan > irbesartan > losartan High lipophilicity is required to bind to intracellular PPARγ Schupp M et al. Circulation. 2004;109:

22 RAAS Blockade: Focus on ACEI

23 Role of ACEI as established in clinical trials ACE inhibition Hypertension Restenosis Atherosclerosis Aneurysm formation Results in large clinical trials: /- Remarks: Comparable to other antihypertensive treatment Not effective in 2 trials Effective for highrisk patients only? Shown in 1 trial, independent of Ang II generation? Heeneman S et al. Circ Res. 2007;101:

24 Evolution of ACE inhibition for treating patients with CHD Severe HF Low LVEF Acute MI CHD without HF or LV dysfunction CONSENSUS SOLVD-Prevent SOLVD-Treat SAVE AIRE GISSI-3 ISIS-4 CCT* CONSENSUS II QUIET HOPE EUROPA PEACE *Chinese Captopril Trial Adapted from Yusuf S, Lonn E. Eur Heart J. 1998;19(suppl J):J Lonn EM et al. Circulation. 1994;90:

25 EUROPA, HOPE, PEACE, QUIET: Effect of ACEIs on CV endpoints Patients (%) EUROPA CV death/mi/cardiac arrest* 20% RRR HR 0.80 ( ) P = PEACE CV death/mi/cabg/pci* Placebo Perindopril 8 mg % RRR HR 0.96 ( ) P = 0.43 Trandolapril 4 mg Placebo HOPE CV death/mi/stroke* 22% RRR HR 0.78 ( ) P < % RRR HR 0.87 ( ) QUIET CV death/mi/cardiac arrest Placebo Ramipril 10 mg Placebo Quinapril 20 mg 0 *Primary endpoint Secondary endpoint Time (years) Fox KM et al; EUROPA study. Lancet. 2003;362: Yusuf S et al; HOPE study. N Engl J Med. 2000;342: Braunwald E et al; PEACE trial. N Engl J Med. 2004;351: Pitt B et al; QUIET study. Am J Cardiol. 2001;87:

26 HOPE, EUROPA, PEACE: Reduction in all-cause mortality ACEI Events (%) Placebo Favors ACEI Favors placebo HOPE EUROPA PEACE Total Odds ratio (95% CI) Dagenais GR et al. Lancet. 2006;368:581-8.

27 DREAM: Effect of ramipril on new diabetes or death/ regression to normoglycemia in low-risk patients N = 5269 without CVD; with IFG or IGT T2DM or death* Regression to normoglycemia Cumulative hazard ratio % HR 0.91 ( ) P = 0.15 Placebo group Ramipril group Year of follow-up % HR 1.16 ( ) P = Ramipril group Year of follow-up Placebo group *Primary outcome, Secondary outcome DREAM Trial Investigators. N Engl J Med. 2006;355:

28 Beyond Current Strategies: Focus on Angiotensin Receptors

29 ARBs: Evolution of protective benefits BP Stroke Heart failure Renal dysfunction Glycemic control CHD (?)

30 Clinical trials of RAAS manipulation with ARBs CAD/MI VALIANT OPTIMAAL Val-PREST Diabetes and/or renal disease RENAAL ABCD-2V AMADEO IDNT DETAIL IRMA-2 MARVAL Stroke SCOPE MOSES Hypertension VALUE SCOPE TROPHY LIFE CHF ELITE 1 and 2 Val-HEFT CHARM Dzau V. J Hypertens Dahlof B. Am J Cardiol Barnett AH et al. N Engl J Med Bakris G et al. ASH 2007 Scientific Sessions.

31 Meta-analysis of CV events with ARBs vs comparators Blood Pressure Lowering Treatment Trialists Collaboration 4 trials; N = 16, Relative risk of event with ARB vs comparator Stroke CHD Heart failure Major CV event BPLTTC. Lancet. 2003;362:

32 ARB exhibits BP-lowering effects and some anti-inflammatory effects N = 1668 patients with stage 2 HTN, 6-week follow-up 0 Systolic Diastolic 10 change in BP (mm Hg) hscrp (median, %) Valsartan * Valsartan/ HCTZ Valsartan Valsartan/HCTZ *P < 0.001, P < 0.01 vs valsartan hscrp = high-sensitivity C-reactive protein HCTZ = hydrochlorothiazide Ridker PM et al. Hypertension. 2006;48:73-9.

33 TROPHY: Reduction in new-onset HTN N = 772 Cumulative incidence (%) Placebo Candesartan vs placebo Placebo only RRR 66% HR = 0.34 ( ) P < Study year Candesartan 16 mg qd RRR 16% HR = 0.84 ( ) P = Number of patients without HTN Candesartan Placebo Julius S et al. N Engl J Med. 2006;354:

34 CHARM: ARB reduces death, CV deaths, and HF hospitalizations N = 7601 with HF; randomized to candesartan vs placebo; 2-year follow-up All-cause mortality* CV death or hospital admission for CHF Favors candesartan Favors placebo Favors candesartan Favors placebo Alternative Added Preserved Overall 0.91 P = P < Hazard ratio Hazard ratio *P heterogeneity = 0.37 P heterogeneity = 0.33 Pfeffer MA et al. Lancet. 2003;362:

35 VALIANT: ACEI and ARB show similar effects in post-mi patients with LV dysfunction 0.4 Death from any cause 0.4 Combined CV endpoint* Probability of event Valsartan n = 4909 Months 0.0 Valsartan/captopril n = Months Captopril n = 4909 *CV death, reinfarction, or hospitalization for HF Pfeffer MA et al. N Engl J Med. 2003;349:

36 ARBs in CAD Similar effect to ACEI in post-mi patients with LV dysfunction (VALIANT) No conclusive data on patients with chronic stable CAD No clear BP-independent benefit (Meta-analysis) No evidence of adverse CV outcomes (Meta-analyses) Pfeffer MA et al. N Engl J Med. 2003;349: BPLTTC. J Hypertens. 2007;25: Volpe M et al. J Hypertens. 2005;23:

37 LIFE study: CV effects of ARBs are chiefly due to stroke reduction N = 9193 with HTN 1.4 Adjusted hazard ratio (95% CI) Favors atenolol Favors losartan 0.6 Primary composite endpoint* CV mortality Stroke Myocardial infarction *CV mortality, stroke, and MI Dahlöf B et al. Lancet. 2002;359:

38 MOSES: ARB surpasses CCB for secondary stroke prevention N = 1405 with HTN and prior cerebral event 0 Primary composite outcome* Fatal/nonfatal CV events Fatal/nonfatal stroke -5 RRR Eprosartan vs nitrendipine (%) P = P = P = *Cerebrovascular, CV events, and all-cause death Events per 100 person-years, including recurrent events Schrader J et al. Stroke. 2005;36:

39 SCOPE: Impact of ARBs on cognitive decline in hypertensive patients N = 4937 aged 70 to 89 years Low cognitive function (MMSE score 24-28) High cognitive function (MMSE score 29-30) 0 Candesartan (n = 998) Control (n = 1010) Total (n = 2008) Candesartan (n = 1419) Control (n = 1399) Total (n = 2818) -0.2 MMSE (mean) P = *Adjusted for country and baseline value MMSE = Mini Mental State Examination P > 0.20 P = Skoog I et al. Am J Hypertens. 2005;18:

40 PRoFESS trial: Secondary stroke prevention 2 2 factorial design N = 20,332 with recent ischemic stroke DP + ASA Clopidogrel Telmisartan (DP + ASA) + Clopidogrel placebo + Telmisartan Clopidogrel + (DP + ASA) placebo + Telmisartan Telmisartan placebo (DP + ASA) + Clopidogrel placebo + Telmisartan placebo Clopidogrel + (DP + ASA) placebo + Telmisartan placebo n = 10,000 n = 10,000 DP + ASA = extended-release dipyridamole + aspirin Diener H-C et al. Cerebrovasc Dis. 2007;23: Yusuf S et al. N Engl J Med. 2008;359:

41 PRoFESS: Effect of angiotensin receptor blockade on recurrent stroke N = 20,332 with recent ischemic stroke Placebo Cumulative probability of recurrent stroke Telmisartan Time from randomization (years) Yusuf S et al. N Engl J Med. 2008;359;

42 ARBs decrease renal complications in T2DM T2DM (N) Treatment Primary outcome IRMA-2 Microalbuminuria (590) Irbesartan 150/300 mg vs placebo Time to nephropathy: 39% (150 mg, P = 0.08) 70% (300 mg, P < 0.001) IDNT Nephropathy (1715) Irbesartan/ amlodipine/ placebo ESRD/ Cr 2 /mortality: 20% vs placebo (P = 0.02) 23% vs amlodipine (P = 0.006) MARVAL Microalbuminuria (332) Valsartan/ amlodipine UAER at 24 weeks: 44% valsartan vs 8% amlodipine (P < 0.001) RENAAL Nephropathy (1513) Losartan/ placebo ESRD/Cr 2 /all deaths: 16% vs placebo (P = 0.02) Cr = creatinine UAER = urinary albumin excretion rate Adapted from Sharma AM. Hypertension. 2004;44:12-19.

43 AMADEO: Comparative effect of telmisartan vs losartan on proteinuria N = 860 with HTN and T2DM, 1-year follow-up UPC from baseline (mean) * 0.8 Proteinuria from baseline (%) Telmisartan Losartan 0 Telmisartan Losartan UPC = urine protein:creatinine ratio Bakris G et al. Kidney Int. 2008;74:364-9.

44 Emerging Mechanisms in Glucose Metabolism

45 LIFE: Total mortality by treatment in cohort with diabetes 24 Adjusted risk ratio: 39%; P = Unadjusted risk ratio: 40%; P = Proportion of patients (%) Study (month) Atenolol Losartan Lindholm LH et al. Lancet 2002;359:

46 Comparative effect of telmisartan and losartan on metabolic parameters N = 40 with HTN and metabolic syndrome 5 FPG FPI HOMA-IR A1C 0-5 Change from baseline (%) P < 0.05 P < 0.06 P < Losartan Telmisartan P < 0.05 FPG = fasting plasma glucose, FPI = fasting plasma insulin HOMA-IR = homeostatic model assessment - insulin resistance Vitale C et al. Cardiovasc Diabetol. 2005;4:6-13.

47 Effect of ACEIs and ARBs on new-onset diabetes Meta-analysis: 12 randomized controlled trials; N = 72,333 patients without T2DM at baseline CAPPP STOP-2 HOPE LIFE ALLHAT ANBP2 SCOPE ALPINE CHARM SOLVD VALUE PEACE All pooled ACEI pooled ARB pooled Less likely to develop T2DM Relative risk (95% CI) More likely to develop T2DM Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.

48 RAAS, ACEIs, and ARBs: Summary RAAS is a major regulator of CV and renal function RAAS blockade Reduces BP Exerts antiatherosclerotic effects Delays or avoids onset of T2DM ACEIs and ARBs are the major RAAS blockers in use ACEIs do not inhibit Ang II formation by non-ace pathways ACEIs block AT 1 and AT 2 receptors, whereas ARBs inhibit AT 1 receptors and leave AT 2 receptors open for stimulation Schmieder RE et al. Lancet. 2007;369:

49 Combining ACEI and ARB Therapy: The Next Step?

50 Pharmacokinetic rationale for combination ACEI and ARB therapy Provides more complete RAAS blockade Improves BP control Preserves and increases tissue protective properties of bradykinin Averts negative consequences of Ang II escape Excess Ang II will stimulate AT 2 receptors with potential for benefit Enhances vascular and metabolic pleiotropic effects of ACEIs and ARBs Potential for additive clinical benefits in selected patients Dzau V. J Hypertens. 2005;23(suppl 1):S9-17. Unger T, Stoppelhaar M. Am J Cardiol. 2007;100(suppl):25J-31.

51 Key biochemical and hormonal effects of dual RAAS blockade ACEIs ARBs ACEIs + ARBs Enzymes Plasma/tissue ACE --- Substrate Bradykinin --- Receptor stimulation AT 1 R AT 2 R Bradykinin (B2) or * End products Ang II Non-ACE-induced Ang II Aldosterone or --- * Miscellaneous Tissue RAAS Nitric oxide * *Theoretical = Increased, = Decreased, --- = No change or = Additive effect Adapted from Azizi M, Ménard J. Circulation. 2004;109:

52 ACEI-ARB combination vs ACEI monotherapy in ambulatory SBP: Meta-analysis Favors combination Favors ACEI alone Jacobsen 2002 Azizi 2000 Stergiou 2000 Agarwal 2001 Ferrari 2002 Rossing 2002 Jacobsen 2003 Jacobsen 2003a Rossing 2003 Morgan 2004 Total SBP for combination vs ACEI alone (mm Hg, 95% CI) Doulton TWR et al. Hypertension. 2005;45:880-6.

53 ACEI-ARB combination vs ARB monotherapy in ambulatory SBP: Meta-analysis Favors combination Favors ARB alone Azizi 2000 Ferrari 2002 Jacobsen 2003 Morgan 2004 Overall effect SBP for combination vs ARB alone (mm Hg, 95% CI) Doulton TWR et al. Hypertension. 2005;45:880-6.

54 Meta-analysis: ACEI + ARB reduces proteinuria compared with monotherapy (1 to 4 months) Patients with microalbuminuria or proteinuria, with/without diabetes ACEI + ARB (n) Comparator (n) Favors ACEI + ARB Favors comparator Comparator: ARB (14 studies) ( ) Comparator: ACEI (21 studies) ( ) Ratio of means (95% confidence interval) Adapted from Kunz R et al. Ann Intern Med. 2008;148:30-8.

55 DETAIL: ARB and ACEI yield similar changes in GFR N = 250 with T2DM and early nephropathy, 5-year follow-up 5 GFR (ml/min per 1.73 m 2 ) GFR at 5 years Telmisartan: 17.5 Enalapril: 15.0 GFR Treatment difference -2.6 (-7.1 to 2.0) Year No. at risk (no. carried forward) Enalapril Telmisartan 103 (0) 86 (0) 110 (22) 99 (23) 113 (23) 102 (21) 113 (40) 102 (31) 113 (39) 103 (41) Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with T2DM GFR = glomerular filtration rate Barnett AH et al. N Engl J Med. 2004;351:

56 ACEI + ARB in HF HF hospitalization All-cause mortality ARB + ACEI better ACEI alone better ARB + ACEI better ACEI alone better Val-HeFT (HF) CHARM (HF) VALIANT (post MI + HF/LV dysfunction) Odds ratio (95% CI) Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

57 ACEI + ARB enhances regression of LV hypertrophy N = 33 with T2DM and nephropathy LVMI (g/m 2 ) * * * * * * Months Losartan 100 mg Enalapril 10 mg Combination *P < 0.05 vs baseline, P < 0.05 vs enalapril and losartan LVMI = left ventricular mass index Suzuki H et al. Ther Apher Dial. 2004;8:320-7.

58 RAAS inhibition in prevention of atrial fibrillation ACE inhibitors CAPP GISSI HOPE SOLVD STOP-H2 TRACE Ueng Van Den Berg Subtotal Captopril Lisinopril Ramipril Enalapril Enalapril Trandolapril Enalapril Lisinopril Favors treatment Favors control ARBs CHARM LIFE Madrid ValHeFT Subtotal Candesartan Losartan Irbesartan Valsartan Subtotal Total Total RR (random) 95% CI Salehian O et al. Am Heart J. 2007;154: Healy JS et al. J Am Coll Cardiol. 2005;45:

59 Meta-analysis: Adverse effects of ACEIs + ARBs in symptomatic LV dysfunction (LVD) VALIANT, CHARM-Added, Val-HeFT, RESOLVD; N = 17,337; mean follow-up 25 months Rx (%) Control (%) Relative risk (95% CI) Discontinued Rx for AE Chronic HF ( ) AMI with LVD ( ) Worsening renal function Chronic HF ( ) AMI with LVD ( ) Hyperkalemia Chronic HF ( ) AMI with LVD ( ) Symptomatic hypotension Chronic HF ( ) AMI with LVD ( ) Phillips CO et al. Arch Intern Med. 2007;167:

60 Risk of MI with ARBs vs ACEIs, other active drugs, and placebo Meta-analysis of 11 major ARB trials Favors ARBs Favors other drugs ARBs vs ACEI ARBs vs placebo and active drug ARBs vs active drug ARBs vs placebo RR (95% CI) Volpe M et al. J Hypertens. 2005;23:

61 ONTARGET/TRANSCEND trials: RAAS modulation after HOPE the next chapter ONTARGET 730 centers, 40 countries TRANSCEND N = 25,620 N = 5776 Telmisartan + placebo Ramipril + placebo Telmisartan + Ramipril Telmisartan Placebo Noninferiority Superiority Superiority Primary outcome: CV death, MI, stroke, hospitalization for HF Follow-up 5.5 years Primary outcome: CV death, MI, stroke, hospitalization for HF ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

62 ONTARGET/TRANSCEND: Substudies ONTARGET Overview ONTARGET Principle trial TRANSCEND Parallel trial Substudies Ambulatory BP monitoring Cardiac MRI OGTT Erectile dysfunction Health economics Blood markers Arterial stiffness ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

63 ONTARGET: Study design Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial N = 25, Years with coronary, cerebrovascular, or peripheral vascular disease or diabetes + end-organ damage Ramipril 10 mg Telmisartan 80 mg Ramipril 10 mg + telmisartan 80 mg Primary outcome: CV death, MI, stroke, hosp for HF Secondary outcomes: Newly diagnosed HF, T2DM, or AF; revascularization procedures; development of dementia/cognitive decline, nephropathy ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

64 ONTARGET: Baseline medical conditions vs HOPE Current (%) Hypertension Diabetes History (%) MI Stable angina Unstable angina CABG PCI Stroke/TIA Intermittent claudication Peripheral artery surgery Carotid endarterectomy ONTARGET HOPE ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

65 ONTARGET: Baseline medications vs HOPE Medications (%) ACEIs ARBs β-blockers Statins Aspirin CCBs Diuretics Nitrates Oral hypoglycemics Insulin ONTARGET HOPE ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

66 ONTARGET: Time to primary outcome Cumulative hazard ratio Follow-up (years) Telmisartan Ramipril Telmisartan plus ramipril ONTARGET Investigators. N Engl J Med. 2008;358:

67 Primary outcome of ONTARGET compared to HOPE Ramipril Telmisartan Telmisartan vs ramipril n (%) n (%) RR (95% CI) P* n Primary outcome CV death, MI, stroke, HF hosp 1412 (16.5) 1423 (16.7) 1.01 ( ) (Adjusted for SBP) 1.02 ( ) HOPE primary outcome CV death, MI, stroke 1210 (14.1) 1190 (13.9) 0.99 ( ) (Adjusted for SBP) 0.99 ( ) *P for noninferiority ONTARGET Investigators. N Engl J Med. 2008;358: Yusuf S.

68 ONTARGET: Noninferiority comparison Telmisartan better Primary composite outcome P = 0.004* Noninferiority margin Ramipril better CV death/mi/stroke (HOPE composite outcome) P = 0.001* Relative risk (95% CI) *Comparison with noninferiority margin ONTARGET Investigators. N Engl J Med. 2008;358:

69 ONTARGET: Combination vs ramipril in pre-specified subgroups Incidence of primary outcome in ramipril group (%) Telmisartan + ramipril better Ramipril better Primary composite Hx of CVD No Hx of CVD SBP 134 mm Hg SBP 134 to 150 mm Hg SBP >150 mm Hg Diabetes No Diabetes HOPE low risk score HOPE medium risk score HOPE high risk score Age <65 years Age 65 to <75 years Age 75 years Male Female Relative risk (95% CI) ONTARGET Investigators. N Engl J Med. 2008;358:

70 ONTARGET: Effects of telmisartan, ramipril, and combination on primary renal outcome Cumulative incidence of primary renal outcome* T vs R; P = T+R vs R; P = Follow-up (years) Telmisartan (T) + ramipril (R) Telmisartan Ramipril *Dialysis, doubling of serum creatinine, death Mann JFE et al. Lancet. 2008;372:

71 ONTARGET: Relative risk of primary renal outcome by subgroup: Ramipril vs telmisartan n Incidence of 1 0 outcome in ramipril group (%) Favors telmisartan Favors ramipril P for interaction Primary composite 17, Diabetes No diabetes 10, Overt diabetic nephropathy No overt diabetic nephropathy 16, No diabetes, no hypertension Diabetes or hypertension 13, Micro- or macroalbuminuria No micro- or macroalbuminuria 12, egfr <60 ml/min per 1.73 m egfr 60 ml/min per 1.73 m 2 12, History of hypertension 11, No history of hypertension RR in telmisartan group (95% CI) egfr = estimated GFR Mann JFE et al. Lancet. 2008;372:

72 ONTARGET: Relative risk of primary renal outcome by subgroup: Ramipril vs ramipril plus telmisartan n Incidence of 1 0 outcome in ramipril group (%) Favors ramipril + telmisartan Favors ramipril P for interaction Primary composite 17, Diabetes No diabetes 10, Overt diabetic nephropathy No overt diabetic nephropathy 16, No diabetes, no hypertension Diabetes or hypertension 13, Micro- or macroalbuminuria No micro- or macroalbuminuria 12, egfr <60 ml/min per 1.73 m egfr 60 ml/min per 1.73 m 2 12, History of hypertension 11, No history of hypertension RR in ramipril + telmisartan group (95% CI) Mann JFE et al. Lancet. 2008;372:

73 ONTARGET: Decline in egfr with ramipril, telmisartan, and combination Decrease in egfr from run-in Run-in Week 6 Year 2 Study Time period end Telmisartan + ramipril Telmisartan Ramipril Mann JFE et al. Lancet. 2008;372:

74 ONTARGET: Time to permanent discontinuation of study medication Cumulative hazard ratio Follow-up (years) Telmisartan Ramipril Yusuf S.

75 ONTARGET: Study medication discontinuation telmisartan vs ramipril Reason for permanent discontinuation Ramipril (n = 8576) n Telmisartan (n = 8542) n Telmisartan vs ramipril RR P Hypotension <0.001 Syncope Cough <0.001 Diarrhea Angioedema Renal Impairment All discontinuations* *Includes permanent and temporary discontinuations ONTARGET Investigators. N Engl J Med. 2008;358:

76 ONTARGET: Study medication discontinuation ramipril vs combination Reason for permanent discontinuation Ramipril (n = 8576) n Combination (n = 8502) n Combination vs ramipril RR P Hypotension <0.001 Syncope Cough Diarrhea <0.001 Angioedema Renal Impairment <0.001 All discontinuations* <0.001 *Includes permanent and temporary discontinuations ONTARGET Investigators. N Engl J Med. 2008;358:

77 ONTARGET: Conclusions Telmisartan is noninferior to ramipril, with most benefits preserved Primary composite outcome (P = 0.004) HOPE primary outcome (P = 0.001) Results are consistent over a range of secondary outcomes and subgroup data Telmisartan exhibits slightly superior tolerability: Fewer discontinuations due to cough and angioedema More mild hypotensive symptoms, no difference in severe hypotensive symptoms or syncope Combination therapy vs ramipril: Not more effective in reducing primary outcome More adverse events ONTARGET Investigators. N Engl J Med. 2008;358:

78 ONTARGET: Implications In patients with vascular disease or high-risk diabetes and no heart failure, telmisartan is an equally effective alternative to ramipril and less likely to cause angioedema Risk/benefit ratios should be considered when guiding optimal therapy in high-risk patients ONTARGET Investigators. N Engl J Med. 2008;358:

79 TRANSCEND: Study design N = Years with coronary, cerebrovascular, or peripheral vascular disease or diabetes + end-organ damage; intolerant of ACEI Telmisartan 80 mg Placebo Primary outcome: CV death, MI, stroke, hosp for HF Secondary outcomes: Newly diagnosed HF, T2DM, and AF; revascularization procedures; development of dementia/cognitive decline, nephropathy ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

80 TRANSCEND: Baseline medical conditions vs HOPE Current (%) Hypertension Diabetes TRANSCEND Telmisartan Placebo HOPE History (%) MI Stable angina Unstable angina CABG PCI Stroke/TIA Peripheral artery disease ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148: TRANSCEND Investigators. Lancet. 2008;372:

81 TRANSCEND: Baseline medications vs HOPE Medications (%) ACEIs ARBs β-blockers Statins Aspirin Thienopyridines Diuretics CCBs TRANSCEND Telmisartan Placebo HOPE ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148: TRANSCEND Investigators. Lancet. 2008;372:

82 TRANSCEND: Treatment effect on the primary outcome 0.20 Hazard ratio 0.92 (95% CI ) P = Cumulative incidence (%) Follow-up (years) Placebo Telmisartan TRANSCEND Investigators. Lancet. 2008;372:

83 TRANSCEND: Treatment effect on components of primary outcome Event rate (%) Telmisartan Placebo HR (95% CI) P CV death ( ) MI ( ) Stroke ( ) HF hosp ( ) TRANSCEND Investigators. Lancet. 2008;372:

84 TRANSCEND and PRoFESS combined results: Evidence for delayed benefit CV death, MI, stroke, HF hospitalization Event rate (%) Telmisartan Placebo HR (95% CI) P PRoFESS ( ) TRANSCEND ( ) Combined data at 6 mo ( ) Combined data at >6 mo ( ) <0.001 TRANSCEND Investigators. Lancet. 2008;372:

85 TRANSCEND: Conclusions and implications In a population of high-risk, ACEI-intolerant patients, treatment with angiotensin receptor blockade (telmisartan) Was well tolerated Showed no effect vs placebo on hospitalizations for heart failure, consistent with PRoFESS Demonstrated modest, nonsignificant reduction in MI and stroke Analyses suggested greater benefit might have been achieved with more prolonged treatment Telmisartan is a potential treatment for patients with vascular disease or high-risk diabetes, if they are unable to tolerate an ACEI TRANSCEND Investigators. Lancet. 2008;372:

86 Evaluation of combined ACEI/ARB therapy: What the evidence shows BP reduction Evidence for additive BP-lowering effects Renal protection Evidence for additive benefit in hypertensive renal disease but not in atherosclerotic vascular disease or diabetes with end-organ damage Cardiac effects Some evidence for additive benefit in HF/post MI LVD but not in atherosclerotic vascular disease or diabetes with end-organ damage Doulton TWR et al. Hypertension Nakao N et al. Lancet Kasama S et al. J Nucl Med Voors AA, van Veldhuisen DJ. Int J Cardiol ONTARGET Investigators. N Engl J Med Mann JFE et al. Lancet TRANSCEND Investigators. Lancet

87 Achieving the Clinical Potential of RAAS Blockade

88 57-year-old African American male New patient, school teacher Severe cramping in right thigh and calf walking Hypertension treated with ACEI + diuretic Nonadherent with ACEI because of cough Erectile dysfunction Family history Father: Fatal heart attack, age 60 y Mother: Breast cancer, age 70 y Social history Former smoker, stopped 3 years ago 1 pack per day for 20 years ~ 2 beers daily/no illicit drugs

89 Physical examination HT (in) WT (lb) BMI (kg/m 2 ) Waist circumference (in) HR (bpm) BP (mm Hg) HEENT CV Peripheral pulses Respiratory Abdomen /95 Normal Normal Diminished bilaterally Chest clear Benign

90 Diagnostics LDL-C (mg/dl) HDL-C (mg/dl) Total-C (mg/dl) Non-HDL-C (mg/dl) TG (mg/dl) Creatinine (mg/dl) Liver function Urine Fasting glucose (mg/dl) ECG ABI Angiography WNL Dipstick positive for protein (1+) 100 Normal 0.72 (right) 0.95 (left) Stenotic lesion in R femoral artery treated successfully with stenting; minimal luminal irregularities in L femoral artery

91 What is the diagnosis? Hypertension Dyslipidemia Peripheral arterial disease Metabolic syndrome Other

92 Impact of individual lifestyle modifications on systolic blood pressure Modification Weight reduction Approximate SBP reduction, range 5-20 mm Hg/10-kg weight loss Adopt DASH eating plan 8-14 mm Hg Dietary sodium reduction 2-8 mm Hg Physical activity 4-9 mm Hg Moderation of alcohol consumption 2-4 mm Hg Chobanian AV et al. JAMA. 2003;289:

93 JNC 7: Classification of blood pressure for adults BP classification SBP (mm Hg) DBP (mm Hg) Normal <120 and <80 Prehypertension or Stage 1 HTN or Stage 2 HTN 160 or 100 Chobanian AV et al. Hypertension. 2003;42:

94 AHA recommendations for prevention and management of IHD: BP targets Class IIa: Level of Evidence B Patient type Diabetes Chronic renal disease CAD or CAD risk equivalents Carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm High-risk patients* Goal BP (mm Hg) LVD <120/80 Uncomplicated hypertension (ie, none of the above) <130/80 <140/90 *10-year Framingham risk score 10% Rosendorff C et al. Circulation. 2007;115:

95 Factors for consideration Does race/gender play a role in ACEI/ARB metabolism? African Americans tend to develop hypertension earlier in life than whites African Americans are at double the risk of developing PAD vs other ethnicities Rosamond W et al. Circulation. 2007;115:e69-e171.

96 What are the clinical strategies? Aggressively reduce BP and lipids to reduce risk of CV events Initiate statin Initiate low-dose aspirin Considering race Add ARB or CCB to diuretic therapy Dose at highest level Niacin or fibrates should be considered after getting LDL-C to goal with statins

97 AHA/ACC goals Lifestyle modification Diet: salt intake, calories, fat Exercise, cardiac rehab Lipid management (LDL-C <70 mg/dl) Statin dose to LDL-C goal BP control (<130/80 mm Hg) Smith SC Jr et al. Circulation. 2006;113:

98 AHA/ACC guidelines for secondary CVD prevention 2006 Update: ACEI and ARB ACEI Use indefinitely in all patients with LVEF 40% and in those with HTN, T2DM, or chronic kidney disease unless contraindicated LOE I (A) Consider in all other (high-risk) patients LOE I (B) ARB Use in ACEI-intolerant patients with HF and in post-mi patients with LVEF 40% LOE I (A) Consider in other ACEI-intolerant patients LOE I (B) LOE = level of evidence Smith SC Jr et al. J Am Coll Cardiol. 2006;47:

99 JNC 7 indications in hypertension management ACEI ARB Diuretic β-blocker CCB AA Heart failure Post-MI High coronary disease risk Diabetes Chronic kidney disease Recurrent stroke prevention AA = aldosterone antagonist Chobanian AV et al. Hypertension. 2003;42:

100 AHA/ASA Guidelines: BP recommendations after stroke or TIA Antihypertensive treatment is recommended for prevention of recurrent stroke and other vascular events after the hyperacute period (Class I, LOE A) Because this benefit extends to persons with/without a history of HTN consider for all patients with ischemic stroke or TIA (Class IIa, LOE B) Absolute target BP is uncertain and should be individualized, but an average reduction of ~10/5 mm Hg has proven to be beneficial, and JNC 7 has defined normal BP as <120/80 mm Hg (Class IIa, LOE B) Sacco RL et al. Circulation. 2006;113:e

101 HFSA 2006 HF Practice Guideline: ACEI and ARB in symptomatic/asymptomatic patients ACEI High risk of HF, LOE = A LVEF 40%, LOE = A ARB LVEF 40% who are ACEI-intolerant due to cough,* LOE = A ACEI-related angioedema, LOE = B Consider as initial therapy HF post-mi, LOE = A HF and systolic dysfunction, LOE = B Consider adding an ARB in HF due to systolic dysfunction if symptoms persist or worsen on optimized ACEI + β-blocker, LOE = A *ie, for reasons other than hypokalemia or renal insufficiency HFSA = Heart Failure Society of America HFSA. J Cardiac Fail. 2006;12:10-38.

102 RAAS modulation to reduce CV risk: Summary RAAS modulation is a cornerstone of management strategies to reduce CV risk ACEIs and ARBs are first-line treatment for the protection of the cardiovascular, cerebrovascular, and renal systems ACEIs may be considered in all patients with vascular disease ARBs are an alternative in ACEI-intolerant patients Although ARBs have been less extensively studied than ACEIs, they may have similar or complementary protective effects Several large trials will address these issues Dagenais GR et al. Lancet Schmieder RE et al. Lancet Smith SC Jr et al. J Am Coll Cardiol ONTARGET/TRANSCEND Investigators. Am Heart J