RENIN ANGIOTENSIN SYSTEM MODULATION IN CARDIOVASCULAR DISEASE

DR. CHARLES KARIUKIINTERVENTIONAL CARDIOLOGIST

THE CARDIOVASCULAR CONTINUUM Concept proposed in 1991 by Victor Dzau and Eugene

Branwald Proposed that there is a progressive chain of

pathophysiologic events linking cardiovascular riskfactors to clinical manifestations of diseases and lifethreatening CVS events. They indentified significantstages in the development of advanced cardiac diseasefrom asymptomatic persons at risk of coronaryatherosclerosis to patients with end stage heart failure.Interruption of this chain at multiple sites mightprevent or slow development of symptomatic heartdisease and hopefully prolong life.

The RAAS is involved in all stages of the CV continuum .

Effect or molecules of RAAS, Ang II, have direct pathobiological effects on a variety of tissues.

EndotheliumVSMCRenal Mesangium

Structural and functional changes in myocardiumkidneys and vasculature

Questions have arisen as to the rate of RAAS inpatients with primary hypertension

Widely anticipated that interrupting this systemwould represent a clear step forward in reducing CVS morbidity and mortality.

ACE I and ARBs proven to lower blood pressure effectively and ARBs in particular have placebo like tolerability.

Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Result from:

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Weakening of the fibrous cap

Thrombogenicity of the lipid core

Illustration courtesy of Michael J. Davies, M.D.

Plaque Rupture with Thrombosis

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Thrombus Fibrous cap

1 mm Lipid

coreIllustration courtesy of Frederick J. Schoen, M.D., Ph.D.

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Jessup, M. et. al. N Engl J Med 2003;348:2007-2018

Ventricular Remodelling after Infarction (Panel A) and in Diastolic and Systolic Heart Failure (Panel B)

Total Cardiovascular Risk

Patients presenting with disease involving one of the components with disease involving one of the components of the cardiovascular system often exhibit additional cardiovascular risk factors e.g. hypertension, dyslipidaemia and alterations in glucose metabolism.

These risk factors when present concomitantly potentiate each other leading to a total cardiovascular risk greater than the sum of its individual components .

Subclinical organ damage is an intermediate stage in the continuum of cardiovascular risk.

Signs of organ involvement should be sought carefully.

Treatment reduction in e.g. proteinuria and LVH accompanied by a reduced incidence of CVS events.

Risk Factors For Cardiovascular Disease

Systolic and diastolic BP levels Levels of pulse pressure (in the elderly) Age (M>55 years; W>65 years) Smoking Dyslipidaemia

- TC >5.0 mmol/l (190 mg/dl) or;- LDL-C >3.0 mmol (115 mg/dl) or;- HDL-C: <1.0 mmol/l (40 mg/dl), W >1.2 mmol/l)

(46 mg/dl) or;- TG >1.7 mmol/l (150 mg/dl)

Fasting plasma glucose 5.6-6.9 mmol/l (102-125 mg/dl) Abdominal obesity (waist circumference >102 cm (M), >88 cm (W) Family history of premature CV disease (M at <55 years; W at age <65

years)

In high risk individuals goals for treatment e.g. presence of renal dysfunction or diabetes in the hypertensive patient, thresholds and goals of blood pressure treatment should be different.

Subclinical Organ Damage

Electrocardiographic LVH (Sokolow-Lyon >38 mm; Cornell >2440 mm*ms) or;

Echocardiographic LVH (LVM1 M>125 g/m2, W>110 g/m2) Carotid wall thickening (IMT >0.9 mm) or plaque Carotid-femoral pulse wave velocity >12 m/s Ankle/brachial BP index <0.9 Slight increase in plasma Creatinine;

M: 115-113 umol/l (1.3-1.5 mg/dl);W: 107-124 umol/l (1.2-1.4 mg/dl)

Low estimated glomerular filtration rate+ (>60 ml/min/1.73 m2) or Creatinine clearance (<60 ml/min)

Microalbuminuria 30-300 mg/24/24 h or albumin-Creatinine ratio: >22 (M); or >31 (W) mg/g Creatinine

Diabetes Mellitus Fasting plasma glucose >7.0 mmol/l (126 mg/dl) on

repeated measurements, or Postload plasma glucose >11.0 mmol/l (198 mg/dl)

Established CV or Renal Disease Cerebrovascular disease: ischaemic stroke; cerebral

haemorrhage; transient ischaemic attack Heart disease: diabetic nephropathy; renal

impairment (serum Creatinine M>133, W>124 mmol/l); proteinuria (>300 mg/24 h)

Peripheral artery disease Advanced retinopathy: haemorrhages or exudates;

papilloedema

Definitions and Classification of blood pressure (Bp) levels (mmHg)

Category Systolic Diastolic

Optimal <120 and <80

Normal 120 – 129 and/or 80 – 84

High normal 130 – 139 and/or 85 - 89

Grade 1 Hypertension 140 – 159 and/or 90 - 99

Grade 2 Hypertension

160 – 179 and/or 100 - 109

Grade 3 Hypertension

>180 and/or >110

Isolated systolic Hypertension

>140 and <90

LVHLIFE substudy circ. 2004:110: 1456-1462

Losartan did better than Atenelol accompanied by significantly better CVS outcomes for similar blood pressure reduction.Irbesartan better than Atenelol

Hypertension 2004:44: 61-62

Amlodipine however equal to ACE I

Eplerenone also effective combination with ACE, ARB better.

ACE versus ARB, Candesartan and Enalapril equal.

CATCH Study: J. Hypertens 2002:20:2293-2300

High Risk Patients

ACE I have improved outcomes in clinical trials of High Risk CVS patients (some patients without HTN)

HOPE: Incidence of MI, CVS death or stroke reduced by 225 in patients with CV disease or with complicated diabetes.

EUROPA: Perindopril: 20% reduction in CVS eventsPEACE: Trandolapril added on in patients with CAD

death, MI, RevascCOMELOT: Amlodipine VS Enalapril in patients with

angiographically documented stable CAD No difference

Hypertension Antihypertensive treatments translates into significant

reduction in CVS morbidity and mortality, less significant effect on all course mortality.

30 – 40% reduction in risk of fatal and non-fatal stroke.

20% reduction in coronary events Large reduction in incidence of heart failure.

ACE Inhibitors versus thiazide diuretics andBeta Blockers in HTN.

BPLTT – 47000 patients compairing ACE Inhibitors with diuretics and Beta Blockers.Pooled adds ratios very close to unity and NS total mortality, CVS events, CVS mortality and CHD.NS trends towards less protection of ACE inhibition as far as stroke and CHF were concerned.

ALLHAT Trial

Chlorthalidone versus Lisinopril showed similar incidence of CHD.

HF and stroke significantly lower in the diuretic treated group (also showed a greater blood pressure reduction)

(JAMA 200L, 288:2981-2997)

ACE Inhibitors versus CCBs in HTN

BPLTT metanalysis 26,000 patients from 6 studies Odds ratio expressing relative benefits close to unity

and non-significant for total coronary events CVS mortality, total mortality as well as CHD

CCB more effective in stroke protection ACE Inhibitors more effective against heart failure

(Lancet 2003, 362:1527-1535)

Beta Blockers in HTN VS ACEI/ARBLIFE and ASCOT

(Lancet 2002; 359-995 – 2003, Lancet 2005; 366:895-906)

Both showed superiority of an ARB and CCB over therapy initiated by a Beta Blocker as far as stroke or stroke and mortality were concerned.

Recent metanalysis concluded that Beta Blocker initiated therapy inferior to others in stroke prevention but not in prevention of MI and reduction in mortality.

Metabolic disturbances with Beta Blockers and thiazides.

ARBS in HypertensionLIFE studyVALUE trial was designated to test whether valsartanwould provide cardio protective effects and Bp lowering compared with Amlodipine. Primary composite endpoint virtually identical with Amlodipine.ON TARGET – Ramipril versus TelmisartanRecent meta-regression analysis by the BPLTT indicates that ARBs have the same Bp dependent beneficial effects on coronary events as ACE inhibitors.

(J Hypertens 2007;25:955-958)

Heart Failure

Neurohormonal activation strongly implicated in progression of heart failure. Indicated as First line therapy in reduced LV systolic

function, Ejection fraction 40 – 45% with or without heart failure symptoms (CLASS I)

In 2 pivotal trials ACE-I increased survival in patients with CHF NYHA 1- IV

Sudden death and death due to progressive heart failure reduced in symptomatic patients.

In CONSENSUS 27% reduction in mortality versus placebo (P=0.003)

In SOLVD NNT three patients for 3-5 years to prevent one hospitalization.

(CONSENSUS NEJM 1987: 316:1429-35)(SOLVD NEJM 1991:325:293-302)

In VAL HeFT study, adding Valsartan to existing therapies (including ACE inhibition) led to a 13.2% reduction VS Placebo (P= 0.009) in incidence of primary end point of mortality and CVS morbidity.

Clinical Heart failure early after acute MI. SAVE Study

Captopril achieved a 19% reduction in mortality in post MI patients.

Significant reduction in mortality very early after the initiation in the AIRE Study.

(Lancet 1993: 342:821-8)

Improvement in functional class was not observed in all studies.

ACE VS ARBComparative randomized trials in heart failure or post MI patients with LV dysfunction show no significance between treatment differences in the incidence of stroke, major coronary events and heart failure in ACE or ARB treated patients.

ELITE 2 (Lancet 1993:342:821 – 828)Similar mortality in 3152 patients with CHF followedfor 555 days using Losartan VS Captopril.

OPTIMAL (Lancet 2002;360;752-760)

Post MI patients with heart failure Losartan versus Captopril

2-7 year follow up showed similar mortality 18% versus 16%.

VALIANT (NEJM 2003;349:1893-906)

15,703 with AMI complicated by LV systolic dysfunction, HF or both.

Captopril versus Valsartan or combination 2–7 month follow up.

No differences in outcomes but higher incidences of side effects.

Charm-Added

Addition of ARB in patients remaining asymptomatic under ACE I above.

15% reduction in death and hospitalization.

Renal Protection

Several placebo controlled studies have shown ARB, ACEI or a low dose ACE-thiazide diuretic combination to delay ESRD or a significant increase in Serum Creatinine also shown to reduce or prevent microalbuminuria or proteinuria in patients with both diabetic and non-diabetic proteinuria.

Antiproteinuritic effect also shown with spiornolactone.

MDRD Trial – long term follow up

Significant reduction in ESRD in patients with predominantly non-diabetic kidney disease when randomized to mean blood pressure reduction <92 mmHg rather than <107 mmHg (i.e. <140/90)

J Am Soc. Nephrol 1999; 10:2426-2439) Trial in diabetic normotensives BP <120/80 mmHg by Valsartan No difference in Creatinine Urinary protein excretion reduced

AM J. Hypertens. 2006:19:1241-1248 IDNT trial Blood pressure reduction down to at least 120 mmHg may be

beneficial.

(J Am Soc. Nephrol 2005:16:3027-3037)

Post Hoc subanalysis of ALLHAT trial on HTN patients with reduced renal function at baseline (proteinuria unknown) showed no difference between diuretic, CCB or ACE I

Effects on Microalbuminuria or proteinuria ARBs >Beta Blockers, CCB or ThiazideAldosterone antagonist >CCBACE I > CCB

COOPERATIVE Study (Lancet 2003:361:117-124)

Reported a reduced progression of non-diabetic nephropathy by the combination versus the combination components in monotherapy without a blood pressure difference between groups.

Two small studies suggest very high doses of ARB may exert a greater antiproteinuric action than a standard dose without incremental antihypertension effect.

Irbesartan in T2 DM: Kidney Int. 2005:68:1190-1198Candesartan; J.AM Soc. Nephrol 2005:16:3038-3045

AMADEO STUDYTelmisartan 80 mg VS Losartan 100 mg 29% reduction

2 Small studies have shown that very high doses of ARB, may exert a greater antiproteinuritic effect than a standard dose without an increment of the antihypertensive effect.

(Irbesartan; Kidney Int: 2005: 68:1190-1195Candesartan; J. Am. Soc. Nephrol: 2005; 16:3078-7045)

New Onset Diabetes Almost all trials of antihypertensive therapy have

shown a significantly greater incidence of new onset diabetes in patients treated with diuretics +/- Beta Blockers compared with ACE I, ARB or CCBs.

Recently ARBs and ACE Is have been shown to be associated with significantly less new diabetes than calcium antagonists.

Lancet 2004;363: 2022-20311JAMA 2002; 288;298102997 (ALLHAT)Lancet 2003; 362:759-766 (CHARM OVERALL)JAMA 2001; 286:1882-1885 (HOPE)

Long term (16 – 30 years) observational studies have shown a significantly higher incidence of cardiovascular complications in patients developing diabetes during antihypertensive treatment predominantly with diuretics +/- Beta Blockers.

Brain and Cognitive Function No convincing data in differences between groups

Aware of the PROGRESS study effect of Perindopril plus Indapamide on progression of white matter disease.

Improvement in cognitive function noted on reduction of blood pressure by 4.8/2.6 mmHg but outcomes have varied.

Post stroke Patients

In PROGRESS risk of stroke significantly reduced by 435 (P<0.001)

MOSES study (Stroke 2005:36:1218-1226) At same level of Bp reduction, Eprosartan based

treatment regimen significantly reduced incidence of mortality and all cardiovascular and cerebrovascular events by 21% (P=0.04) compared with nitrendipine.

Atrial fibrillation

Two large hypertension trials have shown ARBs (Losartan and Valsartan) associated with lower incidence of new atrial fibrillation than Atenelol or Amlodipine.

In recurrent atrial fibrillation Irbesartan versus placebo added to Amiodorone has shown reduced recurrence rates.

Circ. 2002:106:331-336

CONCLUSIONSClinical trials of ARB and ACE I have demonstrated the validity of the theory held of the involvement of the RAAS in the Cardiovascular Continuum .

Interruption of the RAAS has been shown to reduce cardiovascular morbidity and mortality in patients with LVH, Heart Failure and post MI as well as renal disease.

Key questions however remain i.e. combination of ACE/ARB and others.

Question of Race

Place of Renin inhibitors