Hypertension Management Focus on new RAAS blocker. Disclosure

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1 Hypertension Management Focus on new RAAS blocker Rameshkumar Raman M.D Endocrine Associates of The Quad Cities Disclosure Speaker bureau Abbott, Eli Lilly, Novo Nordisk, Novartis, Takeda, Merck, Solvay pharmaceuticals

2 JNC 7 blood pressure classification in adults aged 18 years BP Classification SBP (mm HG) DBP (mm HG) Normal <120 and <80 Prehypertension or Stage 1 hypertension Stage 2 hypertension or or 100 National Heart, Lung, and Blood Institute. JNC 7 Express. The Seventh Report of the Joint National Committee Hypertension on the Online Prevention, Detection, Evaluation and Treatment of High Blood Pressure % Prevalence of Hypertension in the United States by Age Group * Hypertension Prevalence Age 80% 60% 40% 20% 0% 6% 16% 31% 48% 65% 78% *Based on data from the National Health and Nutrition Examination Survey. Hypertension is defined as blood pressure 140/90 mm Hg or as receiving antihypertensive treatment. Low reliability due to large relative error. Fields LE, et al. Hypertension. 2004;44:

3 Lifetime Risk of Developing Hypertension Among Adults at 65 Years of Age * Risk of Hypertension (%) Men Years *Residual lifetime risk of developing hypertension among adults at 65 years of age with a blood pressure <140/90 mm Hg. Women Vasan RS, et al. JAMA. 2002;287:

4 Adults (%) Hypertension Control Rates Are Slowly Improving (NHANES Data) *Controlled blood pressure was defined as <140/90 mm Hg and expressed as a % of all hypertensives. NHANES = National Health and Nutrition Examination Survey. Chobanian AV, et al. JAMA. 2003;289: ; Ong KL, et al. Hypertension. 2007;49: Treatment Controlled*

5 Cardiovascular Mortality Risk Cardiovascular Mortality Risk Increases as Blood Pressure Rises * 2x 4x 8x 115/75 135/85 155/95 175/105 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 Complications of Hypertension: End-Organ Damage Hypertension Hemorrhage, Stroke LVH, CHD, CHF Retinopathy CHD = coronary heart disease CHF = congestive heart failure LVH = left ventricular hypertrophy Chobanian AV, et al. JAMA. 2003;289: Peripheral Vascular Disease Renal Failure, Proteinuria Relationship of Hypertension to Its Comorbidities Comorbidity Coronary artery disease Left ventricular hypertrophy Ischemic stroke Chronic kidney disease Diabetes Peripheral artery disease Relationship to Hypertension 50% of patients with coronary artery disease have hypertension 15% to 20% of hypertensive adults have an increased left ventricular mass 77% of patients who have a first stroke have a blood pressure >140/90 mm Hg 8% to 15% of hypertensive adults have decreased renal function 75% of added cardiovascular risk in diabetic patients is attributable to hypertension 74% of patients with peripheral artery disease have hypertension Diamond JA, Phillips RA. Hypertens Res. 2005;28: ;El-Atat F, et al. Curr Hypertens Rep. 2004;6: ; Pepine CJ. Am J Cardiol. 1998;82(3A):21H- 24H; Rosamond W, et al. Circulation. 2007;115:69-171; Segura J, et al. Curr Opin Nephrol Hypertens. 2004;13: ; Selvin E, Erlinger P. Circulation. 2004;110:

7 Diabetes Increases Hypertension-Related Cardiovascular Risk: MRFIT Cardiovascular Mortality Rate per 10,000 Person-Years Nondiabetic Men (n = 342,815) Diabetic Men (n = 5,163) < Systolic Blood Pressure (mm Hg) MRFIT = Multiple Risk Factor Intervention Trial Stamler J, et al. Diabetes Care. 1993;16:

8 Current Blood Pressure Targets for Various Chronic Conditions Uncomplicated Hypertension Systolic Blood Pressure Chronic Kidney Disease Coronary Artery Disease Diabetes Diastolic Blood Pressure mm Hg American Diabetes Association. Diabetes Care. 2003;26:S80-S82; Hansson L, et al. Lancet. 1998;351: ; National Kidney Foundation. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266; Rosendorff C, et al. Circulation. 2007;115: Patient Evaluation Evaluation of patients with documented HTN has three objectives: 1. Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment. 2. Reveal identifiable causes of high BP. 3. Assess the presence or absence of target organ damage and CVD.

9 Target Organ Damage Heart Left ventricular hypertrophy Angina or prior myocardial infarction Prior coronary revascularization Heart failure Brain Stroke or transient ischemic attack Chronic kidney disease Peripheral arterial disease Retinopathy Laboratory Tests Routine Tests Electrocardiogram Urinalysis Blood glucose, and hematocrit Serum potassium, creatinine, or the corresponding estimated GFR, and calcium Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides Optional tests Measurement of urinary albumin excretion or albumin/creatinine ratio More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved

10 Development of Antihypertensive Therapies Classes of Antihypertensive Drugs Aldosterone receptor antagonists (blockers) Angiotensin II antagonists Angiotensin-converting enzyme inhibitors α-blockers α 1 -Selective Nonselective β-blockers β-1/β-2 β-1 predominant α/β Intrinsic sympathomimetic activity Calcium channel antagonists Nondihydropyridine Dihydropyridine Central α 2 agonists Direct renin inhibitors Direct vasodilators Diuretics Thiazide-type Loop-type Potassium-sparing Ganglionic blockers

11 Antihypertensive Drug Classes: Action Sites Blood Pressure = Cardiac Output Total Peripheral Resistance Antihypertensive Drug Classes β-blockers Non-DHP CCBs Diuretics β-blockers ACE Inhibitors AT 1 Blockers Direct renin inhibitors α 1 -Blockers α 2 -Agonists All CCBs Diuretics Sympatholytics Vasodilators ACE = angiotensin-converting enzyme; AT 1 = angiotensin type 1; CCBs = calcium channel blockers; DHP = dihydropyridine Compelling Indications for Individual Drug Classes Compelling Indication Initial Therapy Options Clinical Trial Basis Heart failure Postmyocardial infarction High CAD risk THIAZ, BB, ACEI, ARB, ALDO ANT BB, ACEI, ALDO ANT THIAZ, BB, ACE, CCB ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

12 Compelling Indications for Individual Drug Classes Compelling Indication Initial Therapy Options Clinical Trial Basis Diabetes Chronic kidney disease THIAZ, BB, ACE, ARB, CCB ACEI, ARB NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent stroke prevention THIAZ, ACEI PROGRESS JNC-7 7 Report: Treatment Algorithm Initial Drug Choices No Compelling Indication Stage 1 HTN SBP mm Hg, DBP mm Hg Usually thiazide-type diuretic Also consider ACEI, ARB, BB, or CCB alone or in combination Stage 2 HTN SBP 160 mm Hg, DBP 100 mm Hg 2-drug combination Usually thiazide-type diuretic and ACEI, ARB, BB, or CCB ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BB = β-blocker; CCB = calcium channel blocker; DBP = diastolic blood pressure; HTN = hypertension; JNC = Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; SBP = systolic blood pressure Chobanian AV, et al. JAMA. 2003;289:

13 Goals of Therapy Reduce CVD and renal morbidity and mortality. Treat to BP <140/90 mmhg or BP <130/80 mmhg in patients with diabetes or chronic kidney disease. Achieve SBP goal especially in persons >50 years of age. Lifestyle Modification Modification Weight reduction Adopt DASH eating plan Dietary sodium reduction Physical activity Approximate SBP reduction (range) 5 20 mmhg/10 kg weight loss 8 14 mmhg 2 8 mmhg 4 9 mmhg Moderation of alcohol consumption 2 4 mmhg

14 Benefits of Lowering BP Average Percent Reduction Stroke incidence 35 40% Myocardial infarction 20 25% Heart failure 50% Causes of Resistant Hypertension Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication Inadequate doses Drug actions and interactions (e.g., nonsteroidal anti-inflammatory (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) Over-the-counter (OTC) drugs and herbal supplements Excess alcohol intake Identifiable causes of HTN drugs

15 Physiology of RAAS Bradykinin ACE Angiotensinogen Angiotensin I Angiotensin II Renin Aldosterone Angiotensin III Angiotensin IV Angiotensin II Receptor Goodfriend et al. N Engl J Med ;334: PRA is Correlated With RAAS Activation Plasma renin activity (PRA) is a measure of the conversion of angiotensinogen to ANG1 Elevated PRA is correlated to increased levels of ANG 1 and ANG 2 and therefore is a marker for RAAS activation

16 Consequences of Overactivation of RAAS ANG II is the metabolically active end product of RAAS Increases vasoconstrictiom Increases renal sodium reabsorption Stimulates aldosterone and antidiuretic hormone secretion Angiotensin II as a Cardiac and Renal Toxin Angiotensin Renin Chymase Cathepsin G Carboxypeptidase ARB Ang I Ang II ACEI Bradykinin Inactive Fragments AT 1 R Aldosterone Reactive O 2 Species Cell Growth Sympathetic Activation Renal Na +, H 2 O Vasoconstriction Cardiac, Vascular, Collagen CHF Renal Hypertrophy Carey et al. Endocr Rev ;24:

17 Inappropriate RAAS Activation as a Cause of Impaired Vascular and Metabolic Health Angiotensin II Endothelial Dysfunction Vascular Remodeling Impaired Adipogenesis Elevated BP Atherosclerosis Glucose Intolerance Brasier et al. Arterioscler Thromb Vasc Biol. 2002;22: ; 1266; Dzau. J Hypertens. 2005;23(suppl 1):S9-S17; S17; Engeli et al. Int J Biochem Cell Biol. 2003;35: ; 825; Taniyama et al. Hypertension ;43: Studies investigating effects of RAAS manipulation on CV disease outcomes ACE inhibition Angiotensin receptor blockade GISSI-3 ISIS-4 Myocardial ischemia Coronary thrombosis Myocardial Infarction LV Dysfunction Arrhythmia AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT HOPE EUROPA CAD Remodeling ALLHAT ANBP2 ASCOT INVEST LIFE VALUE Atherosclerosis LVH Hypertension Adapted from: Dzau V, et al. Am Heart J. 1991;121: End-stage heart disease Ventricular dilation Heart failure SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS

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21 RAAS and Direct Renin Inhibition: Mechanism of Action

22 Aliskiren Reduced PRA, Alone and in Combination With Ramipril* Aliskiren Reduced PRA Alone and in Combination With Valsartan*

23 TEKTURNA Monotherapy: Powerful BP Reductions (at 8 Weeks) TEKTURNA 300 mg Combined With HCTZ 25 mg: 50% More SBP Efficacy

24 TEKTURNA Combined With Ramipril: Study Trial Design TEKTURNA Combined With Ramipril: Study Results

25 TEKTURNA Combined With an ARB: Study Trial Design TEKTURNA Combined With an ARB: 30% Greater Efficacy With Combination Therapy

26 Summary of Clinical Experience to Date With TEKTURNA Conclusion Benefits of reducing blood pressure on risks of major cardiovascular disease are well established Commonly used antihypertensive medications reduce major CV events by % Large blood pressure reductions correlate with larger reductions of major CV events.