Evidence Based Treatment of Hypertension

1. Evidence Based Treatment of Hypertension Harleen Singh, Pharm.D. Ted D. Williams, Pharm.D. Candidate OSU/OHSU College of Pharmacy

2. P4 Year – Investing in your Education Lab Lecture

3. Learning Objectives • Demonstrate an understanding of the different roles of pharmacology, pathophysiology, and evidence based medicine as they apply to patient therapy • Demonstrate understanding of pathological disorders caused by chronic, poorly controlled hypertension • Identify signs and symptoms of end-organ damage due to hypertension • Demonstrate an understanding of sites of action and most likely side effects of various antihypertensive drug classes and differences between drugs in the same class • Classify patients by JNC-7 Hypertension levels • Assign blood pressure goals according to AHA 2007 Scientific Statement for patients based on comorbidities • Select most appropriate therapy for patients based on Evidence Based Medicine Compelling Indications • Apply outcomes of landmark hypertension studies to selecting patient therapy

4. The Road Ahead • Evidence Based Medicine (EBM) Primer • Hypertension Defined, Epidemiology, Complications • Goals of Hypertension Therapy • Hypertension Treatment Guidelines • Non-Pharmacological Treaments of Hypertension • Pharmacology Review • By Drug Class • Assessing Drug Interactions • EBM for pharmacological treatment selection

5. Evidence Based Medicine • Evidence-based medicine (EBM) • EBM is the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients.(Sackett 1998)

6. Pathophysiology, Pharmacology and EBM • Pathophysiology suggests where we can intervene to improve outcomes • Pharmacology helps predict likely targets • Therapeutic Effects • Adverse Effects • Clinical Trials show what happens when we treat 10,000 patients • Evidence Based Medicine lives here

7. Types of Significance • Statistical Significance • Can we detect any difference • Clinical Significance • Do we care if there is a difference • Patient Significance • Blood Glucose level differences with Thiazide Diuretics are significantly higher vs. placebo • Increase in Blood Glucose 3-5mg/dL in non-diabetics • Is this clinically significant?

8. EBM In Real Life • Question for PharmD: Recommend a therapy for a patient on 25mg HCTZ QDay with BP 140/95 • Answer from PharmD: “Continue HCTZ 25mg Q Day and add Lisinopril 10mg Q Day, titrating to 40mg Q Day” • Response: “Why not increase HCTZ to 50mg Q Day. Micromedex says the max daily dose is 100mg” • PharmD: ???

9. JNC-7 • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure • Gold Standard EBM in Hypertension diagnosis and treatment

10. Case

11. More Cases

12. Hypertension Defined • Elevated Blood Pressure (BP) • Systolic Blood Pressure (SBP) >=140mmHg • Diastolic Blood Pressure (DBP) >=90mmHg

13. Epidemiology of Hypertension • Approximately 50 million people in the U.S. have hypertension. • The incidence of hypertension increases steadily with age and prevalence is higher in blacks than in whites. Prevalence exceeds 60% in people over age 60. • There is a strong correlation between blood pressure and cardiovascular morbidity and mortality. • Systolic BP has a stronger correlation than diastolic BP, but both are important

14. Epidemiology of Hypertension • The higher the pressure, the greater the risk of myocardial infarction, angina, stroke, heart failure, renal failure, peripheral vascular disease and retinopathy. • For each 20mm increase in SBP or 10mm increase in DBP over 115/75, risk doubles • Complication rates increase with each additional CVD risk factor that is present • Hypertension accounts for 2/3 of strokes and about 25% of MIs • Preventing and controlling hypertension is a major strategy for reducing CVD morbidity and mortality. • While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled.

15. Determinants of Blood Pressure • Arterial blood pressure is generated by the interplay of cardiac output and total peripheral resistance: BP = CO x TPR • It reaches a peak during cardiac contraction (systolic pressure) and a nadir at the end of cardiac relaxation (diastolic pressure). • Blood pressure is measured in millimeters of mercury and recorded as systolic (SBP) over diastolic pressure (DBP). • The difference between the systolic and the diastolic pressure is the pulse pressure (PP) • Mean arterial pressure (MAP) = 1/3 PP + DBP.

16. Pathophysiology of Hypertension Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004

17. Pathophysiology of Hypertension(HTN) • Increased Sympathetic Activation • Excessive vascular volume • Activation of the ReninAnginotensinAldosterone System • Peripheral Resistance

18. Causes of Hypertension • Idiopathic • 90-95% of cases have no known etiology • Secondary • Renal Insufficiency • Coarcation of the aorta • Primary Aldosteronism • Thyroid/parathyroid disease • Cushing’s Syndrome • Pheochromocytoma • Sleep Apnea • Increased Intracranial pressure • Look for secondary causes, but don’t expect to find them

19. Hypertension as a Risk Factor Chronic Kidney Disease Peripheral Vascular Disease Retinopathy HTN Ischemic Heart Disease Cerebrovascular Disease Heart Failure

20. Hypertension as a Risk Factor • Hypertension is a primary risk factor for multiple co-morbidities • Ischemic Heart Disease (IHD) • aka Carotid Artery Disease (CAD), Coronary Heart Disease(CHD) • Myocardial Infarction (MI) • Angina • Heart Failure (HF) • Left Ventricular Hypertrophy or Dysfunction (LVH, LVD) • Cerebrovascular Disease • Stroke • Transient Ischemic Attack (TIA) • Chronic Kidney Disease (CKD) • Retinopathy

21. Types of Hypertension • Chronic • What we will focus on today and what we will call Hypertension • Hypertensive Crisis • Hypertensive Emergency • Hypertensive Urgency • Dr Marrs will discuss this in detail in subsequent lectures

22. Hypertensive Crisis • Less than 1% of all hypertensives will ever have a hypertensive crisis. • Hypertensive crisis is defined as a diastolic pressure above 120mm Hg. • There are 2 types of hypertensive crisis: • hypertensive emergency • hypertensive urgency

23. Goals of Hypertensive Therapy • Long Term • Short Term

24. Long Term Goals of Hypertension Therapy • Direct Measures • Reduced Mortality • Reduced incidence of end organ damage • Cardiovascular • Cerebrovascular • Renal • Retinopathy • Trailing indicators

25. Short Term Goals of Hypertension Therapy • Surrogate markers • Blood Pressure • Leading indicator • Why is blood pressure a good surrogate marker?

26. Hypertension and Ischemic Heart Disease • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

27. Hypertension and Stroke • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

28. Hypertension and Cardiovascular Disease • High Normal = 130-139/85-89mmHg • Normal = 120-129/80-84mmHg • Optimal <120/<80mmHg • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

29. JNC-7 Hypertension Classifications DBP = Diastolic Blood Pressure, SBP = Systolic Blood Pressure *Treatment should be determined by the highest blood pressure ‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80mmHg 2 Agent Initial Therapy • JNC-7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

30. From JNC-7 to 2007 AHA Guidelines Past Medical History Blood Pressure Goal Framingham Risk Score <10% Primary Prevention <140/90 mmHg >10% Diabetes Melitus Chronic Kidney Disease <130/80 mmHg CAD Risk Equivalents CAD Left Ventricular Dysfunction <120/80 mmHg • Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008

31. Framingham Risk Factors and CAD Equivalents • Framingham Risk Factors • Age > 45 • Total Cholesterol • Smoking • HDL Cholesterol • Systolic Blood Pressure • See ATP III Guidelines for scoring algorithm • CAD Equivalents • Ischemic Stroke • Transient Ischemic Attack • Peripheral Arterial Disease • Abdominal Aortic Aneurysm

32. Therapy • Therapeutic Lifestyle Changes (TLC) • Pharmacological Therapy

33. Therapeutic Lifestyle Changes vs. Pharmacotherapy Adapted From: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

34. Weight Reduction

35. Dash Diet

36. 30 Minutes of Exercise

37. Sodium Restriction Trial • 412 subjects randomized to typical American diet (control) or DASH diet and to three different sodium levels for 30 days with a 2 week run in period • High 3.5g • Intermediate 2.3g (Recommended DASH) • Low 1.2g • Typical American diet is 4,100 mg per day for men and2,750 for women (JNC-7) Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10

38. SodiumRestriction Trial Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10

39. Smoking • Smoking • In the first year after quitting, excess risk of a cardiovascular event is cut in half, and after 5-15 years, the rate approaches that of a never smoker Annual Smoking Related Deaths 1995-1999 from Center for Disease Control and Prevention

40. Caffeine • Caffeine

41. JNC-7 Recommendations by Hypertension Stage

42. JNC-7 Recommendations by Compelling Indication The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

43. 2007 AHA Scientific Statement Recommendations First Line Therapy Past Medical History Blood Pressure Goal Framingham Risk Score <10% <140/90 mmHg ACEI/ARB or CCB or Thiazide Diuretic Primary Prevention >10% ACEI/ARB or CCB or Thiazide Diuretic Diabetes Melitus Chronic Kidney Disease <130/80 mmHg CAD Risk Equivalents BB‡ and ACEI/ARB CAD (ACEI/ARB or BB) And Diuretic And Aldosterone Antagonist And Hydralazine/IsosorbideDinitrate¥ Left Ventricular Dysfunction <120/80 mmHg • Adapted From Saseen, JJ. Essential Hypertnesion. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008 and Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788. • ‡ Only use BB in patients who are hemodynamically stable • ¥ African American

44. 2007 AHA Scientific Statement Recommendations Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788.

45. Antihypertensive Therapies • Volume Management • Loop Diuretics • Thiazide Diuretics • Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents • Angiotensin Converting Enzyme Inhibitors (ACEI) • Angiotensin II Receptor Blockers (ARB) • Renin Inhibitors • Direct Cardiac Agents • Beta Blockers (BB) • Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators • Dihydropyridine Calcium Channel Blockers (DHP CCB) • Alpha 1 Antagonists

46. Antihypertensive Therapies • Volume Management • Loop Diuretics • Thiazide Diuretics • Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents • Angiotensin Converting Enzyme Inhibitors (ACEI) • Angiotensin II Receptor Blockers (ARB) • Renin Inhibitors • Direct Cardiac Agents • Beta Blockers (BB) • Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators • Dihydropyridine Calcium Channel Blockers (DHP CCB) • Alpha 1 Antagonists

47. Loop Diuretics – Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

48. Loop Diuretics – Mechanism of Action • Act mainly in ascending loop of Henle to decrease sodium reabsorption • Action is shorter but more intense than other diuretics • Preferred for edema vs. BP management Na↑ Ca↑ Mg↑ K↑

49. Thiazide Diuretics – Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

50. Thiazide Diuretics– Mechanism of Action • Increase urinary excretion • Works at the distal convoluted renal tubules • Increase urinary excretion of potassium • Additional MOA • May cause peripheral vasodilation, but this is unclear Na Cl↑ + K↑