Evidence Based Treatment of Hypertension

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

2. P3 Year – Investing in your Education

3. Objectives • Describe the epidemiology of hypertension • Identify various physiologic systems that can contribute to the development of elevated blood pressure. • Identify the complications of untreated hypertension. • Describe the classification of blood pressure in adults. • Identify appropriate blood pressure goals for patients with hypertension. • Know the disease states and other factors that increase the risk of cardiovascular complications for a patient with hypertension. • Be able to identify secondary causes of hypertension, including drugs. • Summarize our current knowledge on the relative effectiveness of antihypertensive therapy in preventing complications of hypertension. • Describe the role of non-pharmacologic management of hypertension and various lifestyle changes that can be recommended. • Describe when drug therapy for hypertension is indicated.

4. Objectives • Be able to articulate the advantages, disadvantages, effectiveness as monotherapy, side effects, contraindications, relative cost, and monitoring parameters for the following classes of antihypertensives: • Diuretics (Loop, Thiazide, Potassium Sparing) • Beta-blockers • Angiotensin-converting enzyme (ACE) inhibitors • Calcium blockers • Centrally-acting sympatholytics • Peripheral sympatholytics and arteriolar dilators • Alpha blockers • Angiotensin receptor blockers (ARBs) • Direct rennin inhibitors

5. Objectives • Describe differences among various agents in the same antihypertensive class. • Identify antihypertensives that should not be abruptly discontinued. • Taking into consideration demographics, socio-economic factors, and medical disorders for a given hypertensive patient, be able to develop an appropriate therapeutic plan (recommend appropriate agent, patient education, and monitoring). • Identify factors that can lead to a poor response to antihypertensive therapy. • Describe the factors that can influence compliance with antihypertensive therapy. • Be able to distinguish between true hypertensive emergency and hypertensive urgency.

6. The Road Ahead • Evidence Based Medicine (EBM) Primer • Hypertension Defined, Epidemiology, Complications • Goals of Hypertension Therapy • Hypertension Treatment Guidelines • Non-Pharmacological Treatments of Hypertension • Pharmacology Review • EBM for pharmacological treatment selection

7. 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)

8. 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

9. 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?

10. EBM In Real Life • Question : A patient is taking 25mg HCTZ QDay with BP 140/95. What should the next step be? • 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: ???

11. 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 • Express and Full Version

12. Case • JD is a pleasant 56 yo female with • Hypertension (HTN) • type 2 diabetes • occasional gout attacks. • Her last three home BP readings were 145/95mmHg, 153/98mmHg, and 143/92mmHg. • Today in the clinic she had a BP of 142/89mmHg. • Her last Lipid panel was 2 months ago: LDL 153mg/dL, HDL 63mg/dL, triglycerides 121 • Lisinopril 40mg once daily • Metformin 1000mg BID

13. Hypertension (HTN) Defined • Elevated Blood Pressure (BP) • Systolic Blood Pressure (SBP) >=140mmHg • Diastolic Blood Pressure (DBP) >=90mmHg • Why these values will be discussed later • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

14. Hypertensive Crisis • Less than 1% of all hypertensive patients 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

15. White Coat Hypertension • Elevated blood pressure in a clinical setting • Believed to be tied to anxiety • Documented lower blood pressures at home

16. Epidemiology of Hypertension • Approximately 50 million people in the U.S. have hypertension. • The risk of CVD beginning at 115/75 mmHg doubles with each increment of 20/10 mmHg • 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

17. Epidemiology of Hypertension • While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled.

18. Epidemiology of Hypertension Prevalence Doubles From 40s to 60s

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

20. Definitions - 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.

21. Schematic of the 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

22. Pathophysiology of Hypertension • Increased Sympathetic Activation • Excessive vascular volume • Activation of the ReninAnginotensinAldosterone System • Peripheral Resistance

23. 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 be surprised if you don’t find them

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

25. 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 (Stable and Unstable) • Heart Failure (HF) • Left Ventricular Hypertrophy or Dysfunction (LVH, LVD) • Cerebrovascular Disease • Stroke • Transient Ischemic Attack (TIA) • Chronic Kidney Disease (CKD) • Retinopathy

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

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

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

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

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

31. 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

32. 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 • JNC-7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

33. 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

34. 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

35. Therapy • Therapeutic Lifestyle Changes (TLC) • Weight • Exercise • Diet • Smoking • Caffeine • Pharmacotherapy

36. 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

37. Weight Reduction EBM • Trials of Hypertension Prevention, Phases I and II (TOHP I, TOHP II) Late 1980s, early 1990s • Evaluated Multiple Non-Pharmacological Methods of weight loss (weight reduction, sodium restriction, mineral supplementation) in pre-hypertensive (DBP 83-89mmHg female, 80-89mmHg male) and BMI approximately 25-35 • Sodium Restriction and Weight Loss were the most effective methods for reducing both SBP and DBP

38. More Weight Reduction EBM He, J et. al Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of Hypertension. Hypertension 2000;35:544-549 77% Reduction in HTN Rate

39. DASHDiet & Sodium Restriction

40. DASH Diet & Sodium Restriction • Restricted Sodium • Low Fat • High Fiber • Emphasis on Fruits and Vegetables • High Potassium • High Calcium

41. EBM of DASH Diet & Sodium Restriction • 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

42. EBM of DASH Diet & Sodium Restriction • Controlling for sodium content, the DASH diet provides significant BP reductions • Add sodium restrictions and further reductions in BP are obtained 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

43. Exercise 30 minutes most days • A 2002 systematic Meta-analysis of Randomized Control Trials (RCTs) showed the following results • BP reductions appear to be independent of weight loss • Method of aerobic activity (biking, walking, etc) did not show a statistically significant link to BP reductions • Neither frequency nor intensity of exercise showed statistically significant reductions in BP Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: A meta-analysis of randomized, controlled trials. Ann Intern Med 2002;136:493-503. M

44. 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

45. Caffeine • Acute vs. Chronic Effects • Surrogate endpoints vs. Primary Endpoints

46. Caffeine increases BP • Acute elevations in Systolic and Diastolic BP • But what about Morbidity and Mortality ? Hartley, et al Hypertension Risk Status and Effect of Caffeine on Blood Pressure. Hypertension 2000;36:137-141

47. Caffeine’s effects on morbidity and mortality • No controlled trials have demonstrated an increased risk of cardiovascular endpoints • Several studies have demonstrated no linear relationship between caffeine consumption and hypertension rates • MacDonald, TM, et al. Caffeine Restriction: effect on mild hypertension BMJ 1991(303)1235-8 • Winkelmayer, WC, et al. Habitual Caffeine Intake and the Risk of Hypertension in Women. JAMA 2005:(294)18:2330-2335 • JNC-7 only mentions caffeine in the context of abstention 30 minutes before taking a BP reading

48. 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

49. 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

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