1. Management of Hypertension Ghada A Bawazeer. MSc, Pharm.D., BCPS Ibrahim Sales, Pharm.D. Assistant Professors-Clinical Pharmacy Dept College of Pharmacy Sept. 2013

2. Background • Most diagnoses occurring between the third and fifth decades of life. • Hypertension accounts for significant morbidity and mortality • One billion individual suffer from hypertension worldwide ( 26%). WHO year 2000 estimation • Seven millions deaths/year are attributed to hypertension • Billions of dollars are spent annually in direct and indirect cost of hypertension

3. Hypertension in Saudi Arabia • Elkhalifaet al (2011): prevalence of HTN 26% • Alzahrani(2011): prehypertension 37%, hypertension 18% • Alshehri(2008): 57.8% in diabetic patients

4. BP Control Rate • National Health and Nutrition Examination Survey (NHANES), United States, 2003–2010 • Controlled 46.5% • Uncontrolled 53.5% • Unaware 39.4% • Aware and not treated 15.8% • Aware and treated 44.8 % Data from National Health & Nutrition Examination Survey (NHNES)

5. What is the recommendation for BP screening? • JNC VII • NICE • No National policy in KSA Age: >40 yrs Recheck in 5 yrs if normal Recheck freq if Pre–HTN If > 180 / 110, treat now Age:> 18 yrs Every 2 yrs if normal Recheck in 1 yr if Pre–HTN Stage 1 - Confirm in 2 months Stage 2 - Confirm in 1 month If > 180 / 110, treat now

6. Blood Pressure Classification:JNC VII

7. Blood Pressure Classification:2007 European Societies of HTN and Cardiology ISH according to NICE: SBP >160 and DBP <90 mm Hg

8. Cardiovascular Risk and Blood Pressure • Strong correlation between BP and CV morbidity and mortality. • Risk increases • Patients with prehypertension • SBP vs DBP

9. Etiology • Essential HTN • > 90% unknown causes • Genetics • monogenic and polygenic forms of BP dysregulation • Genes affect • sodium balance, urinary kallikrein excretion, nitric oxide release, excretion of aldosterone, and angiotensinogen

10. Etiology • Secondary • <10% have identifiable causes • removing the offending agent (when feasible) or treating/correcting the underlying comorbid condition should be the first step in management. • A: Accuracy, Apnea, Aldosteronism ( ) • B: Bruits, Bad Kidneys: RAS / Renal Parenchyma/ • Pheochromocytoma • C: Cushings, Coarctation of Aorta, Catechol ( ) • D: Drugs, Diet • E: Erythropoietin ( ), Endocrinopathies/

11. Hypertension Pathophysiology • Multiple factors that control BP are potential contributing components in the development of essential hypertension: • Genetics • Cardiac output • Sodium regulation • RAAS system • Sympathetic drive • Peripheral resistance • Vascular endothelium and smooth muscle • Electrolyte

12. How much blood flow How much resistance to blood flow BP Cardiac Output (CO) Total peripheral resistance (TRP) • Functional vascular constriction and/or Structural vascular hypertrophy • Excess stimulation of the RAAS • ↑ Sympathetic • Genetic alterations of cell membranes • Endothelial-derived factors • Hyperinsulinemia (metabolic syndrome) • Increase pre-load • Increased fluid volume • excess sodium intake • renal sodium retention • Venous constriction: • Excess stimulation of • RAAS • Sympathetic

13. Neuro-Humoral Mechanisms • Renin-Angiotensin-Aldosterone System (RAAS) • Very complex endogenous system • Controlled mainly by the kidney • Influences vascular tone and sympathetic nervous system activity • Sympathetic nervous system

14. Diagnostic algorithm for hypertension HypertensionVisit1 BP Measurement, History and Physical examination Hypertensive Urgency / Emergency Hypertension Visit 2 Target Organ Damage or Diabetes or BP ≥ 180/110? Diagnosis of HTN Yes No BP: 140-179 / 90-109 Office BPM ABPM (If available) Home BPM (If available)

15. Office BP ABPM (If available) Home BPM Hypertension visit 3 >160 SBP or >100 DBP Diagnosis of HTN Awake BP <135/85 and 24-hour <130/80 Awake BP >135 SBP or >85 DBP or 24-hour >130 SBP or >80 DBP < 135/85 >135/85 <160 / 100 ABPM or HBPM or Hypertension visit 4-5 >140 SBP or >90 DBP Diagnosis of HTN Diagnosis of HTN Continue to follow-up Continue to follow-up Diagnosis of HTN Continue to follow-up < 140 / 90 Criteria for the diagnosis of hypertension and recommendations for follow-up BP: 140-179 / 90-109 Repeat Home BPM If < 135/85 Patients with high normal blood pressure (office SBP 130-139 and/or DBP 85-89) should be followed annually.

16. Diagnosis • Blood pressure measurement • Based on average of > 2 accurate measurements taken during two or more clinical encounters

17. Patient Evaluation • Routine Laboratory Tests : • Urinalysis • Blood chemistry (potassium, sodium and creatinine) • Fasting glucose • Fasting total cholesterol and high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides • Standard 12-leads ECG • Microalbuminurea (if diabetic patient)

18. Patient Evaluation • Optional Laboratory Tests • Investigation in specific patient subgroups • For those with diabetes or chronic kidney disease: assess urinary albumin excretion, since therapeutic recommendations differ if proteinuria is present. • For those suspected of having an endocrine cause for the high blood pressure, or renovascular hypertension, see following slides. • Other secondary forms of hypertension require specific testing.

19. Assess global cardiovascular risk in all hypertensive patients 91% of hypertensive patients have at least 1 additional risk factor  Risk factors =  Global CV risk Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41

20. III. Assessment of the overall cardiovascular risk Cardiovascular Risk Factors • Presence of Risk Factors • Increasing age • Male gender • Smoking • Family history of premature cardiovascular disease (age< 55 in men and < 65 in women) • Dyslipidemia • Sedentary lifestyle • Unhealthy eating • Abdominal obesity • Dysglycemia (diabetes, impaired glucose tolerance, impaired fasting glucose) • Presence of Target Organ Damage • Microalbuminuria or proteinuria • Left ventricular hypertrophy • Chronic kidney disease (glomerular filtration rate < 60 ml/min/1.73 m2) • Presence of atherosclerotic vascular disease • Previous stroke or TIA • Coronary Heart Disease • Peripheral arterial disease CV Risk Factors that may alter thresholds and targets in the treatment of HTN

21. Methods of Risk Assessment • Clinical impression • Risk factor counting • Risk calculation or equation tools • Framingham hard coronary heart disease (CHD)http://www.framinghamheartstudy.org/risk/hrdcoronary.html • SCORE Canada – Systematic Cerebrovascular and Coronary Risk Evaluation www.score-canada.ca • Cardiovascular Age™ www.myhealthcheckup.com • Others: see notes Will be discussed in more details during PPL 3 and Dyslipidemia lecture

22. What is the optimal BP target in hypertensive patients? • Optimal goal of BP is still debatable • J-curve phenomena: not conclusive hypothesis • Current evidences have many limitations to conclusively support 140/90 or 130/80 in HTN without diabetes, or <130/80 in patients with diabetes, CKD • There is a trend towards better outcomes with the lower range

23. Blood pressure treatment goals among the different guidelines

24. Blood pressure treatment goals among the different guidelines

25. Blood pressure treatment goals among the different guidelines

26. Management of Hypertension

27. Goals of Therapy • Patient-oriented outcome: • Reducing CV risk • reduce HTN-associated morbidity and mortality. • target-organ damage (e.g., CV events, cerebrovascular events, heart failure, kidney disease). • Surrogate • to achieve a desired target BP • a tool that clinicians use to evaluate response to therapy • Not a guarantee of prevention of hypertension-associated TOD

28. Approach to Treatment • Lifestyle modification AND • Pharmacological therapy

29. Lifestyle Recommendations for Prevention and Treatment of Hypertension To reduce the possibility of becoming hypertensive, Reduce sodium intake to less than 1500 mg/day • Healthy diet: high in fresh fruits, vegetables, low fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, low in saturated fat, cholesterol and salt in accordance with Canada's Guide to Healthy Eating. • Regular physical activity: accumulation of 30-60 minutes of moderate intensity dynamic exercise 4-7 days per week in addition to daily activities; For non-hypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise (such as free weight lifting, fixed-weight lifting, or handgrip exercise) does not adversely influence blood pressure. • Low risk alcohol consumption: (≤2 standard drinks/day and less than 14/week for men and less than 9/week for women) • Attaining and maintaining ideal body weight (BMI 18.5-24.9 kg/m2) • Waist Circumference: Men <102 cm Women <88 cm • Tobacco free environment

30. Impact of Lifestyle Therapies on Blood Pressure in Hypertensive Adults Padwal R et al. CMAJ 2005;173;(7);749-751

31. Lifestyle Therapies in Adults with Hypertension: Summary

32. Drug Therapy for Hypertension

33. General Principles • Use first line classes • ACE, ARB, CCB, Diuretics, BB • All classes demonstrated CV risk reduction benefits • Major determinant in reduction of Cardiovascular Risk is BLOODPRESSUREREDUCTION • recommend treatment with drugs taken only once a day. • recommend generic where appropriate and minimize cost.

34. II. Indications for PharmacotherapyUsual blood pressure threshold values for initiation of pharmacological treatment for hypertension Lifestyle modification is recommended for all regardless of BP TOD=target organ damage

35. Target Organ Damage (TOD) • Cerebrovascular disease • transient ischemic attacks • ischemic or hemorrhagic stroke • vascular dementia • Hypertensive retinopathy • Left ventricular dysfunction • Left ventricular hypertrophy • Coronary artery disease • myocardial infarction • angina pectoris • congestive heart failure • Chronic kidney disease • hypertensive nephropathy (GFR < 60 ml/min/1.73 m2) • albuminuria • Peripheral artery disease • intermittent claudication • ankle brachial index < 0.9

36. When to initiate drug therapy? • Stage 1 HTN • No TOD, low CV risk • Life style modification (LS) • TOD, moderate-high risk • LS + drug therapy • Stage 2 HTN • LS + drug therapy • JNC 7 recommend 2 combination therapy as initial therapy • Isolated Systolic HTN • When BP >140/90 mm Hg

37. Algorithm for treatment of HTN presence of compelling Indications degree of BP elevation

38. ARB ACEI III. Treatment of Adults with Systolic/Diastolic Hypertension WITHOUT Other Compelling Indications TARGET <140/90 mmHg INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification therapy Thiazide Long-acting CCB Beta-blocker* A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target *BBs are not indicated as first line therapy for age 60 and above ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

39. III. Considerations Regarding the Choice of First-Line Therapy • ACEI, renin inhibitors and ARBs are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential. • BBs are not recommended as first line therapy for patients age 60 and over without another compelling indication. • Diuretic-induced hypokalemia should be avoided through the use of potassium sparing agents if required. • The use of dual therapy with an ACEI and an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. • ACEI are not recommended (as monotherapy) for black patients without another compelling indication.

40. Does the CV benefits seen in ALLHAT for Chlortahlidone extend to hydrochlorothiazide? • Chlorthalidone is the diuretic that was use in most of the influential trials • It is 2X more potent in lowering BP on a mg-per-mg basis than HCTZ • HCTZ has not been as extensively studied in major long term hypertension clinical trials. • It is notdefinitively known if the clinical benefits of reducing CV morbidity and mortality that have been proven with chlorthalidone can be extrapolated to HCTZ. • In clinical practice, however, CV benefits in hypertension apply to all thiazide-type diuretics, and benefits are considered a class effect.

41. 1. Add-on Therapy • IF BLOOD PRESSURE IS NOT CONTROLLED CONSIDER • Nonadherence • Secondary HTN • Interfering drugs or lifestyle • White coat effect 2. Triple or Quadruple Therapy Add-on Therapy for Systolic/Diastolic Hypertension without Other Compelling Indications If partial response to monotherapy If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as alpha blockers or centrally acting agents).

42. III. Summary: Treatment of Isolated Systolic Hypertension without Other Compelling Indications TARGET <140 mmHg, < 150 mmHg for age > 80 years Lifestyle modification therapy Thiazide diuretic ARB Long-acting DHP CCB *If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as ACE inhibitors, alpha blockers, centrally acting agents, or nondihydropyridine calcium channel blocker). Dual therapy • CONSIDER • Nonadherence • Secondary HTN • Interfering drugs or lifestyle • White coat effect Triple therapy

43. Partial response • Option 1: Increase the dose of the first agent, remember: • Dose response curves for efficacy are relatively flat • 80% of the BP lowering efficacy is achieved at half-standard dose • Option 2: Add another drug from the 1st line classes • Combinations of standard doses have additive blood pressure lowering effects.

44. Combination therapy • Most patients will require 2 or more agents to achieve BP control • Consider combination from among the first line drugs • Different possible combinations, consider patient factors and cost. • CHEP GL: • DHP-CCB + Diuretic • DHP-CCB + ACEI or ARB • DHP-CCB + BB

45. Considerations when Selecting a Combination Therapy • Use combination from first line classes • Many fixed-dose combination products are commercially available, consider patient factors and cost • some are generic • Most products contain a thiazide-type diuretic and have multiple dose strengths available. • Individual dose titration is more complicated with fixed-dose combination

46. Considerations when Selecting a Combination Therapy • ACEI + ARB, not recommended (Grade A) • If a diuretic is not used as first or second line therapy, triple dose therapy should include a diuretic, when not contraindicated • If a BB was used initially, a CCB is preferred over thiazide-type diuretic, to reduce the person’s risk of developing diabetes. • Caution should be exercised in combining anon-DHP CCB and a BB to reduce the risk of bradycardia or heart block

47. Considerations when Selecting a Combination Therapy • Use caution in initiating therapy with 2 drugs in whom adverse events are more likely (e.g. frail elderly, those with postural hypotension or who are dehydrated).

48. Choice of antihypertensive agent HTN with compelling indications:

49. Choice of Pharmacological Treatment for Hypertension Individualized treatment • Compelling indications: • Ischemic Heart Disease • Recent ST Segment Elevation-MI or non-ST Segment Elevation-MI • Left Ventricular Systolic Dysfunction • Cerebrovascular Disease • Left Ventricular Hypertrophy • Non Diabetic Chronic Kidney Disease • Renovascular Disease • Smoking • Diabetes Mellitus • With Nephropathy • Without Nephropathy • Global Vascular Protection for Hypertensive Patients • Statins if 3 or more additional cardiovascular risks • Aspirin once blood pressure is controlled

50. 2013 Canadian Hypertension Education Program (CHEP) Important messages from past recommendations • Patients with diabetes are at high cardiovascular risk • Most patients with diabetes have hypertension • Treatment of hypertension in patients with diabetes reduces total mortality, myocardial infarction, stroke, retinopathy and progressive renal failure rates. • Treating hypertension in patients with diabetes reduces death and disability and reduces health care system costs • In diabetes, TARGET <130 systolic and <80 mmHg diastolic • If a patient has both diabetes and CKD, TARGET <130 systolic and <80 mmHg diastolic • The use of the combination of ACE inhibitor with an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.