1. Hypertension: New Trials – Best Treatments Karen Moncher, MD Assistant Professor University of Wisconsin School of Medicine and Public Health

2. Overview Epidemiology Clinical Trials and Trends –“All things old become new again” Management Guidelines –Compelling reasons for treatment –Management based on patient problems and pharmacology Patient Adherence

3. Top 10 HTN RX Problems 10. Lack of Public Awareness 68% 9. Lack of Provider Awareness - Systolic BP 8. Lack of Treatment 54% 7. Lack of Provider Awareness Lifestyle RX 6. Providers / Patients - office BP is higher 5. Thought that BP rise with age is not a risk

4. Top 10 HTN RX Problems 4. Lack of use of combination therapy, especially with inexpensive thiazide diuretic (concept that thiazide is synergistic with all) 3. Inappropriate choice of antihypertensive agent based on patient 2. Providers and patients underestimate the benefits of RX, assume less Quality of Life 1. Adherence - Adherence - Adherence

5. The decline in age-adjusted mortality for stroke in the total population is 59.0%. *Age-adjusted to the 1940 U.S. census population. Percent Decline in Age-Adjusted* Mortality Rates for Stroke by Sex and Race: United States, 1972-94

6. The decline in age-adjusted mortality for CHD in the total population is 53.2%. *Age-adjusted to the 1940 U.S. census population. Percent Decline in Age-Adjusted* Mortality Rates for CHD by Sex and Race: United States, 1972-94

7. Incidence of Reported End-Stage Renal Disease Therapy, 1982-1995 253* *Provisional data. Adjusted for age, race, and sex.

8. Demographic Trends Elderly US population will double “baby boomer” generation Projected Elderly Population Age 65+ (millions) 31 million 12.6% total US population 65 million 21.8% total US population

9. HypertensionDyslipidemiaDiabetes Liao. Clin Chem. 1998;44:1799-1808; Spieker et al. J Hum Hypertens. 2000;14:617-630; Belton et al. Circulation. 2000;102:840-845; Ross. N Engl J Med. 1999;340:115-126. Risk Factors, Including Hypertension and Dyslipidemia, Promote CVD by Contributing to Endothelial Dysfunction Endothelial dysfunction CVDInflammation Leukocyte adhesion Endothelial permeability Foam cell formation T-cell activation Atherosclerosis Thromboxane A 2 Prostaglandin H 2 Prostacyclin COX-1 Activity  NO Synthesis VasoconstrictionThrombosisSuperoxide   Endothelin Vasoconstriction Calcium mobilization Smoking

10. Overview Epidemiology Clinical Trials and Trends –“All things old become new again” Management Guidelines –Compelling reasons for treatment –Management based on patient problems and pharmacology Patient Adherence

11. U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) ALLHAT JAMA. 2002;288:2981-2997 Dec. 18, 2002

12. ALLHAT Trial Design Randomized, double-blind, multi-center clinical trial Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACE-I, alpha- blocker) compared with a diuretic Known ASCVD, DM, smoker, LVH, low HDL 42,418 high-risk hypertensive patients ≥ 55 years

13. ALLHAT JAMA 2002 Dec. 18 33357 men and women - diverse races HTN and at least one other CHD risk factor Compared: Thiazide, Lisinopril, Amlodipine, and previously stopped doxazosin arm Primary outcome Fatal CHD or non-fatal MI Secondary outcomes: –Total Mortality- CVA –Combined CHD- CHF

14. ALLHAT Step 1 Treatment Protocol Step 1 AgentInitial Dose*Dose 1*Dose 2*Dose 3* Chlorthalidone12.5 25 Amlodipine2.5 510 Lisinopril10 2040 Doxazosin1248 * mg/day

15. BP Results by Treatment Group Compared to chlorthalidone: SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg).

16. Cumulative Mortality Rate Years to Death 01234567 0.05.1.15.2.25.3 Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group HR (95% CI)p value A/C0.96 (0.89-1.02)0.20 L/C1.00 (0.94-1.08)0.90 Chlorthalidone Amlodipine Lisinopril

17. Cumulative Combined CVD Event Rate Years to Combined CVD Event 01234567 0.1.2.3.4.5 Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group RR (95% CI)p value A/C1.04 (0.99-1.09)0.12 L/C1.10 (1.05-1.16)<0.001 Chlorthalidone Amlodipine Lisinopril

18. Cumulative CHF Rate Years to HF 01234567 0.03.06.09.12.15 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group HR (95% CI)p value A/C1.38 (1.25-1.52)<.001 L/C1.19 (1.07-1.31)<.001 Chlorthalidone Amlodipine Lisinopril

19. Biochemical Results ChlorthalidoneAmlodipineLisinopril Serum cholesterol- mg/dL Baseline216.1 (43.8)216.5 (44.1)215.6 (42.4) 4 Years197.2 (42.1)195.6 (41.0)*195.0 (40.6)* Serum potassium – mmol/L Baseline4.3 (0.7) 4.4 (0.7)* 4 Years4.1 (0.7)4.4 (0.7)*4.5 (0.7)* Estimated GFR† – mL/min/1.73m 2 Baseline77.6 (19.7)78.0 (19.7)77.7 (19.9) 4 Years70.0 (19.7)75.1 (20.7)*70.7 (20.1)* * p<.05 compared to chlorthalidone † Ann Intern Med. 1999;130:461-470

20. ALLHAT Conclusions Amlodipine (representing CCB), lisinopril (representing ACE-I) and chlorthalidone (representing thiazide-type diuretics) were comparable in preventing major coronary events or increasing overall survival. Although chlorthalidone did not differ from amlodipine in overall CVD event prevention, it was superior to amlodipine in preventing heart failure.

21. ALLHAT Conclusions Chlorthalidone was superior to lisinopril in preventing aggregate CV events, principally stroke, HF, angina, and coronary revascularization Chlorthalidone was superior to doxazosin (representing alpha-blockers) in preventing CV events, including both HF and other CVD.

22. Overall Conclusions ALLHAT Because of the effectiveness of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy, unless there are other compelling indications.

23. Isolated Systolic Hypertension Systolic Pressure  140 mmHg & Diastolic < 90 mmHg JNC VI Report, NIH, NHLBI

24. SHEP Study Treatment of elderly patients with ISH Thiazide diuretic plus atenolol if needed Stroke, total mortality, CVD events 63% patients had BP controlled with diuretic alone CVA reduced 36% (3/100) and CVD events reduced 6 per 100 in 4.5 years JAMA 1991;265;3255-3264

27. HTN in the Elderly Trial* ACE (enalapril) vs. HCTZ 6083 adults with HTN aged 65 - 84 years Australia Family Practice clinics Open-label study in multiple practices BP reduction was the same: 26/12 mm Hg All CVD events or death reduced for men (17% or approximately 4 / 100) No difference in events for women NEJM 2003;348:583-592

28. BP-Lowering Treatment Trialists’ Meta-analysis: Comparisons of Active Treatments and Control Favors Active Favors Control 0.51.02.0 Relative Risk RR (95% CI) RR (95% CI) Stroke Coronary heart disease Heart failure BP Difference From Placebo (SBP/DBP mm Hg) Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535. Major CV events CV mortality Total mortality -5/-2 -5/-2 -5/-2 -5/-2 0.72 (0.64, 0.81) 0.72 (0.64, 0.81) ACEI vs placebo ACEI vs placebo-5/-2 0.80 (0.73, 0.88) 0.80 (0.73, 0.88)-5/-2 ACEI vs placebo ACEI vs placebo 0.82 (0.69, 0.98) 0.82 (0.69, 0.98) ACEI vs placebo ACEI vs placebo 0.88 (0.81, 0.96) 0.88 (0.81, 0.96) ACEI vs placebo ACEI vs placebo 0.78 (0.73, 0.83) 0.78 (0.73, 0.83) ACEI vs placebo ACEI vs placebo 0.80 (0.71, 0.89) 0.80 (0.71, 0.89) 0.62 (0.47, 0.82) 0.62 (0.47, 0.82) CA vs placebo CA vs placebo-8/-4 0.78 (0.62, 0.99) 0.78 (0.62, 0.99)-8/-4 CA vs placebo CA vs placebo 0.82 (0.71, 0.95) 0.82 (0.71, 0.95)-8/-4 1.21 (0.93, 1.58) 1.21 (0.93, 1.58) CA vs placebo CA vs placebo -8/-4 0.78 (0.61, 1.00) 0.78 (0.61, 1.00)-8/-4 CA vs placebo CA vs placebo 0.89 (0.75, 1.05) 0.89 (0.75, 1.05)-8/-4

29. 0.51.02.0 BP-Lowering Treatment Trialists’ Meta-analysis: Comparisons of Different Active Treatments Relative Risk RR (95% CI) RR (95% CI) BP Difference Between Rx (SBP/DBP mm Hg) Favors First Listed Favors Second Listed Major CV events CV mortality Total mortality 1.02 (0.98, 1.07) 1.02 (0.98, 1.07)2/0 ACEI vs D/BB ACEI vs D/BB 1.03 (0.95, 1.11) 1.03 (0.95, 1.11) 2/0 ACEI vs D/BB ACEI vs D/BB 1.00 (0.95, 1.05) 1.00 (0.95, 1.05) 2/0 ACEI vs D/BB ACEI vs D/BB 1.04 (1.00, 1.09) 1.04 (1.00, 1.09)1/0 CA vs D/BB CA vs D/BB 1.05 (0.97, 1.13) 1.05 (0.97, 1.13) 1/0 CA vs D/BB CA vs D/BB 0.99 (0.95, 1.04) 0.99 (0.95, 1.04) 1/0 CA vs D/BB CA vs D/BB 0.97 (0.92, 1.03) 0.97 (0.92, 1.03)1/1 ACEI vs CA ACEI vs CA 1.03 (0.94, 1.13) 1.03 (0.94, 1.13) 1/1 ACEI vs CA ACEI vs CA 1.04 (0.98, 1.10) 1.04 (0.98, 1.10)1/1 ACEI vs CA ACEI vs CA D=diuretic; BB=  -blocker. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

30. Favors First Listed Favors Second Listed 0.51.02.0 BP-Lowering Treatment Trialists’ Meta-analysis: Comparisons of Different Active Treatments Relative Risk RR (95% CI) RR (95% CI) BP Difference Between Rx (SBP/DBP mm Hg) CA vs D/BB CA vs D/BB 1.33 (1.21, 1.47) 1.33 (1.21, 1.47)1/0 0.93 (0.86, 1.00) 0.93 (0.86, 1.00) CA vs D/BB CA vs D/BB1/0 1.01 (0.94, 1.08) 1.01 (0.94, 1.08) CA vs D/BB CA vs D/BB1/0 ACEI vs CA ACEI vs CA 0.82 (0.73, 0.92) 0.82 (0.73, 0.92)1/1 1.12 (1.01, 1.25) 1.12 (1.01, 1.25) ACEI vs CA ACEI vs CA 1/1 0.96 (0.88, 1.04) 0.96 (0.88, 1.04) ACEI vs CA ACEI vs CA 1/1 Stroke Coronary heart disease Heart failure 1.09 (1.00, 1.18) 1.09 (1.00, 1.18) ACEI vs D/BB ACEI vs D/BB2/0 0.98 (0.91, 1.05) 0.98 (0.91, 1.05) ACEI vs D/BB ACEI vs D/BB 2/0 1.07 (0.96, 1.19) 1.07 (0.96, 1.19) ACEI vs D/BB ACEI vs D/BB2/0 Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

31. Overview Epidemiology Clinical Trials and Trends –“All things old become new again” Management Guidelines –Compelling reasons for treatment –Management based on patient problems and pharmacology Patient Adherence

32. National Guidelines Recognize the Relationship Between Hypertension and Dyslipidemia JNC 7 recommends assessing a patient’s lipid profiles when setting appropriate BP treatment goals NCEP ATP III recognizes hypertension as a major risk factor that modifies lipid goals When hypertension or dyslipidemia is diagnosed, test for the other condition. Chobanian et al. JAMA. 2003;289:2560-2572. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

33. JNC 7: Classification and Management of BP for Adults BP Classification SBP* mm Hg DBP* mm Hg Lifestyle Modification Initial Drug Therapy Without Compelling Indications With Compelling Indications Normal <120and <80Encourage Prehypertension 120- 139 or 80-89Yes No antihypertensive drug indicated. Drug(s) for compelling indications. † Stage 1 Hypertension 140- 159 or 90-99Yes Thiazide-type diuretics for most. May consider ACEI, ARB,  -blocker, CCB, or combination. Drug(s) for compelling indications. † Stage 2 Hypertension  160or  100 Yes Two-drug combination for most ‡ (usually thiazide-type diuretic and ACEI or ARB or  -blocker or CCB). Other antihypertensive drugs (diuretics, ACEI, ARB,  -blocker or CCB) as needed. *Treatment determined by highest BP category. † Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mm Hg. ‡ Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ARB=angiotensin-II receptor blocker; CCB=calcium-channel blocker. Chobanian et al. JAMA. 2003;289:2560-2572.

34. Not at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed With Compelling Indications Lifestyle Modifications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved Consider consultation with hypertension specialist Stage 2 Hypertension (SBP  160 or DBP  100 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, ARB, BB, or CCB) Stage 1 Hypertension (SBP 140-159 or DBP 90-99 mm Hg) Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combination Without Compelling Indications JNC 7 Algorithm for Treatment of Hypertension Chobanian et al. JAMA. 2003;289:2560-2572.

35. Not at Goal Blood Pressure Algorithm for Treatment of Hypertension Begin or Continue Lifestyle Modifications Lose weight Limit alcohol Increase physical activity Reduce Sodium Maintain potassium, calcium, magnesium Stop smoking Reduce saturated fat, cholesterol

36. Laboratory Tests Recommended Before Initiating Therapy Urinalysis Complete blood count Blood chemistry (potassium, sodium, creatinine, and fasting glucose) Lipid profile 12-lead electrocardiogram

37. Physical Examination Blood pressure readings (2 or more) Height, weight, and waist circumference Funduscopic examination Examination of the neck, heart, lungs, abdomen, and extremities S4 IMPORTANT! Neurological assessment

38. Examples of Identifiable Causes of Hypertension Renovascular disease Renal parenchymal disease Polycystic kidneys Aortic coarctation Pheochromocytoma Primary aldosteronism Cushing syndrome Hyperparathyroidism Exogenous causes

39. Blood Pressure & Lifestyle Blood Pressure is highly sensitive to weight loss: 5 - 10# weight loss will often control BP Dietary Approaches: DASH (SBP 11 DBP 8) 6 servings of fruits / vegetables low sodium (no added salt) low to no alcohol high calcium, low fat NEJM 2001;344:3-9 www.nhlbi.nih.gov/health/public/heart/hbp/dash

40. Sodium Recommendations No Added Salt (2400 mg/day) Hypertension, impaired liver function, cardiovascular disease, cardiac failure, and acute and chronic renal failure. 1000 mg* (45 mEq) Cirrhosis of the liver, pulmonary edema, moderate to severe cardiac failure, acute and chronic liver failure. *For short term use only due to decreased palatability and adherence.

41. Pharmacologic Treatment Decreases cardiovascular morbidity and mortality based on randomized controlled trials. Protects against stroke, coronary events, heart failure, progression of renal disease, progression to more severe hypertension, and all-cause mortality.

42. Initial Drug Choices* Uncomplicated Diuretics  -blockers When other compelling reasons (or others are contraindicated): ACE or Calcium Blocker Algorithm for Treatment of Hypertension *Based on randomized controlled trials.

43. Initial Drug Choices* Algorithm for Treatment of Hypertension (continued) Compelling Indications Heart failure –ACE inhibitors –Diuretics Myocardial infarction  -blockers (non-ISA) –ACE inhibitors (with systolic dysfunction) Diabetes mellitus (type 1) with proteinuria –ACE inhibitors Isolated systolic hypertension (older persons) –Diuretics preferred –Long-acting dihydropyridine calcium antagonists *Based on randomized controlled trials.

44. Initial Drug Choices Specific indications for the following drugs: Algorithm for Treatment of Hypertension (continued) ACE inhibitors Angiotensin II receptor blockers  -blockers  -  -blockers  -blockers Calcium antagonists Diuretics

45. Specific Drug Indications Angina –  -blockers – Calcium blockers Atrial tachycardia and fibrillation –  -blockers – Non-dihydropyridine calcium antagonists Some antihypertensive drugs may have favorable effects on co-morbid conditions: Heart failure –Carvedilol –Losartan Myocardial infarction –Diltiazem –Verapamil

46. Specific Indications (continued) Cyclosporine-induced hypertension –Calcium blockers Diabetes mellitus (1 and 2) with proteinuria –ACE inhibitors (preferred) –Calcium blockers Diabetes mellitus (type 2) –Low-dose diuretics Dyslipidemia  -blockers Prostatism (benign prostatic hyperplasia)  -blockers Renal insufficiency (caution in renovascular hypertension and creatinine < 3 mg/dL - ACE inhibitors Some antihypertensive drugs may have favorable effects on comorbid conditions:

47. Patients Undergoing Surgery Those not on prior drug therapy may be best treated with cardio-selective  - blockers before and after surgery. Those with controlled blood pressure should continue medication until surgery and begin as soon after surgery as possible.

48. Using Thiazide Diuretics Can use either HCTZ or chlorthalidone Use only 12.5 - 25 mg. Daily Higher doses no more effective, and have more side effects and electrolyte problems Do not affect lipids or glucose significantly Do result in LVH regression Synergistic with all other classes of medications – reduce plasma volume

49. Gout Diuretics can increase serum uric acid levels. Diuretics should be avoided in patients with gout. Diuretic-induced hyperuricemia does not require treatment in the absence of gout or urate stones.

50. Using ACE Inhibitors Patients with: –Diabetes Mellitus –Nephropathy / Albuminuria –Post- MI –Congestive Heart Failure Once daily (except captopril) Use ARB if cough develops Use with care if hyperkalemia / CRF

51. Angiotensin Receptor Blocker and Hypertension LIFE Trial: Losartan vs. Atenolol (w / HCTZ if needed) for 9193 patients: Hypertension aged 55-80 years BP decrease 28/9 mmHg both groups CVD mortality*: 8.7 vs 16.9 (46% reduction) Stroke*: 10.6 vs 18.9 (40% reduction) New DM*: 12.6 vs 20.1 (38% reduction) Total Mortality*: 21.2 vs 30.2 (54% reduction) * per 1000 patient-yrs JAMA 2002;288:1491

52. Uses of Calcium Blockers Isolated Systolic HTN / Elderly African Americans w/better response CHD – Angina HTN – resistant – especially with a diuretic Exercise induced HTN Peripheral arterial disease Migraine + HTN

53. Calcium Blockers A calcium blocker is not a calcium blocker: AV node inhibitors / modest vasodilators: –Verapamil –Diltiazem Vasodilators: Dihydropyridines –Amlodipine (Norvasc) –Felodipine (Plendil) *Nifedipine: also negative iontrope / adrenergic

54. Not at Goal Blood Pressure (< 140/90 mm Hg) No response or troublesome side effects Inadequate response but well tolerated Substitute another drug from different class Add second agent from different class (diuretic if not already used) Initial Drug Choices Algorithm for Treatment of Hypertension

55. Causes for Inadequate Response to Drug Therapy Nonadherence to therapy / lifestyle Alcohol use Volume overload ***Failure to add a diuretic*** Drug-related causes Non-steroidal anti-inflammatories Identifiable causes of hypertension

56. Overview Epidemiology Clinical Trials and Trends –“All things old become new again” Management Guidelines –Compelling reasons for treatment –Management based on patient problems and pharmacology Patient Adherence

57. Guidelines for Improving Adherence to Therapy Close follow-up 4 – 6 weeks Prescribe long-acting / once daily medications Adjust therapy to minimize adverse affects Use synergistic medications Utilize other health professionals Consider using nurse case management Involve the patient in self-care

58. Advantages of Self-Measurement Identifies “white-coat hypertension” Assesses response to medication Improves adherence to treatment Potentially reduces costs May confirm HTN to patient and may provide lower readings than those recorded in clinic

59. Thank you! Questions?

60. Additional Slides

61. A population-wide strategy to reduce overall blood pressure by only a few mm Hg could affect overall cardiovascular morbidity and mortality as much as or more than treatment alone. A Population-Wide Strategy

62. Lifestyle Modifications For Prevention and Management Lose weight if overweight. Limit alcohol intake. Increase aerobic physical activity. Reduce sodium intake. DASH diet* For Overall and Cardiovascular Health Maintain adequate intake of calcium and magnesium. Stop smoking. Reduce dietary saturated fat and cholesterol. Increase fruits/vegetables/fiber and healthy oils

63. Children and Adolescents Blood pressure at 95th or higher percentile is considered elevated. Lifestyle modifications should be recommended. Drug therapy should be prescribed for higher levels of blood pressure. Attempts should be made to determine other causes of high blood pressure and other cardiovascular risk factors.

64. 95th Percentile of Blood Pressure by Selected Ages and Height in Girls

65. 95th Percentile of Blood Pressure by Selected Ages and Height in Boys

66. Classification of Blood Pressure for Adults