1. 1 The JNC 7 recommendations for initial or combination drug therapy are based on sound scientific evidence.

2. 2 7 th Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

3. 3 Algorithm for Drug Treatment of Hypertension Initial Drug Choices Without Specific or Compelling Indications Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension* (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) * Combination therapy may also be appropriate initial therapy in patients with diabetes or renal disease

4. 4 Most of the trials upon which the JNC 7 recommendations were based were multiple drug trials. Specific recommendations for monotherapy for specific patient groups may be difficult to justify.

5. 5 What were the results of the diuretic/ B-blocker controlled long-term hypertension treatment trials?

6. 6 Results of Therapy Effect of Antihypertensive Drug Treatment on Cardiovascular Events *Combined results from 17 randomized placebo controlled treatment trials (48.000 subjects) Diuretic or Beta-blocker based **All differences are statistically significant J Am Coll Cardiol. 1996;27:1214-1218; Arch Intern Med 1993;S76-S71 % Reduction in Events ** CHFStrokesLVHCVDCHD events Fatal/Non-fatalDeathsFatal/Non-fatal

7. 7 A diuretic or diuretic-based treatment regimen has lowered blood pressure reduced cerebro and cardiovascular events been as well tolerated as any treatment program based on other antihypertensive regimens

8. 8 Specific or Compelling Indications for Different Medications Initial TherapyIndication Thiazide diuretic, ACEI ACEI, ARB Thiazide diuretic, BB, ACEI, ARB, CCB Recurrent stroke prevention Chronic kidney disease Diabetes

9. 9 Specific or Compelling Indications for Different Medications Initial TherapyIndication Thiazide diuretic, BB, ACEI, CCB BB, ACEI, aldosterone antagonist Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist High CAD risk Post-myocardial infarction Heart failure

10. 10 JNC 7 Key Messages  Thiazide-type diuretics should be initial drug therapy for most hypertensive patients, alone or combined with other medications  If BP is >160/100 mmHg, therapy should probably started with two medications, one of which should be a thiazide-type diuretic

11. 11 Antihypertensive 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, ACEI, alpha-blocker) compared with a diuretic 42,418 high-risk hypertensive patients ALLHAT

12. 12 Step 1 Treatment Protocol 8421Doxazosin * mg/day 402010 Lisinopril 1052.5 Amlodipine 2512.5 Chlorthalidone Dose 3*Dose 2*Dose 1*Initial Dose*Step 1 Agent ALLHAT

13. 13 Percent of Patients Who Received a Step -2 or Step-3 Medication in the ALLHAT Study Percent *JAMA 2000;283(15):1967-1973

14. 14 ALLHAT Trial Results indicate that in hypertensive patients (mean age of 67 years) >90% can be controlled with a DBP 60% with a SBP <140 mm Hg and >60% with BPs <140/90 mm Hg – with a less than ideal regimen.

15. 15 Blood Pressure Differences in the ALLHAT Trial: Diuretic compared to ACE-I SBP 4 mm Hg less in Blacks 3 mm Hg less in >65

16. 16 Years to CHD Event 01234567 Cumulative CHD Event Rate 0.04.08.12.16.2 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group 0.810.99 (0.91-1.08)L/CL/C 0.650.98 (0.90-1.07)A/CA/C p valueRR (95% CI) Chlorthalidone Amlodipine Lisinopril

17. 17 Cumulative CHF Rate Years to HF 01234567 0.03.06.09.12.15 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group <.0011.19 (1.07-1.31)L/C <.0011.38 (1.25-1.52)A/C p valueHR (95% CI) Chlorthalidone Amlodipine Lisinopril

18. 18 Significant Differences in Outcomes in the Clinical Trials Heart Failure: Other Rx Compared to Diuretics/B-Blockers LA Nifedipine 2xINSIGHT Amlodipine 1.4xALLHAT Verapamil (high risk) 1.3xCONVINCE

19. 19 Antihypertensive monotherapy is effective in only about 40-60% of hypertensive patients, irrespective of the category of the agent that is used. Therefore, there is frequently a need for the use of two medications with different mechanisms of action. Monotherapy

20. 20 BP Control Rates with Low-dose Beta-blocker /Diuretic Combination Compared to Monotherapy with Other Agents PlaceboBisoprolol/AmlodipineEnalapril N=78 HCTZ N=82N=84 N=77 † P=.0001 vs Placebo‡ P=.075 vs Amlodipine*P=.0001 vs Enalapril Cardiovascular Rev Rep. 1996;17:1-9. Patients with DBP <90 mmHg (%) 80 70 60 50 40 30 20 10 0

21. 21 ACE Inhibitor/Diuretic Combination Therapy: Racial Differences in Response  mm Hg 0 -5 -10 -15 -20 -25 Vidt. J Hypertens. 1984;2(suppl 2):81-88 EnalaprilHCTZEnalapril/HCTZ 10mg BID25 mg BID10/25 mg BID (n=66)(n=110)(n=97)(n=92)(n=41)(n=49) Black Nonblack - 6.8 -14.3-14.6 -11.8 -21-21.7

22. 22 Percentage Response (SBP <140 mm Hg; DBP <90 mm Hg) on Combination Therapy with 2 Drugs that Either Do or Do Not Include Hydrochlorothiazide* 100 80 60 40 20 0 30/3929/6327/3932/63 Systolic BPDiastolic BP * Example, captopril + diltiazem, or captopril +diuretic From Materson, et al. J Human Hypertension 1995;9:791-796 Percent Response With HCTZ Without HCTZ 77 46 51 69

23. 23 Stroke Risk Reduction ACE/diuretic Treated Patients Compared to Patients on Other Medications Lancet 2001:358:1033-41 – PROGRESS Study (Years) Proportion with Event 0.20 0.15 0.10 0.05 0.00 0123401234

24. 24 In several trials in high-risk patients (HOPE, IRMA, IDNT, RENAAL, and LIFE), the use of an ACE-I (or an ARB) usually with a diuretic) reduced CV events more than a regimen that did not include these medications.

25. 25 Conclusions Among non diabetics, incidence of fasting glucose  126 mg/dL at 4 years was 1.8% higher in chlorthalidone vs amlodipine, and 3.5% higher in chlorthalidone vs lisinopril. Overall, metabolic differences did not translate into more adverse cardiovascular events, or into higher all-cause mortality, with chlorthalidone. ALLHAT

26. 26 Are JNC goal levels based on good data?

27. 27 Cardiovascular Events in Diabetics in the Hypertension Optimal Treatment Study CV Events/1000 Patient-Years Major CV Events Myocardial Infarctions CV Mortality CV events were reduced to a greater degree in diabetics who achieved the lowest levels of diastolic blood pressure Hansson L, et al. Lancet 1998;351:1755-1762

28. 28 Cardiovascular Event Free Survival Adjusted for age ANBP2 Female Male ACEI DIURETIC || 0.00 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Years Since Randomization 012345

29. 29 Oftentimes, all of the i s cannot be dotted or the T s crossed in finalizing recommendations. These are based on judgement and interpretation of outcome data.

30. 30

31. 31

32. 32 Results of Different Levels of Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes: B-Blocker compared with ACE Inhibitor-Based Treatment Program Better control of blood pressure compared with less aggressive treatment in 8.4-year follow-up of 1148 subjects (achieved blood pressure of 144/82 mm Hg compared with 154/87 mm Hg) Reduced risk of: –Stroke (44%) –Fatal strokes (58%) –Death related to diabetes (32%) –Heart failure (56%) –Fatal and nonfatal coronary heart disease events (21%) (trend but not significant) No difference in outcome between a captopril-based and an atenolol- based treatment program UKPDS. BMJ 1998;317:703-713

33. 33 Suggested Approaches for Initiation of Pharmacologic Therapy *Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity Low Risk Male <55 years of age Female <65 years of age Stage 1 hypertension (140-159/90-99 mm Hg) with no other risk factors* Lifestyle modifications for 3 to 4 months If BP >140/90 mm Hg, begin medicaton

34. 34 Suggested Approaches for Initiation of Pharmacologic Therapy Medium Risk Stage 1 hypertension with one other risk factor* Lifestyle modifications for 2 to 3 months If BP >140/90 mm Hg, begin medication *Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

35. 35 High Risk BP >140/90 mm Hg with evidence of CVdisease and/or diabetes, with/without other risk factors* Stage 2 hypertension Stage 1 or 2 hypertension with at least three other risk factors* Lifestyle modifications and medication Suggested Approaches for Initiation of Pharmacologic Therapy * Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

36. 36 2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

37. 37 Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular Events in the Systolic Hypertension in the Elderly program Active Therapy Placebo Therapy Placebo Major CHD events 9.2 16 6.9 7.6 Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7 Nonfatal and fatal strokes 9.7 14.4 4.4 7.5 Major cerebrovascular disease events21.4 31.5 13.3 10.4 Placebo-treated diabetic patients had about 2-3 times the risk of a cardiovascular event as placebo-treated nondiabetics DiabeticNon Diabetic

38. 38 Nonfatal MI + CHD Death0.97 (0.88 - 1.08) All-Cause Mortality0.96 (0.88 - 1.03) Combined CHD1.04 (0.96 - 1.12) Combined CVD1.05 (0.99 - 1.12) Stroke0.93 (0.81 - 1.08) Heart Failure1.33 (1.18 - 1.49) End Stage Renal Disease1.12 (0.85 - 1.48) AHT Age 65+ Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Favors Amlodipine Favors Chlorthalidone 0.50 1 2 ALLHAT 05/15/03

39. 39 Nonfatal MI + CHD Death1.01 (0.91 - 1.12) All-Cause Mortality1.03 (0.95 - 1.12) Combined CHD1.11 (1.03 - 1.20) Combined CVD1.13 (1.06 - 1.20) Stroke1.13 (0.98 - 1.30) Heart Failure1.20 (1.06 - 1.35) End Stage Renal Disease1.01 (0.76 - 1.36) AHT Age 65+ Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Favors Lisinopril Favors Chlorthalidone 0.50 1 2 ALLHAT 05/15/03

40. 40 05/11/03 ALLHAT Nonfatal MI + CHD Death1.06 (0.89 - 1.26) All-Cause Mortality1.00 (0.89 - 1.13) Combined Coronary Heart Disease1.06 (0.92 - 1.23) Combined Cardiovascular Disease1.12 (1.01 - 1.24) Stroke1.10 (0.88 - 1.37) Heart Failure1.20 (1.00 - 1.45) End Stage Renal Disease1.39 (0.84 - 2.31) 0.50 1 2 Favors Lisinopril Favors Chlorthalidone Relative Risk and 95% Confidence Intervals Lisinopril/Chlorthalidone AHT Age 75+

41. 41 Nonfatal MI + CHD Death0.95 (0.79 - 1.13) All-Cause Mortality0.91 (0.81 - 1.03) Combined Coronary Heart Disease1.02 (0.88 - 1.18) Combined Cardiovascular Disease1.03 (0.92 - 1.14) Stroke0.86 (0.68 - 1.09) Heart Failure1.22 (1.01 - 1.46) End Stage Renal Disease0.98 (0.56 - 1.72) 0.50 1 2 05/11/03 ALLHAT Favors Amlodipine Favors Chlorthalidone Relative Risk and 95% Confidence Intervals Amlodipine/Chlorthalidone AHT Age 75+

42. 42 3-5 Year Studies Directly Comparing a Diuretic-Based Treatment Regimen to other Therapies Diuretic vs B-blocker MRC Elderly Diuretic vs ACE inhibitor ALLHAT Double blind ANBP-2Open STOP-2Open CAPPP (B-blocker or diuretic) Open

43. 43 Systolic and Diastolic Blood Pressure after Randomization N Engl J Med. 2003;348(7):583-592. Diastolic 6083 6035 5583 54874320 1183 Systolic 6083 6035 5585 5487 4323 1183 ACEI Diuretic 0 75 80 85 90 95 130 140 150 160 170 012345

44. Second Australian National Blood Pressure Study (ANBP 2) To determine in hypertensive patients aged 65-84 years whether there is any difference in total cardiovascular events (fatal and non- fatal) over a 5 year treatment period between treatment with either a diuretic-based regimen or an ACE inhibitor-based regimen ANBP2

45. 45 ANBP 2 Conclusion Initiation of antihypertensive treatment in older patients with an ACE inhibitor in males has an advantage over a diuretic.

46. 46 Primary Result ANBP2 Hazard Ratio (95% CI) p ACEI betterDiuretic better 0.21.0 5.0 All CV Events or Any Death 0.89 (0.79,1.00) 0.05 First CV Event or Any Death 0.89 (0.79,1.01) 0.06 Any Death 0.90 (0.75,1.09) 0.27

47. 47 JNC 7 Key Messages For persons over age 50, SBP is more important than DBP as CVD risk factor Normotensive individuals at age 55 have a 90% lifetime risk for developing hypertension Those with SBP 120-139 mm Hg or DBP 80-90 mm Hg should be considered prehypertensive; they may require lifestyle modifications to prevent CVD

48. 48 “Intensive control of blood pressure reduces cardiovascular morbidity and mortality in diabetic patients regardless of whether low- dose diuretics, B-blockers, angiotensin- converting enzyme inhibitors, or calcium antagonists are used as first-line treatment.” Grossman, Messerli…Arch Intern Med 2000;?60;2447-2452

49. 49 Primary Result - Females ANBP2 All events Hazard Ratio (95% CI) p ACEI betterDiuretic better 0.21.0 5.0 All CV Events or Any Death1.00 (0.83,1.21) 0.98 First CV Event or Any Death1.00 (0.83,1.20) 0.98 Any Death1.01 (0.76,1.35) 0.94

50. 50 Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular Events in the Systolic Hypertension in the Elderly program Active Therapy Placebo Therapy Placebo Major CHD events 9.2 16 6.9 7.6 Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7 Nonfatal and fatal strokes 9.7 14.4 4.4 7.5 Major cerebrovascular disease events21.4 31.5 13.3 10.4 Placebo-treated diabetic patients had about 2-3 times the risk of a cardiovascular event as placebo-treated nondiabetics DiabeticNon Diabetic

51. 51 3-5 Year Studies Directly Comparing a Diuretic-Based Treatment Regimen to other Therapies Diuretic vs CCBINSIGHT Double-blind NORDIL (BB or D)Open SHELL Open STOP-2 Open VHAS Open

52. 52 Results of Tight Blood Pressure Control Compared with Less-Tight BP Control in the UKPDS Study Risk Reduction (%) Any diabetes related end- point Diabetes related death StrokeMicro vascular endpoints Retinopathy progression Deterior- ation of vision Heart failure BMJ 1998;317:703-713