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The JNC 7 recommendations for initial or combination drug therapy

The JNC 7 recommendations for initial or combination drug therapy are based on sound scientific evidence. 7 th Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Algorithm for Drug Treatment of Hypertension. Initial Drug Choices.

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The JNC 7 recommendations for initial or combination drug therapy

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

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

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

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

  6. Results of Therapy Effect of Antihypertensive Drug Treatment on Cardiovascular Events % Reduction in Events ** CHF Strokes LVH CVD CHD events Fatal/Non-fatal Deaths Fatal/Non-fatal *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

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

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

  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. ALLHAT AntihypertensiveTrial 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

  12. ALLHAT Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone 12.5 12.5 12.5 25 Amlodipine 2.5 2.5 5 10 Lisinopril 10 10 20 40 Doxazosin 1 2 4 8 * mg/day Step 1Treatment Protocol

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

  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. RR (95% CI) p value A/C 0.98 (0.90-1.07) 0.65 L/C 0.99 (0.91-1.08) 0.81 .2 .16 .12 Cumulative CHD Event Rate .08 .04 0 0 1 2 3 4 5 6 7 Years to CHD Event Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril

  17. HR (95% CI) p value A/C 1.38 (1.25-1.52) <.001 L/C 1.19 (1.07-1.31) <.001 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group .15 .12 Chlorthalidone Amlodipine Lisinopril .09 Cumulative CHF Rate .06 .03 0 0 1 2 3 4 5 6 7 Years to HF

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

  19. Monotherapy 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.

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

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

  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 With HCTZ Without HCTZ 77 69 Percent Response 51 46 30/39 29/63 27/39 32/63 Systolic BP Diastolic BP *Example, captopril + diltiazem, or captopril +diuretic From Materson, et al. J Human Hypertension 1995;9:791-796

  23. Stroke Risk Reduction ACE/diuretic Treated Patients Compared to Patients on Other Medications 0.20 0.15 0.10 0.05 0.00 Lancet 2001:358:1033-41 – PROGRESS Study Proportion with Event 0 1 2 3 4 (Years)

  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. ALLHAT 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.

  26. Are JNC goal levels based on good data?

  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. Cardiovascular Event Free Survival 1.00 0.95 Female 0.90 0.85 0.80 0.75 Male ACEI DIURETIC 0.70 || 0.00 0 1 2 3 4 5 Years Since Randomization ANBP2 Adjusted for age

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

  30. 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

  31. Suggested Approaches for Initiation of Pharmacologic Therapy 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 *Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

  32. 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

  33. Suggested Approaches for Initiation of Pharmacologic Therapy 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 *Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

  34. 2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

  35. Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular Events in the Systolic Hypertension in the Elderly program Diabetic Non Diabetic Active 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 events 21.4 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

  36. ALLHAT AHT Age 65+ Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Amlodipine Favors Chlorthalidone 05/15/03

  37. ALLHAT AHT Age 65+ Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Lisinopril Favors Chlorthalidone 05/15/03

  38. AHT Age 75+ ALLHAT Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Lisinopril Favors Chlorthalidone 05/11/03

  39. AHT Age 75+ ALLHAT Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Amlodipine Favors Chlorthalidone 05/11/03

  40. 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-2 Open STOP-2 Open CAPPP (B-blocker or diuretic) Open

  41. ACEI Diuretic Systolic and Diastolic Blood Pressure after Randomization 6083 170 Systolic 160 6035 5585 5487 150 4323 1183 140 130 95 6083 90 Diastolic 85 6035 5583 5487 4320 1183 80 75 0 0 1 2 3 4 5 N Engl J Med. 2003;348(7):583-592.

  42. ANBP2 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

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

  44. Primary Result ACEI better Diuretic better 0.2 1.0 5.0 Hazard Ratio (95% CI) p 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 ANBP2

  45. 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

  46. “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

  47. Primary Result - Females ACEI better Diuretic better 0.2 1.0 5.0 Hazard Ratio (95% CI) p All CV Events or Any Death 1.00 (0.83,1.21) 0.98 First CV Event or Any Death 1.00 (0.83,1.20) 0.98 Any Death 1.01 (0.76,1.35) 0.94 ANBP2 All events

  48. Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular Events in the Systolic Hypertension in the Elderly program Diabetic Non Diabetic Active 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 events 21.4 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

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