1 / 88

What were the results of the placebo/ controlled long-term hypertension treatment trials?

What were the results of the placebo/ controlled long-term hypertension treatment trials?. 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.

delores
Télécharger la présentation

What were the results of the placebo/ controlled long-term hypertension treatment trials?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. What were the results of the placebo/ controlled long-term hypertension treatment trials?

  2. 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

  3. 100 90 80 70 60 50 40 7 6 5 4 3 2 1 0 Probability of event-free survival (%) Rate of events (per 100 patient-years) Reversal of cardiac hypertrophy in hypertensive patients with initial LVH treated by antihypertensive drug therapy. Non regressors (solid line and bar) (N=52) Regressors (hashed line and bar) (N=50) Verdecchia, Circ. 1998;97:48 0 100 200 300 400 500 Time to event (wk)

  4. Is It Blood Pressure Alone That Makes The Difference or Specific Drugs? Confusing Data from the Clinical Trials

  5. In the: • Verapamil in Hypertension and Atherosclerosis Study • (VHAS) • Controlled Onset Verapamil Investigation of CV • Endpoints (CONVINCE) and • United Kingdom Prospective Diabetes Study (UKPDS), • There were no differences in primary endpoints with • different medications with similar BP outcomes.

  6. Differences in Outcome with Different Therapies but Same BP Results(STOP-2 Study) *Significant difference. Hansson L et al. Lancet. 1999;354:1751-1756

  7. In several other 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.

  8. Recent studies have demonstrated that a CCB based treatment regimen is as effective in reducing CV events as other therapies. • VALUE • ASCOT

  9. In the VALUE trial: • MIs were lower in amlodipine compared to • Valsartan-based treatment groups • BP control better with amlodipine • Differences in BP: 4/2 mm Hg at 1 month • 1.5/1.3 mm Hg at 1 year • Did the differences in BP or specific treatments • determine the outcome?

  10. Primary Composite Endpointsin Value Study

  11. In the ASCOT Trial: • A CCB/ACE-I regimen reduced mortality, MIs and • strokes more than a B-blocker/diuretic based • regimen • BP control better with CCB/ACE-I, especially 1st • few months • Mean trial differences: 2.9/1.8 mm Hg between • therapies • Did the differences in BP or specific treatments determine the outcome?

  12. 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.

  13. 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.

  14. 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

  15. 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)

  16. 2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),

  17. 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

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

  19. 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.

  20. 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

  21. 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

  22. .1 p value A/C 0.28 L/C 0.02 .08 .06 Cumulative Stroke Rate .04 .02 0 0 1 2 3 4 5 6 7 Years to Stroke Cumulative Event Rates for Stroke by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril

  23. 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

  24. 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

  25. ALLHAT AHT Age < 65 Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Amlodipine Favors Chlorthalidone 05/14/03

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

  27. ALLHAT AHT Age < 65 Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 05/14/03 Favors Lisinopril Favors Chlorthalidone

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

  29. ALLHAT results - No difference in fatal or non fatal MIs or death with a thiazide diuretic compared to an ACE or CCB based treatment regimen • Fewer incidents of hospitalized/fatal episodes of heart failure with a diuretic than with a CCB • Fewer strokes with a thiazide than with an ACE-1 based treatment regimen BUT (BP differences or medication?)

  30. Implications of ALLHAT • Diuretics should be the drug of choice for first step therapy of hypertension in most patients • Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen.

  31. Direct and Indirect Comparisons of Diuretics: Chlorthalidone and Nonchlorthalidone in Placebo Controlled Hypertension Trials * RR Indirect Outcome Chlorthalidone Non Chlorthalidone Comparison* Coronary disease 0.74 0.72 1.03 (NS) Stroke 0.64 0.71 0.90 (NS) Heart failure 0.63 NA NA CVD events 0.70 0.76 0.92 (NS) CVD mortality 0.80 0.79 1.01 (NS) Total mortality 0.89 0.91 0.98 (NS) No. CHD Events Deaths Diuretics 7146 214 660 Placebo 7940 370 871 JAMA 2004;292(1):44

  32. 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

  33. 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.

  34. 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

  35. Incidence of New Onset Diabetes with Various Medications. How significant is it?

  36. Effects of High-Dose Diuretic Therapy Compared To Control or Placebo on Glucose Metabolism Study Yrs Serum Glucose (mg/dL) Hyperglycemia or Diabetes Oslo 5 No difference D/Pl No data EWPHE Increase of 6.6 D/Pl MRC 3-4 Excess of 6 new cases/1000 pt yrs HAPPY HDFP 5 1.6% (57/3,563) SHEP 1 Difference of 5 D/Pl No diff – new onset diabetes Rx/C MRFIT 6 Excess of 5% (SI) diuretics vs (UC) no diuretics** *Diuretics compared with placebo **Fasting glucose >110 mg/dL Cleve Clin J Med 1993;60:27-37

  37. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials % Trial Yrs % New Absolute Duration Onset Diabetes Difference UC or D/B-Bl I. ACE-I compared to conventional Rx ACE-I CAPPP ACE-I/B-Bl/D 6.1 6.5 7.5 1.0 STOP-2 ACE-I/B-Bl/D 6+ 4.7 4.9 0.2 ANBP-2 ACE-I/ 4+ 4.5 6.6 2.1 ALLHAT ACE-I/D 4.9 8.1 11.6 3.5 II. CCB compared to conventional Rx CCB NORDIL CCB/B-Bl/D 4.5 4.3 4.9 0.6 ALLHAT CCB/D 4.9 9.8 11.6 1.8 INVEST CCB/B-Bl 4.0 6.2 7.3 1.1 INSIGHT CCB/D 3.5 5.4 7.0 1.6 STOP-2 CCB/B/Bl/D 6+ 4.8 4.9 0.1

  38. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials Trial Yrs % New Absolute Duration Onset Diabetes Difference • III. ARB vs other Rx ARBOther Rx • VALUE ARB/CCB 4.2 13.1 16.4 3.3 • LIFE ARB/B-Bl 4.8 6.0 8.0 2.0 • SCOPE ARB/UC 5 4.3 5.3 1.0 • CHARM ARB/other Rx 3+ 6.0 7.4 1.4 • IV. ACE-I vs CCB ACE CCB • ALLHAT ACE-I/CCB 4.9 8.1 9.8 1.7 Approximate overall difference ACE or ARB vs D/B-Bl: 2.0%; ACE/CCB: 2.0%; CCB vs D/B-Bl: 1.5%

  39. Many clinical trial* results demonstrate that: • Fewer cases of new onset diabetes occur if an ACE or an ARB is included in therapy • Diabetic patients, especially those with proteinuria, have a better outcome if an ACE or an ARB rather than a CCB is included in therapy *IDNT, RENAAL, LIFE, HOPE, CAPPP, AASK, VALUE, ALLHAT

  40. SHEP Follow-Up - New Onset Diabetes To assess the long term (14.3 years) mortality of Systolic Hypertension in Elderly Program (SHEP) participants by diabetes status: • No diabetes • Diabetes at Baseline • New onset diabetes (during SHEP) From Kostis, et al

  41. Results-6 CV death (%) SHEP-X 14.3 Year Follow-up PLACEBO ACTIVE From Kostis et al

  42. Conclusions • Chlorthalidone based treatment of hypertension results in improved long-term outcomes. • The diabetes related to chlorthalidone therapy has better prognosis than diabetes at baseline. • The benefit of chlorthalidone-based therapy on long-term total and CV mortality is most pronounced in hypertensive patients with diabetes. From Kostis, et al

  43. 7th Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

  44. BP Classification SBP mmHg DBP mmHg Normal <120 and <80 Prehypertension 120–139 or 80–89 Stage 1 Hypertension 140–159 or 90–99 Stage 2 Hypertension >160 or >100 JNC 7 Blood Pressure Classification

  45. European Guidelines - 2003 • Do not support the term “pre hypertension” • Definition of high normal may be • “hypertension” in people with other risk • factors or “normal” or acceptable in people • without other risk factors

  46. Pre hypertension (120/80 - 140/90 mm Hg) - Is It a Risk Factor for T.O.D.? 1) LV mass greater in pre hypertensives than in normotensives (Strong Heart Study) 2) CRP as a marker of inflammation may be increased 3) “Pre hypertension does not increase stroke risk.” 4) CHD mortality not increased with pre hypertension

  47. Lifestyle Interventions in the Management of Hypertension Intervention Possible SBP Effect 5-10 mm Hg (>30 min >3x/wk) Exercise Weight reduction Alcohol intake reduction Sodium intake reduction 1-2 mm Hg/Kg 1 mm Hg/drink/d 1-3 mm Hg/40 mmol/d

  48. 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

  49. 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

  50. 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

More Related