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CONFUSING MESSAGES FROM GUIDELINES AND THE HYPERTENSION TREATMENT TRIALS

CONFUSING MESSAGES FROM GUIDELINES AND THE HYPERTENSION TREATMENT TRIALS . What and whom shall we believe?. 7 th Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. BP Classification. SBP mmHg. DBP mmHg. Normal. <120.

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CONFUSING MESSAGES FROM GUIDELINES AND THE HYPERTENSION TREATMENT TRIALS

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  1. CONFUSING MESSAGES FROM GUIDELINES AND THE HYPERTENSION TREATMENT TRIALS What and whom shall we believe?

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

  3. 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

  4. 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

  5. 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

  6. WHAT REALLY MATTERS IN DECIDING ON THERAPY? CONFLICTING TRIAL RESULTS Is it blood pressure alone that makes the difference or specific medications?

  7. Some comparative trials where blood pressure levels were the determining factors in outcome

  8. 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.

  9. Results of Different Levels of Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes: B-Blocker compared with ACE Inhibitor-Based Treatment Program • 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

  10. CV Events in Swedish Trial in Old Persons (Stop-2) Conventional Rx (diuretics and B-blockers) compared to ACE-Is and CCBs No difference in BP outcomes No overall difference in EVENTS Lancet 1999;354:751

  11. 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.

  12. 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.

  13. 2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),

  14. 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

  15. 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.

  16. 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

  17. ALLHAT results. • Diuretic based therapy resulted in fewer CHD events than an ACEI or CCB regimen? • Fewer CVD events occurred in Diabetics treated with ACEIs? • Strokes were more frequent in CCB treated subjects.?

  18. 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?

  19. 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

  20. .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

  21. 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

  22. 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

  23. 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. *[BP levels were lower in diuretic treated patients ]

  24. Comments on the ALLHAT Conclusions Conclusions were based solely on analyses of secondary endpoints. “ We should remember [as we were told by the ALLHAT investigators] that secondary endpoints are ‘soft data’ that should not form a basis for main conclusions or lead to a labeling of a drug class as preferred” Messerli

  25. 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 Stage 1 Hypertension* (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most -May consider other medications or combination. *Combination therapy may also be appropriate initial therapy in patients with diabetes or renal disease JNC 7

  26. 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

  27. ANBP 2 Protocol • ACE Inhibitor Group • Step 1. ACE Inhibitor • Step 2. Beta or alpha blocker or calcium antagonist • Step 3. Drug from class not used in Step 2 or diuretic • Step 4. Drug from class not used in step 2 or 3 • Diuretic Group • Step 1. Thiazide type diuretic • Step 2. Beta or alpha blocker or calcium antagonist • Step 3. Drug from class not used in Step 2 • Step 4. Drug from class not used in step 2 or 3

  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. ANBP-2 CONCLUSIONS • ACEI BASED TREATMENT IS MORE EFFECTIVE IN REDUCING C.V. EVENTS INMALES THAN A DIURETIC BASED TREATMENT REGIMEN. No difference in BP between groups

  30. Valsartan Antihypertension Long-Term Use Evaluation Trial (VALUE) Valsartan (V) Compared to Amlodipine (A) Based Regimen No. 15,245 high risk - 4.2 years Rx V - 80-160 mg/qd + HCTZ; A - 5-10 mg + HCTZ BP differences:1 month - (A) -4.0 / -2.0; 6 months - (A) -2.1/ -1.6; 1 year - (A) -1.5/ -1.3 mm Hg lower than with (V) Results: Cardiac endpoints - no difference MI: 25.8% lower with (A) (S) Heart failure: 12.7% greater with (A) (NS) Stroke: 17.1% lower with (A) (NS)

  31. VALUE: Systolic Blood Pressure in Study Sitting SBP by Time and Treatment Group 155 Valsartan (N= 7649) Amlodipine (N = 7596) 150 mmHg 145 140 135 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 Baseline Months (or final visit) Difference in SBP Between Valsartan and Amlodipine 5.0 4.0 3.0 2.0 mmHg 1.0 0 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 –1.0 Months (or final visit) Julius S et al. Lancet. June 2004;363.

  32. Primary Composite Endpointsin Value Study

  33. In the VALUE trial: • MIs were lower in amlodipine compared to • Valsartan-based treatment groups • BP control better withAmlodipine • Differences in BP: 4/2 mm Hg at 6 mos. • 1.5/1.3 mm Hg at 1 year • Did the differences in BP or specific treatments • determine the outcome?

  34. Valsartan Antihypertension Long-Term Use Evaluation Trial (VALUE) Early control of BP appears to make a difference in outcome

  35. ASCOT Trial* Baseline: 19,339 patients - 77% men; 95% white - age 63 yrs - 27% diabetics BP: 164/94 mm Hg + 3 other risk factors 80% on 1 or 2 medications prior to study *Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895

  36. ASCOT Trial* Primary Objectives To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of an antihypertensive regimen based on a B-blocker +/- diuretic with a regime based on a CCB +/- an ACE inhibitor *Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895

  37. ASCOT Trial BP Targets <140/90 m Hg or <130/80 mm Hg in Patients with Diabetes Unblinded - Probe Design Amlodipine 5-10 mg Atenolol 50-100 mg add add Perindopril 4-8 mg Bendroflumethiazide-K 1.25 - 2.5 mg add Doxazosin 4-8 mg Other medications More than 50% in each group were on 2 or more medications; 26% crossed over to other study drugs; 40% used Rx not prescribed by investigators *Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895

  38. ASCOT Trial • CCB/ACEI therapy resulted in fewer CHD events than therapy with a B/BL /diuretic?

  39. ASCOT Trial* • No significant difference in primary outcome (fatal & non fatal MI) but CCB/ACE-I significantly reduced secondary endpoints, i.e., total CHD and CV events including strokes • BP control better with CCB/ACE-I, especially 1st few months (differences 5.9/2.1 mm Hg at 3 months) • Mean trial differences: 2.7/1.9 mm Hg between therapies • Did the differences in BP or specific treatments determinethe outcome? *Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895

  40. ASCOT Trial* Report failed to reference or mention ALLHAT, SHEP or STOP-2 studies where results were somewhat different *Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895

  41. Should conclusions of a clinical trial be based on results of primary or secondary outcomes? How much statistical manipulation is acceptable to prove a point?

  42. Conflicting Data 1. ALLHAT (favors a diuretic) 2. ASNBP-2 (favors an ACE-I) 3. STOP-2 (equal outcomes B-BL/D vs CCB or ACE-I) 4. ASCOT (different outcomes CCB/ACE-I vs B-BL/D) 5.VALUE (CCB reduces MI events more than an ARB) Are there explanations for these differences?

  43. ALLHAT Critics: • Wrong add-on drugs • Demographics favored diuretics • Should have adhered to primary outcome results • BP differences accounted for difference in outcome VALUE - ASCOT Statistical manipulations to demonstrate that BP differences did not explain different results • ASCOT • Wrong comparator medications? • Secondary analyses for conclusions? • Are these “generalizable results?”

  44. The combination of an ACEI and a CCB is effective and a reasonable choice for therapy for many hypertensives. At present, however, there is no strong evidence that this is a better combination than other available agents

  45. THE MESSAGE IS CLEAR. WHILE THERE MAY BE REASONS TO USE SPECIFIC DRUGS, MOST OF THE BENEFIT REPORTED IN THE CLINICAL TRIALS RESULTED FROM BP LOWERING. TRIAL RESULTS ARE,THEREFORE, NOT REALLY CONFUSING.

  46. Is the Development of new onset diabetes as a result of antihypertensive therapy of clinical significance.?

  47. Recommendations for a change in treatment approaches should be made based on consistent evidence from well controlled clinical trials. At present data on new onset diabetes do not satisfy these criteria.

  48. Therefore----The concerns about new onset diabetes with various antihypertensive medications should not be a major determining factor in the choice of initial therapy.

  49. While data indicate that NOD is increased by about 1% with diuretics compared to CCBs and 1-3.5% compared to ACEIs, long-term CV outcomes are not affected

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

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