More Confusing Data from the Hypertension Treatment Clinical Trials Should they influence treatment decisions?

1. More Confusing Data from the Hypertension Treatment Clinical Trials Should they influence treatment decisions?

2. WHAT REALLY MATTERS IN DECIDING ON THERAPY? It is still the same old question Is it blood pressure lowering alone that makes the difference or specific medications?

3. 2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

4. 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

5. 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. [Targets for clinical practice]

6. 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

7. Q and A ALLHAT Conclusions?????? • 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?

8. 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?

9. 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

10. .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

11. 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

12. Implications of ALLHAT • Diuretics should be the drug of choice for first step therapy of hypertension in most patients* • Most hypertensive patients require more thanone drug. Diuretics should generally be part of the antihypertensive regimen. *[BP levels were lower in diuretic treated patients ]

13. Criticisms of 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 endpointsare ‘soft data’ that should not form a basis for main conclusions or lead to a labeling of a drug class as preferred” Messerli

14. 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 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)

15. 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?

16. 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.

17. Primary Composite Endpointsin Value Study

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

19. 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

20. Primary Objectives ASCOT Trial* 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 , Lancet 2005;366:895

21. 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 *Lancet 2005;366:895

22. Q & A ASCOT Trial Conclusions????? CCB/ACEI therapy resulted in fewer CHD events than therapy with a B/BL /diuretic?

23. ASCOT Trial* • No significant difference in primary outcome (fatal & non fatal MI) but CCB/ACE-I significantly reducedsecondaryendpoints, i.e., total CHD and CV events including strokes • BP control better with CCB/ACE-I, especially 1st fewmonths(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?

24. ASCOT CONCLUSIONS • “Contemporary therapy is superior to older therapy in the management of hypertension”------- conclusions based on secondary endpoints

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

26. 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?

27. THE 2006 Band Wagon ----- Comments from some investigators “Based on recent clinical trial data, B-blockers should no longer be used as initial antihypertensive therapy” What are the data???

28. It is well-known that in the elderly B-blockers are not as effective in lowering BP as a CCB or a diuretic

29. The B-blocker used in the ASCOT trial was inappropriately dosed Atenolol is not a once-a-day drug

30. 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 preferred combination when compared to a diuretic/ ACEI or ARB

31. Conflicting Data 1. ALLHAT (favors a diuretic) Blinded 2. ASNBP-2 (favors an ACE-I) not blinded. 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?

32. CRITICS ALLHAT • 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 explain results • ASCOT • Wrong comparator medication • Secondary analyses for conclusions? • Are the results “generalizable”?

33. 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 withmultiple drug therapy. TRIAL RESULTS ARE,THEREFORE, NOT REALLY CONFUSING.

34. Is the development of new onset diabetes as a result of antihypertensive therapy of clinical significance?

35. 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.

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

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

38. Risk of Hyperglycemia with Use of Antihypertensive Drugs Thiazide Central antiadrenergic agents Peripheral antiadrenergic agents ACE inhibitors B-Blockers Calcium channel blockers Vasodilators >1 Agent without thiazide >1 Agent with thiazide 0.51 1.5 2 2.5 3 Decreased Risk Increased Risk GurwitzJH. Arch Intern Med 1993;118:273-278 Adjusted ORs and 95%CI

39. Risk of Diabetes among 3804 Hypertensive Patients with Various Antihypertensive Medications Rx Hazard Ratio* None 1.0 ACEI 0.9 B-Blocker 1.25** CCB 1.17 Thiazides 0.95 * adjusted for age, race, BMI, CV risk factors, etc. ** significant difference Gress, et al. NEJM 2000;342:905-12

40. Conclusions: “Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of B-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of B-blockers in reducing the risk of cardiovascular events.” Gress, et al. NEJM 2000;342:905-12

41. Effects of High-Dose Diuretic Therapy Compared To Control or Placebo on Glucose Metabolism StudyYrsHyperglycemia or Diabetes Oslo 5 No data EWPHE MRC 3-4 Excess of 6 new cases/1000 pt yrs HAPPY HDFP 5 1.6% (57/3,563) SHEP 1 No diff – new onset diabetes Rx/C Moser,M. Cleve Clin J Med 1993;60:27-37

42. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials Years % Absolute Difference Trial Duration New Onset Diabetes I. ACE-I compared to conventional Rx ACE / D/B-BL CAPPP 6.1 -1.0 STOP-2 6+ -0.2 ANBP-2 4+ -2.1 ALLHAT 4.9 - 3.5 II. CCB compared to conventional Rx CCB / D/B-BL NORDIL 4.5 - 0.6 ALLHAT 4.9 - 1.8 INVEST 4.0 - 1.1 INSIGHT 3.5 - 1.6 STOP-2 6+ - 0.1 Approximate overall difference ACEI vs D/B-BL: 2.0%; CCB vs D/B-B/L: 1.5%

43. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials Years %Absolute Difference Trial Duration New Onset Diabetes III. ARB vs other Rx ARB / Other Rx VALUE 4.2 - 3.3 LIFE 4.8 - 2.0 SCOPE 5 - 1.0 CHARM 3+ - 1.4 IV. ACE-I vs CCB ACE / CCB ALLHAT 4.9 -1.7 V. CCB/ACE-I vs B-Bl/D ASCOT 5+ -4.9 Approximate overall difference ARB vs D/B-BL: 2.0%; ACE/CCB: 2.0%;

44. Conflicting data on the significance of new onset diabetes

45. CV RISK WITH NEW ONSET DIABETES New Onset Diabetes as a result of various medications has the same prognosis as preexisting diabetes ?

46. Cardiovascular Events inTreated Hypertensive Subjects 4.70 3.90 Rate of events (per 100 patient years) .97 Total number of CV events - 63 Verdecchia, Hypertens 2004;43:963-968

47. Prognostic Significance of New Diabetes in Treated Hypertensive Subjects* • At entry and at 3+ year follow-up non diabetic • patients who developed diabetes had: • higher SBP and DBP • more LVH • higher glucose levels • 42% vs 6% who developed NOD had IFG Greater baseline risk more diabetes more events Hypertens 2004;43:963-968 (observational cohort study)

48. “Plasma glucose levels at entry and diuretic treatment on follow-up were independent predictors of new diabetes” but" while the occurrence of new diabetes was an independent predictor of cardiovascular risk, the use of diuretics, albeit predictive of new diabetes, did not show any independent relation with the subsequent cardiovascular events.” Verdecchia, Hypertens 2004;43:963-968

49. SHEP STUDY FOLLOW-UP NEW ONSET DIABETES AS A RESULT Of THE USE OF VARIOUS MEDICATIONS DOES NOT HAVE THE SAME PROGNOSIS AS PREEXISTING DIABETES

50. 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