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Recent Clinical Trial Results - A Critique

Recent Clinical Trial Results - A Critique. William Cushman, MD Professor, Preventive Medicine and Medicine University of Tennessee College of Medicine Chief, Preventive Medicine Memphis VA Medical Center. How low should BP be treated with antihypertensive medications?.

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Recent Clinical Trial Results - A Critique

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  1. Recent Clinical Trial Results - A Critique William Cushman, MD Professor, Preventive Medicine and Medicine University of Tennessee College of Medicine Chief, Preventive Medicine Memphis VA Medical Center

  2. How low should BP be treated with antihypertensive medications? • Epidemiologic data suggest a continual gradient of risk with increasing BP beginning at 115/75 mm Hg. • However, most BP trials demonstrating major CVD benefits of antihypertensive treatment have treated to specific goals: • SBP: <150-160 mm Hg: SHEP mean SBP 142-143 mm Hg supports SBP goal 140 mm Hg • DBP: <90 mm Hg (<80 mm Hg in DM) • Trials testing lower goals for CVD or renal outcomes have mostly failed to show further benefit, but are often underpowered

  3. Systolic Blood Pressure and Cardiovascular Mortality in Type 2 Diabetes: MRFIT Screenees 250 Nondiabetic Patients Diabetic Patients 225 200 175 150 CV Mortality Rate/10,000 Person-Years 125 100 75 50 25 0 <120 120–139 140–159 160–179 180–199 ³200 SBP (mm Hg) SBP=systolic blood pressure; CV=cardiovascular. Stamler J, et al. Diabetes Care. 1993;16:434-444.

  4. Cushman, et al. Am J Cardiol 2007;99:44i-55i

  5. Presented at European society of Cardiology, Vienna, 9/2/07 ADVANCE: a factorial randomised trial of blood pressure lowering andintensive glucose control in11,140 patients with type 2 diabetes Effects of a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide on major vascular events Lancet 2007 Sept 8;370:829-40

  6. Randomised study treatments Blood pressure lowering • Double-blind perindopril-indapamide versus matching placebo • 2.0 / 0.625mg or placebo for first 3 months • 4.0 / 1.25mg or placebo thereafter Blood glucose lowering (ongoing) • Open-label gliclazide MR-based intensive therapy targeting an HbA1c of 6.5% versus usual guideline-based care * * 50% of active group and 60% of placebo group also had open-label ACE inhibitor added by end of trial Lancet 2007;370:829-40

  7. Stroke and Major CVD Reduction in PROGRESS ACEI: perindopril 4 mg; Diuretic: indapamide 2.5 mg PROGRESS Collaborative Group. Lancet 2001;358: 1033-41

  8. Primary study outcomes Macrovascular • Non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause (including sudden death) Microvascular • New of worsening nephropathy or diabetic eye disease Prespecified analyses: • Macrovascular and microvascular jointly • Macrovascular and microvascular separately * * Combined outcome added in 2005 Lancet 2007;370:829-40

  9. Average BP during follow-up 140.3 mmHg 134.7 mmHg 77.0 mmHg 74.8 mmHg Blood pressure reduction BP = 145/81 mm Hg @ baseline 165 Placebo Perindopril-Indapamide 155 Systolic 145 135 Δ5.6 mmHg (95% CI 5.2-6.0); p<0.001 125 Mean Blood Pressure (mmHg) 115 105 95 85 Diastolic 75 Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001 65 R 6 12 18 24 30 36 42 48 54 60 Follow-up (Months) Lancet 2007;370:829-40

  10. Primary outcomesMajor macro or microvascular event Number of events Per-Ind Placebo Favours Relative risk Favours (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) * Combined macro+micro 861 938 9% (0 to 17) Macrovascular 480 520 8% (-4 to 19) Microvascular 439 477 9% (-4 to 20) 0.5 1.0 2.0 Hazard ratio *2P=0.04 Lancet 2007;370:829-40

  11. Placebo Perindopril-Indapamide All-cause mortality 10 5 Cumulative incidence (%) Relative risk reduction 14%: 95% CI 2-25% p=0.025 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Lancet 2007;370:829-40

  12. UKPDS ADV ADVANCE BP reduction in context:UK Prospective Diabetes Study SBP UK Prospective Diabetes Study

  13. Sponsored by the National Heart, Lung, and Blood Institute

  14. ACCORD: Three Medical Strategy Questions • Glycemia: • Intensive control (HbA1c<6.0%) vs Standard control (HbA1c 7.0%-7.9%) • BP: • Intensive control (SBP <120 mmHg) vs Standard control (SBP <140 mmHg) • Lipids: • Fibrates to increase HDL-C and lower TG + statins to lower LDL-C vs • Statins to lower LDL-C alone Cushman, et al. Am J Cardiol 2007;99:44i-55i

  15. ACCORD Double 2 x 2 Factorial Design Lipid* BP Fibrate vs Placebo Intensive Std Intensive Glycemic Control 1383 1374 1178 1193 5128* Standard Glycemic Control 1370 1391 1184 1178 5123* 2765* 2362* 2371* 10,251 2753* 5518 4733 * Lipid treatment groups blinded until end of trial * Primary analysis compares marginals for main effects

  16. RFP & Funding Main Trial starts Tx continues FU ends Vanguard Phase starts Recruitment ends Results Published ACCORD Timeline

  17. UKPDS ADV ACCORD BP reduction in context of UK Prospective Diabetes Study and ADVANCE ACCORD SBP UK Prospective Diabetes Study

  18. Meta-analysis of Low-dose Diuretics versus Placebo Outcome RR P Diuretics Diuretics better worse CHD 0.79 0.002 Heart failure 0.51 <0.001 Stroke 0.71 <0.001 CVD events 0.76 <0.001 CVD mortality 0.81 0.001 Total mortality 0.90 0.002 0.40 0.65 0.90 1.15 JAMA. 2003;289:2534-2544

  19. Hypertension Treatment by Drug Class Diuretics ß-Blocker ACE Inhibitors ALLHAT ARBs CCBs IMS Health NDTI, 1978-2002

  20. ALLHAT Hypertension Trial 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS (Double-blind) Chlorthalidone 12.5-25 mg Lisinopril 10-40 mg Doxazosin 1-8 mg Amlodipine 2.5-10 mg N=9,061 N=9,054 N=9,048 N=15,255 Blinded drugs titrated and atenolol, clonidine, reserpine, and/or hydralazine added as needed to achieve BP goal: <140/90 mm Hg

  21. ALLHAT Major Outcomes Relative Risks and 95% Confidence Intervals Amlodipine/Chlorthalidone CHD 0.98 (0.90-1.07) All-Cause Mortality 0.96 (0.89-1.02) Stroke 0.93 (0.82-1.06) Combined CVD 1.04 (0.99-1.09) Heart Failure 1.38 (1.25-1.52) ESRD 1.12 (0.89-1.40) 0.50 1 2 Favors Favors Amlodipine Chlorthalidone All subgroups were similar

  22. ALLHAT Major Outcomes Relative Risks and 95% Confidence Intervals Lisinopril/Chlorthalidone CHD 0.99 (0.91-1.08) All-Cause Mortality 1.00 (0.94-1.08) Stroke 1.15 (1.02-1.30) Combined CVD 1.10 (1.05-1.16) Heart Failure 1.19 (1.07-1.31) ESRD 1.11 (0.88-1.38) 0.50 1 2 Favors Favors Lisinopril Chlorthalidone All subgroups were similar, except race

  23. ALLHAT Only Subgroup Differences:Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Stroke Non-Blacks Blacks CHD 1.10 (0.94 - 1.28) 0.94 (0.85 - 1.05) Mortality 1.06 (0.95 - 1.18) 0.97 (0.89 - 1.06) Combined CVD 1.19 (1.09 - 1.30) 1.06 (1.00 - 1.13) Stroke 1.40 (1.17 - 1.68) 1.00 (0.85 - 1.17) Heart Failure 1.32 (1.11 - 1.58) 1.15 (1.01 - 1.30) ESRD 1.29 (0.94 - 1.75) 0.93 (0.67 - 1.30) 0.50 1 2 0.50 1 2 Favors Favors Lisinopril Chlorthalidone Favors Favors Lisinopril Chlorthalidone

  24. ALLHAT .15 .12 .09 Cumulative HF Rate .06 .03 0 0 1 2 3 4 5 6 7 Years to HF Cumulative Event Rates for Heart Failure by Treatment Group Amlodipine Lisinopril Number at risk: Amlodipine 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313 Lisinopril

  25. VALUE: Heart Failure Hospitalisation for HF or Death From HF 9 8 7 6 5 4 3 2 1 0 Valsartan-based regimen Amlodipine-based regimen Proportion of Patients With First Event (%) HR = 0.89; 95% CI = 0.77–1.03; P = 0.12 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Number at risk Valsartan 7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513 Amlodipine 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511 Julius S et al. Lancet. June 2004;363.

  26. ALLHAT .15 .12 .09 Cumulative CHF Rate .06 .03 0 0 1 2 3 4 5 6 7 Years to HF Heart Failure by Treatment Group Chlorthalidone Amlodipine Lisinopril

  27. ALLHAT Event Rates for Heart Failure by Treatment Group for Year 1 .02 Amlodipine Lisinopril Cumulative HF Rate .01 Chlorthalidone 0 0 .5 1 Years to HF Davis, et al. Circulation. 2006;113:2201-10

  28. ALLHAT Events – Lisinopril vs AmlodipineRelative Risk and 95% Confidence Intervals CHD 1.01 (0.91-1.11) Death 1.05 (0.97-1.13) Combined CHD 1.04 (0.97-1.12) Stroke 1.23 (1.08-1.41) p=0.047 Combined CVD 1.06 (1.00-1.12) ESRD 0.99 (0.77-1.26) Cancer 1.01 (0.91-1.12) GI Bleed 1.20 (1.06-1.37) HF 0.87 (0.78-0.96) p=0.045 Angina 1.09 (1.00-1.19) Revascularization 1.00 (0.91-1.11) PAD 1.19 (1.01-1.40) 0.50 1 2 Favors Lisinopril Favors Amlodipine Leenen, et al. Hypertension. 2006;48:374-384

  29. Second Australian National Blood Pressure Study (ANBP-2) • Enalapril/ACEI vs. HCTZ, n = 6,083 • Randomized, open-label (blinded endpoint review) • All CV events or death from any cause • HR = 0.89 (0.79-1.00), p=0.05 • First events • CVD: HR = 0.88 (0.77-1.01), p = 0.07 • CHD: HR = 0.86 (0.70-1.06), p = 0.16 • Stroke: HR = 1.02 (0.78-1.33), p = 0.91 • HF: HR = 0.85 (0.62-1.18), p = 0.33 NEJM 2003;348:583-92

  30. ALLHAT ANBP-2 Design: Randomized double-blind PROBE* Thiazide dose: similar to SHEP unknown Number in 2 arms: 24,309 6,083 On assigned drug @ 5 yrs: ACEI Diuretic ACEI Diuretic 72% 80% 58% 62% BP @ 5 yrs: 135/75 mm Hg 142/79 mm Hg 5-10 times as many CV events in ALLHAT than ANBP-2 * PROBE = prospective randomized open-label, blinded end-points

  31. ASCOT: Design Treatment algorithm to BP targets < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes Open-label n= 19,257 RZ amlodipine 5-10 mg atenolol 50-100 mg add add bendroflumethiazide-K 1.25-2.5 mg perindopril 4-8 mg add Mean BP difference: 2.7/1.9 mm Hg P<0.0001 Primary endpoint: Nonfatal MI + fatal CHD doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone Lancet. 2005;366:895-906

  32. ASCOT-BPLA: Summary of all End Points Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.69 (0.63-0.77) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryNon-fatal MI (exc. Silent) +fatal CHD Total coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure TertiarySilent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol  thiazide better Amlodipine  perindopril better The area of the blue square is proportional to the amount of statistical information Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

  33. ASCOT vs ALLHAT

  34. INVEST Design n=22,576 Calcium Antagonist Strategy Non-Calcium Antagonist Strategy Verapamil sustained release, 240 mg/d, plus trandolapril, 2 mg/d for patients with diabetes, renal impairment, or heart failure* Atenolol, 50 mg/d, Plus Trandolapril, 2 mg/d for Patients with Diabetes, Renal Impairment, or Heart Failure Step 1 Step 2Add Drug Atenolol, 50 mg/d, Plus Hydrochlorothiazide, 25 mg/d Verapamil sustained Release, 240 mg/d, Plus Trandolapril, 2 mg/d Step 3IncreaseDose Verapamil Sustained Release, 180 mg Twice Daily, Plus Trandolapril, 2 mg Twice Daily Atenolol, 50 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg Twice Daily Verapamil Sustained Release, 180 mg Twice Daily, Plus Trandolapril, 2 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg/d Atenolol, 50 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg Twice Daily, Plus Trandolapril, 2 mg/d Step 4Add Drug MaximumTreatment Maximum Tolerated Dose, and/or Add Nonstudy Antihypertensive Medication Maximum Tolerated Dose, and/or Add Nonstudy Antihypertensive Medication Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org

  35. INVEST: Relative Risk of Primary and Secondary Outcomes FavorsCAS FavorsNCAS 0.6 0.8 1.0 1.2 1.4 CAS = Calcium Antagonist StrategyNCAS = Non-Calcium Antagonist Strategy RR (95% CI) Pepine CJ, et al. JAMA. 2003;290:2805-2816.

  36. Are the difference in ASCOT and INVEST results from: • The INVEST population all having known CAD (vs none in ASCOT)? • Atenolol QD (ASCOT) vs BID (INVEST)? • Different calcium channel blockers? • Different thiazide diuretic dose levels added to atenolol? • lower than previous outcome studies (ASCOT) • Similar to previous outcome studies (INVEST)

  37. Placebo b-blocker Diuretic MRC in the Elderly: Effects of Treatment on Coronary Events N = 4396 Diuretic vs β-blocker, P = 0.006 Cumulative % events Interval from entry (years) MRC Working Party. BMJ. 1992;304:405-412

  38. Elliott 2006 Meta-Analysis:Atenolol (b-blocker) vs Other Treatments Elliott WJ. JACC. 2006;47 (Suppl):361A.

  39. 16 14 12 10 8 6 16 16 4 14 14 12 12 10 10 2 8 8 6 6 0 4 4 2 2 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 30 30 30 36 36 36 42 42 42 48 48 48 54 54 54 60 60 60 66 66 66 0 0 LIFE: Cumulative Event Rates n=9,193 Primary Composite Endpoint Fatal/Nonfatal Stroke ARR 13.0%, P=.021 URR 14.6%, P=.009 ARR 24.9%, P=.001 URR 25.8%, P=.0006 16 14 Atenolol Atenolol 12 10 Patients With First Event (%) Losartan 8 Losartan 6 4 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Fatal/nonfatal MI CV Mortality ARR -7.3%, P=NS URR -5.0%, P=NS ARR 11.4%, P=NS URR 13.3%, P=NS Atenolol Losartan Patients With First Event (%) Atenolol Losartan Study Month Study Month ARR=adjusted risk reduction; URR=unadjusted risk reduction Dahlöf et al. Lancet. 2002;359:995-1003

  40. VALUE Hazard Ratios for Pre-specified Analyses HazardRatio Valsartan/Amlodipine Primary cardiac composite endpoint cardiac mortality cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2 Favours valsartan Favours amlodipine Julius S et al. Lancet. 2004;363:2022-2031.

  41. Conclusions • Thiazide-type diuretics should be preferred initial therapy for hypertension, unless there is a compelling indication for another class: • JNC 7: Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes. • VA-DoD CPGs: Thiazide-type diuretics are preferred in patients with uncomplicated hypertension; most compelling indications should include a diuretic.

  42. ALLHATCumulative Percent Controlled (BP <140/90 mm Hg) at Five Years Derived from Cushman et al. J Clin Hypertens. 2002;4:393-404

  43. Initial Combinations of Medications* Diuretics Can add: reserpine, aldosterone antagonist or amiloride, a-blocker, alternative CCB, vasodilator, b-blocker, ab-blocker, and/or central agonist ACE inhibitors or ARBs Calciumantagonists * Compelling indications may modify this.

  44. Questions?

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