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Towards an Evidence Based Treatment Strategy in Hypertension

Towards an Evidence Based Treatment Strategy in Hypertension. Tony Woolley M.D. Park Nicollet Clinic Clinical Associate Professor of Medicine, University of Minnesota Woolla@parknicollet.com. My First Lesson In Hypertension. CIRCA 1980, first Internal Med clinical rotation

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Towards an Evidence Based Treatment Strategy in Hypertension

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  1. Towards an Evidence Based Treatment Strategy in Hypertension Tony Woolley M.D. Park Nicollet Clinic Clinical Associate Professor of Medicine, University of Minnesota Woolla@parknicollet.com

  2. My First Lesson In Hypertension CIRCA 1980, first Internal Med clinical rotation Begin Treatment if BP>140/90 Start thiazide diuretic, 50mg qd

  3. Towards an Evidence Based Treatment Strategy in Hypertension What should our goal BP be, especially for special populations ( Diabetes, Renal disease, Coronary disease, other high risk populations)? What medication strategies are best supported by evidence, especially for special populations? How does the gap between clinical practice and clinical evidence grow? ( Analysis of Bias)

  4. Evidence Based PracticeMajor Principles Hierarchy of Evidence Level 1 evidence= Systematic Reviews or Meta-analysis of RCTs or Single high quality RCTs (like ALLHAT or ACCORD) Tempered by Clinical Judgment and Patient Preferences

  5. Evidence Hierarchy More of This And less of This

  6. Towards an Evidence Based Treatment Strategy in Hypertension What should our goal BP be, especially for special populations ( Diabetes, Renal disease, Coronary disease, other high risk populations)?

  7. Current Recommendations for BP Goals JNC 7 (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood) Pressure Goal BP <140/90 Goal with Diabetes or CKD <130/80 JNC 8 Expected Mid 2011 Hypertension. 2003;42:1206

  8. Current Recommendations for BP Goals JNC VII <140/90, in Diabetes or CKD <130/80 AHA/ACC 2007 <130/80 “high risk”;CVD, CKD, DM or Framingham 10 yr risk score >10% ADA DM <130/80 WHO/ISH <140/90, in DM, CVD or CKD <130/80 “seems appropriate” N/DOQI 2004 CKD <130/80 BHS <140/90, <130/80 DM,CVD or CKD ESH-ESC “at least” <130/80 DM, CVD or CKD

  9. Hypertension in Diabetes Guidelines say: Treat to <130/80 ADA Recommends ACE/ARB first

  10. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial NHLBI 10,251 Type 2 diabetics Three Trial arms Glycemic control BP <120 Lipids: Fibrate added to Statin BP arm 4,773 randomized to SBP<120 or <140 www.nejm.org March 14, 2010

  11. Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

  12. Primary & Secondary Outcomes Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40)

  13. Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Total Stroke HR = 0.88 95% CI (0.73-1.06) HR = 0.59 95% CI (0.39-0.89) NNT for 5 years = 89

  14. Adverse Events • † Symptom experienced over past 30 days from HRQL sample of • N=969 participants assessed at 12, 36, and 48 months post-randomization

  15. The ACCORD BP trial evaluated the effect of targeting a SBP goal of 120 mm Hg, compared to a goal of 140 mm Hg, in patients with type 2 diabetes The results provide no conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events in such patients.

  16. INVEST Study International Verapamil-Trandolapril Study Diabetic Subgroup 6400, all with CAD Achieved SBP <130, 130-139, 140+ JAMA July 7,2010;304(1)61-68

  17. Hypertension in Diabetes Guidelines say: Treat to <130/80 Evidence says: No renal or cardiovascular benefit with lower BP ACE/ARB therapy do improve renal outcomes in patients with proteinuria including microalbuminuria New ICSI guideline: <140/85 (consider <130/80 in patients with proteinuria)

  18. Hypertension in Coronary Artery Disease and “High Risk” Groups AHA/ACC Guidelines say: Treat to <130/80 High risk includes any vascular disease, Framingham risk score >10% Evidence Level 5 (Expert Opinion)

  19. Framingham Risk Calculation, Ex. Age: 65 Gender: male Total Cholesterol: 200 mg/dL HDL Cholesterol: 40 mg/dL Smoker: No Systolic Blood Pressure: 140 mm/Hg On medication for HBP:      Yes Risk Score* 19% * The risk score shown was derived on the basis of an equation. Other NCEP materials, such as ATP III print products, use a point-based system to calculate a risk score that approximates the equation-based one. ATP III Executive Summary and ATP III At-a-Glance.

  20. Hypertension in Coronary Artery Disease and “High Risk” Groups No Intent to Treat RCT addresses this Lower Achieved BP has been associated with no benefit or worsened outcomes in post hoc analysis of trials INVEST DM and CAD ONTARGET Vascular disease or DM NEJM 358:1547-1559 I-PRESERVE Diastolic CHF JAMA July 7,2010;304(1)61-68, NEJM 358:1547-1559 N Engl J Med 2008;359:2456–67

  21. Hypertension in Coronary Artery Disease and “High Risk” Groups AHA/ACC Guidelines say: Treat to <130/80 High risk includes any vascular disease, Framingham risk score >10% Evidence says: No renal or cardiovascular benefit demonstrated in this overall group 2010 ICSI guideline: <140/90

  22. Hypertension in the Elderly JNC7 and other Guidelines say: Treat to <140/90 High Risk Conditions: Treat to <130/80

  23. Hypertension in the ElderlyMeta-analysis RCTs in Patients ≥60 years 15 trials n=24,055 Frail elderly excluded from trials Results similar for isolated systolic and BP trials No trials have recruited patients with Isolated Systolic Hypertension and SBP<160 Total CV Morbidity reduced RR .68, ARR 4.3% NNT 23 Total Mortality reduced RR .90 ARR 1.2% Citation: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub2.

  24. Issues in Treatment of the Very Elderly (>80) Oates et al.Journal of the American Geriatrics Society Volume 55, Issue 3, pages 383–388, March 2007 Epidemiologic population studies show better survival with higher BP STOP-2 Worse survival in treated hypertensives with SBP<140

  25. Hypertension in the ElderlyMetaanalysis RCTs in Patients ≥80 years 9 trials n=6,798 Frail elderly excluded from trials Achieved SBP 143-148 Stroke benefit: RR .67 ARR 4% NNT 25 Total Mortality: No benefit RR .97 Citation: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub2.

  26. HYVET Only HTN RCT in Patients ≥80 years N=3850 mean age 83 mean SBP 173 Goal SBP<150, mean achieved SBP =143 Placebo vs perendipril/indapamide 18 month BP separation -15/6 mmHg

  27. HYVET Results

  28. Hypertension in the Elderly JNC7 and other Guidelines say: Treat to <140/90 High Risk Conditions: Treat to <130/80 Evidence Suggests: Initiate Treatment at 160 with SBP goal

  29. Hypertension in CKD Guidelines say: Treat to <130/80 ACE or ARB preferred in patients with proteinuria

  30. Hypertension in CKD Relevant clinical trials MDRD 1994 N=884 pt with GFR 13-55 RCT MAP< 93 vs < 107 (<125/75 vs <140/90) Overall result No benefit in CV or renal outcomes Post hoc Subgroup analysis; 54 pts with >3g/24h proteinuria had renal outcome benefit

  31. Hypertension in CKD Relevant clinical trials: AASK 2002 RCT 1094 African American patients with hypertensive nephropathy assigned to MAP<93 vs 102-107 Achieved BP 130/78 vs 141/86 4 year result no benefit 10 year Cohort followup: No benefit overall Protenuric subgroup 27% reduction in doubling of GFR at 10 years

  32. Hypertension in CKD Guidelines say: Treat to <130/80 Evidence says: No renal or cardiovascular benefit in this overall group Long term renal benefit in patients with proteinuria (>300mg/dl) New ICSI guideline: <140/90, consider <130/80 in patients with proteinuria

  33. Evidence Based Goals <140/90 for almost everybody Perhaps <130/80 in patients with proteinuric renal disease at risk for ESRD Perhaps a bit higher (<150 systolic) in older patients with isolated systolic HTN

  34. The gap between what we know and what we think we know or…How Do We Get It so Wrong? • Theraputic Optimism • The bias that the benefit of treatment exceeds the risk/harm • Authority Bias • Overvaluing the opinions of experts • Influence of Industry • More treatment/diagnosis is usually good for business, and sponsorship of research and education tends to support more rather than less treatment

  35. The gap between what we know and what we think we know • Confirmation Bias • We are much more likely to seek information that confirms rather than refutes what we believe to be true • Forgetting the asymmetry of epidemiology and treatment • In many (?most) instances, correcting a causal risk factor does not fully resolve associated risk

  36. Evidence Hierarchy More of This And less of This

  37. My Latest Lesson In Hypertension CIRCA 2010 Begin Treatment if BP>140/90 Start thiazide , Break it in half

  38. Selected References ICSI Hypertension Guideline 2010 revision http://www.icsi.org/guidelines_and_more/... Treatment Blood Pressure Targets for Hypertension: Cochrane Review 2009 http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD004349/frame. html ACCORD BP Study, March 14 2010 The Effects of Intensive Blood Pressire Control in Type 2 Diabetes Mellitus http://www.nejm.org/doi/pdf/10.1056/NEJMoa1001286 INVEST Diabetes Subgroup Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients with Diabetes and Coronary Artery Disease JAMA, Vol 304, 1, 61-67

  39. Selected References Hypertension in the Very Elderly Trial (HYVET) 2008 N Engl J Med 2008; 358(18):1887-98. Pharmacotherapy of Hypertension in the Elderly: Cochrane Review 2010 http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD000028/frame. html AASK 10 year follow up 2010 Intensive Blood-Pressure Control in Hypertensive Chronic Kidney Disease N Engl J Med 2010; 363:918-929 First Line Drugs for Hypertension: Cochrane Review 2009 http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD001841/frame. html

  40. Additional Slides, Treatment • These will not be discussed in the presentation

  41. Drug Rx for HTN Where is the evidence pointing us?

  42. Drug Rx for HTN JNC 7 Thiazides for most Other First line drugs ACE/ARB Beta Blockers CCB

  43. Cochrane Review, Drugs for HTN 57 trials, n=58,040 Conclusion: Low dose thiazides reduce all morbidity and mortality outcomes. ACEI and Calcium blockers may be similarly effective but the evidence is less robust. Beta blockers and high dose thiazides are inferior to low dose thiazides

  44. Cochrane Review, Drugs for HTN The Cochrane Library 2009, issue 3. http//www.thecochranelibrary.com

  45. ALLHAT .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

  46. ALLHAT Total 0.98 (0.90, 1.07) Total 0.99 (0.91, 1.08) Age <65 0.99 (0.85, 1.16) Age < 65 0.95 (0.81, 1.12) Age>=65 0.97 (0.88, 1.08) Age >= 65 1.01 (0.91, 1.12) Men 0.98 (0.87, 1.09) Men 0.94 (0.85, 1.05) Women 0.99 (0.85, 1.15) Women 1.06 (0.92, 1.23) Black 1.01 (0.86, 1.18) Black 1.10 (0.94, 1.28) Non-Black 0.97 (0.87, 1.08) Non-Black 0.94 (0.85, 1.05) Diabetic 0.99 (0.87, 1.13) Diabetic 1.00 (0.87, 1.14) Non-Diabetic 0.97 (0.86, 1.09) Non-Diabetic 0.99 (0.88, 1.11) 0.50 1 2 0.50 1 2 Amlodipine Better Chlorthalidone Better Lisinopril Better Chlorthalidone Better Nonfatal MI + CHD Death – Subgroup Comparisons – RR (95% CI)

  47. Beta blockers: What Happened to My Atenolol? Meta-analysis of trials comparing beta blockers with other antihypertensivesOutcome RR w/beta blockers95% CI Stroke 1.16 1.04-1.30 MI 1.020 .93-1.12 All-cause mort. 1.030 .99-1.08 Lindholm LH, Carlberg B, and Samuelsson O. Should blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366(9496):1545-1553

  48. Atenolol vs other antihypertensives Lindholm LH, Carlberg B, and Samuelsson O. Should blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366(9496):1545-1553

  49. Beta Blockers Are Now 3rd Line Therapy After diuretic, ACE/ARB, CCB… Benefit in clinical trials demonstrated mainly in combination therapy Appear less effective than other classes at preventing stroke Are less effective in older patients Monotherapy mainly in patients with compelling indications (like angina, post-MI, tachyarrhythmias…)

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