AASK about Hypertension- JOURNAL CLUB

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A recent journal club presentation on the AASK trial 2010

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AASK about Hypertension- JOURNAL CLUB

  1. 1. Journal Club 7-October-2010 NSLIJHS/Hofstra University
  2. 2. NKF: K/DOQI <ul><li>Hypertension is both a and a of CKD: </li></ul><ul><ul><li>more than 50% to 75% of patients with CKD have blood pressure >140/90 mm Hg but… </li></ul></ul>cause complication
  3. 3. NKF: K/DOQI <ul><li>Goals of Antihypertensive Therapy: </li></ul><ul><ul><li>Lower Blood Pressure to: </li></ul></ul><ul><ul><ul><li>Reduce the Risk for CVD </li></ul></ul></ul><ul><ul><ul><li>Slow Progression of CKD </li></ul></ul></ul>
  4. 4. BUT, How do we KNOW what the target is???
  5. 5. Current Guidelines <ul><li>JNC 7 (2003) </li></ul>
  6. 6. Where did “130/80” Come From? 130/80
  7. 7. History of Blood Pressure <ul><li>Reverend Stephen Hales </li></ul><ul><ul><li>1711: First History of Blood Pressure Measurement </li></ul></ul><ul><ul><li>Inserted a glass tube into the artery of a horse and watched as the column of blood fluctuated </li></ul></ul><ul><ul><li>The Horse Died Everytime, as the artery used was the carotid artery </li></ul></ul>
  8. 8. History of Blood Pressure <ul><li>1847-1856: First measurement in human </li></ul><ul><ul><li>Faivre, measured during a limb amputation </li></ul></ul><ul><ul><ul><li>(i.e., still not exactly clinically feasible for screening…) </li></ul></ul></ul><ul><li>1855: First Human Non-invasive measurement </li></ul><ul><ul><li>Karl Vierordt used an inflatable cuff with enough pressure to obliterate the arterial pulse </li></ul></ul><ul><ul><li>Tall, bulky machine… </li></ul></ul>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1543468/pdf/procrsmed00089-0065.pdf
  9. 9. History of Blood Pressure <ul><li>1882: Robert Ellis Dudgeon </li></ul><ul><ul><li>Simplified the sphygmograph </li></ul></ul><ul><ul><li>Became standard from the US Navy </li></ul></ul><ul><li>1896: Riva-Rocci </li></ul><ul><ul><li>Developed the standard mercury sphygmomanometer </li></ul></ul><ul><li>1901: Harvey Cushing </li></ul><ul><ul><li>Brought it to the US </li></ul></ul><ul><li>1905: Nikoli Korotkoff </li></ul><ul><ul><li>Identified diastolic blood pressure by ausculatation </li></ul></ul><ul><ul><ul><li>(previously done only by palpation, hence the Korotkoff sounds ) </li></ul></ul></ul>
  10. 10. BP Guidelines <ul><li>From 1905 to Mid-Twentieth Century… </li></ul><ul><ul><li>SBP </li></ul></ul><ul><li>Diastolic Blood Pressure became the “fad”…until JNC 7 came along </li></ul>
  11. 11. Current Guidelines <ul><li>The Urban Legend… </li></ul><ul><ul><li>Is often told that “140/90” was chosen by insurance companies who noticed that people with BP lower than this lived longer than others… </li></ul></ul><ul><ul><li>JNC offers more sound clinical evidence… </li></ul></ul>
  12. 12. JNC-7 Guidelines <ul><li>Age-specific relevance of usual pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. The Lancet 360:9349, Dec 14, 2002; Pages 1903-1913 </li></ul><ul><li>Is THE citation for JNC-7 “Blood Pressure and Cardiovascular Risk” </li></ul>
  13. 13. Age-specific relevance… <ul><li>One million adults </li></ul><ul><li>61 prospective observational studies </li></ul><ul><ul><li>During 12·7 million person-years at risk </li></ul></ul><ul><ul><ul><li>56 000 vascular deaths </li></ul></ul></ul><ul><ul><ul><ul><li>12 000 stroke </li></ul></ul></ul></ul><ul><ul><ul><ul><li>34000 IHD </li></ul></ul></ul></ul><ul><ul><ul><ul><li>10000 “other” vascular </li></ul></ul></ul></ul><ul><ul><ul><li>66 000 other deaths at ages 40–89 years </li></ul></ul></ul><ul><ul><ul><li>Meta-analyses: </li></ul></ul></ul>
  14. 15. Age-Specific Risk… <ul><li>Major Limitation? </li></ul><ul><ul><li>Epidemiologic Observation </li></ul></ul><ul><ul><li>Lack of Therapeutic Intervention </li></ul></ul><ul><li>Early Studies Evaluating Hypertension treatment excluded patients with CKD </li></ul>
  15. 16. ACCORD: Action to Control Cardiovascular Risk in Diabetes blood pressure <ul><li>4377 Patients </li></ul><ul><ul><li>DM 2 + </li></ul></ul><ul><ul><ul><li>CVD, or </li></ul></ul></ul><ul><ul><ul><li>2 additional CV risk factors </li></ul></ul></ul><ul><ul><li>Assigned to either: </li></ul></ul><ul><ul><ul><li>Intensive BP control </li></ul></ul></ul><ul><ul><ul><li>Conventional BP control </li></ul></ul></ul>
  16. 17. ACCORD: Action to Control Cardiovascular Risk in Diabetes blood pressure Intensive BP Control Standard BP Control SBP < 120 mmHg SBP < 140 mmHg Achieved : 119 mmHg 133 mmHg Follow Up: No Difference: All Cause Mortality 4.7 years No Difference: Annual Rate of Nonfatal MI, stroke or death from CVD Decreased risk of total and non-fatal stroke Increased risk anti-hypertensive adverse effects
  17. 18. ACCORD: Action to Control Cardiovascular Risk in Diabetes blood pressure <ul><li>Intensive Control: </li></ul><ul><ul><li>Rx Side Effects: 3.3 vs. 1.3% </li></ul></ul><ul><ul><ul><li>Hypotension </li></ul></ul></ul><ul><ul><ul><li>Syncope </li></ul></ul></ul><ul><ul><ul><li>Bradycardia </li></ul></ul></ul><ul><ul><ul><li>Arrhythmia </li></ul></ul></ul><ul><ul><ul><li>Hyperkalemia </li></ul></ul></ul><ul><ul><ul><li>Angioedema </li></ul></ul></ul><ul><ul><ul><li>Renal Failure </li></ul></ul></ul>
  18. 19. MDRD Trial The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease Saulo Klahr, Andrew S. Levey, Gerald J. Beck, Arlene W. Caggiula, Lawrence Hunsicker, John W. Kusek, and Gary Striker for the Modification of Diet in Renal Disease Study Group N Engl J Med 1994; 330:877-884
  19. 20. MDRD Study <ul><li>Hypothesis: “Lower” BP will decrease the decline in GFR </li></ul><ul><ul><li>Randomized Trial </li></ul></ul><ul><ul><ul><li>840 Patients with CKD </li></ul></ul></ul><ul><ul><ul><li>GFR 25-55 cc/min (Study A) </li></ul></ul></ul><ul><ul><ul><li>GFR 13-24 cc/min (Study B) </li></ul></ul></ul><ul><ul><li>Treatment Goal: </li></ul></ul><ul><ul><ul><li>MAP < 92 mmHg (125/75) or </li></ul></ul></ul><ul><ul><ul><li>MAP < 107 mmHg (140/90) </li></ul></ul></ul>
  20. 21. MDRD Design: Comparison of 2 Groups: “ Usual” BP Control Target MAP <107 mmHg Low BP Control Target MAP <92 mmHg Achieved MAP 96mmHg Achieved MAP 91mmHg 130/80 125/75
  21. 22. Copyright ©2010 American Society of Nephrology
  22. 23. GFR 25-55 cc/min (Study A) GFR 13-24 cc/min (Study B)
  23. 24. Results of MDRD
  24. 25. MDRD: Long Term Follow Up <ul><li>10 years later… </li></ul><ul><ul><li>32% reduction in end-stage renal-disease (ESRD) risk for patients randomized to the low BP arm </li></ul></ul><ul><ul><li>Limitations: </li></ul></ul><ul><ul><ul><li>Lack of blood-pressure measurements for the final seven years </li></ul></ul></ul><ul><ul><ul><li>Higher rate of usage of ACE-I in low BP arm </li></ul></ul></ul>
  25. 26. REIN-2 Study Renoprotection In Patients with Nondiabetic Chronic Renal Disease <ul><li>Renoprotective </li></ul><ul><ul><li>Evaluated effect of BP control in nondiabetic CKD </li></ul></ul><ul><ul><li>Aim: assess the effect of “intense” versus conventional blood-pressure control on progression to end-stage renal disease </li></ul></ul>
  26. 27. REIN-2 <ul><li>Randomized Trial </li></ul><ul><ul><li>338 patients receiving ramipril (2.5-5mg/day) </li></ul></ul><ul><li>Primary Endpoint </li></ul><ul><ul><li>Time to ESRD over 36 months of follow up </li></ul></ul>Conventional Group Goal: DBP<90 mmHg Achieved: 134/82 Intensive Group Goal: <130/80 Achieved: 130/80 Add-On Therapy: Felodipine 5-10mg/day
  27. 28. REIN-2 <ul><li>Reported no decrease in ESRD events </li></ul><ul><ul><li>Concluded: No additional benefit from further blood-pressure reduction by felodipine added to therapy with ACE-I </li></ul></ul><ul><li>Terminated at 19months for “futility” </li></ul>
  28. 29. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Hypothesis: </li></ul><ul><ul><li>Intensive Blood Pressure Control may retard the progression of Chronic Kidney Disease </li></ul></ul>
  29. 30. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Objective: </li></ul><ul><ul><li>To compare the effects of 2 levels of BP control and 3 antihypertensive drug classes of GFR decline in hypertension </li></ul></ul>
  30. 31. AASK: Study Design <ul><li>Patient Population: </li></ul><ul><ul><li>Ages 18-70 years </li></ul></ul><ul><ul><li>Black </li></ul></ul><ul><ul><li>Hypertensive Kidney Disease </li></ul></ul><ul><ul><ul><li>DBP >95 mmHg </li></ul></ul></ul><ul><ul><ul><li>GFR 20-65 mL/min by labeled iothalamate clearance </li></ul></ul></ul>
  31. 32. Exclusion Criteria <ul><li>Diabetes </li></ul><ul><ul><li>Fasting glucose >140 mg/dL </li></ul></ul><ul><ul><li>Random Glucose >200 mg/dL </li></ul></ul><ul><ul><li>Drug therapy for diabetes </li></ul></ul><ul><li>Urinary Tp:Cr > 2.5 </li></ul><ul><li>Malignant Hypertension </li></ul><ul><ul><li>Defined by each center </li></ul></ul><ul><li>“ Serious Systemic Disease” </li></ul><ul><li>Heart Failure </li></ul><ul><li>Specific Indication for, or contraindication to a study drug </li></ul>
  32. 33. Outcomes <ul><li>Primary: Progression of CKD </li></ul><ul><ul><li>Doubling of sCr </li></ul></ul><ul><ul><li>Diagnosis of ESRD </li></ul></ul><ul><ul><ul><ul><li>Initiation of RRT </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Transplant </li></ul></ul></ul></ul><ul><ul><li>Death </li></ul></ul>
  33. 34. Study Design: Two Phases <ul><li>Initial Trial Phase </li></ul><ul><ul><li>1995-1998 </li></ul></ul><ul><ul><li>3 x 2 Design </li></ul></ul><ul><li>Cohort Phase </li></ul><ul><ul><li>April 2002 </li></ul></ul><ul><ul><li>Included Surviving patients without ESRD </li></ul></ul><ul><ul><li>All Switched to Ramipril </li></ul></ul><ul><ul><li>Conventional Control </li></ul></ul><ul><ul><ul><li>140/90 until </li></ul></ul></ul><ul><ul><ul><li>130/80 in 2004 </li></ul></ul></ul>
  34. 35. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Effect of Blood Pressure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease Results From the AASK Trial </li></ul><ul><li>Jackson T. Wright, Jr, MD, PhD; George Bakris, MD; Tom Greene, PhD; Larry Y. Agodoa, MD; Lawrence J. Appel, MD, MPH; Jeanne Charleston, RN; DeAnna Cheek, MD; Janice G. Douglas-Baltimore, MD; Jennifer Gassman, PhD; Richard Glassock, MD; Lee Hebert, MD; Kenneth Jamerson, MD; Julia Lewis, MD; Robert A. Phillips, MD, PhD; Robert D. Toto, MD; John P. Middleton, MD; Stephen G. Rostand, MD; for the African American Study of Kidney Disease and Hypertension Study Group </li></ul><ul><li>JAMA.  2002;288:2421-2431. </li></ul>
  35. 36. Copyright restrictions may apply. Wright, J. T. et al. JAMA 2002;288:2421-2431. Participant Recruitment and Follow-up Flow Diagram 2:2:1 Ratio used for CCB
  36. 37. Initial Phase Feb 1995 – Sept 1998 N = 1094 Intensive Group MAP: 92 mmHg Standard Control Group MAP: 102 - 107 mmHg Ramipril Amlodipine Metoprolol Ramipril Metoprolol Amlodipine Furosemide Doxazosin Clonidine Hydralazine Minoxidil
  37. 38. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Measurements </li></ul><ul><ul><li>Blood Pressure </li></ul></ul><ul><ul><ul><li>3 Consecutive seated BP measurements </li></ul></ul></ul><ul><ul><ul><li>Mean of second two BP recorded </li></ul></ul></ul><ul><ul><li>GFR estimation </li></ul></ul><ul><ul><ul><li>I125 iothalamate </li></ul></ul></ul><ul><ul><ul><ul><li>Twice at baseline </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Once at 3, 6, and Q6 months thereafter </li></ul></ul></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><ul><ul><li>Urinary Tp:Cr Q6months </li></ul></ul></ul>
  38. 39. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Outcome: </li></ul><ul><ul><li>Slope of decline of GFR </li></ul></ul><ul><li>Secondary Composite Outcome: </li></ul><ul><ul><li>Reduction in GFR by 50% </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><ul><li>ESRD </li></ul></ul><ul><ul><li>Death </li></ul></ul>
  39. 40. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Interruptions: </li></ul><ul><ul><li>September 2000: </li></ul></ul><ul><ul><ul><li>Termination of Amlodipine arm of trial </li></ul></ul></ul><ul><ul><ul><li>Data censored after 3 years </li></ul></ul></ul>
  40. 43. Copyright restrictions may apply. Wright, J. T. et al. JAMA 2002;288:2421-2431. Mean Change in Glomerular Filtration Rate by Randomized Group
  41. 46. Copyright restrictions may apply. Wright, J. T. et al. JAMA 2002;288:2421-2431. Mean Change in Glomerular Filtration Rate by Randomized Group for Proteinuria Subgroups
  42. 47. Copyright restrictions may apply. Wright, J. T. et al. JAMA 2002;288:2421-2431. Percentage Changes in Proteinuria by Randomized Group
  43. 48. Trial Phase
  44. 49. AASK: African-American Study of Kidney Disease and Hypertension <ul><li>Cohort Phase </li></ul><ul><ul><li>Published NEJM 2010 </li></ul></ul><ul><ul><li>Follow up of Trial Phase </li></ul></ul><ul><ul><li>Followed patients from </li></ul></ul><ul><ul><ul><li>Transition Phase </li></ul></ul></ul><ul><ul><ul><li>Cohort Phase </li></ul></ul></ul>
  45. 50. Cohort Phase <ul><li>Initiated April 2002 </li></ul><ul><ul><li>Patients who had not progressed to ESRD invited to participate </li></ul></ul><ul><ul><li>All Patients received Ramipril </li></ul></ul><ul><ul><li>Common target BP: </li></ul></ul><ul><ul><ul><li><140/90 from 2002-2004 </li></ul></ul></ul><ul><ul><ul><li><130/80 from 2004 to completion </li></ul></ul></ul>
  46. 51. Cohort Phase <ul><li>Outcomes </li></ul><ul><ul><li>Progression of CKD </li></ul></ul><ul><ul><ul><li>Doubling of creatinine </li></ul></ul></ul><ul><ul><ul><li>ESRD </li></ul></ul></ul><ul><ul><ul><li>Death </li></ul></ul></ul><ul><li>Monitoring </li></ul><ul><ul><li>sCr measured Q6months </li></ul></ul>
  47. 57. Conclusions of AASK: Trial Phase <ul><li>In the comparison of target BP: </li></ul><ul><ul><li>MAP of 102-107 versus <92 mmHg: </li></ul></ul><ul><li>In the comparison of class of antihypertensive: </li></ul>NO Difference in rate of decline of GFR ACE-I may be more effective than B-blockers in slowing GFR decline
  48. 58. However… <ul><li>Average rate of decline of GFR in both BP treatment groups was 2mL/min/year </li></ul>Similar to previous trial of Hypertensive CKD
  49. 59. Cohort Phase Conclusions: <ul><li>After follow up of 8.8-12.2 years: </li></ul>“ Intensive” BP control had no effect on CKD progression There MAY be differential effects on patients with more severe proteinuria
  50. 60. Other Endpoints… <ul><li>???Effect in patients with significant proteinuria </li></ul>
  51. 61. Final Thought… <ul><li>Lower BP goals may be protective in patients with significant proteinuria </li></ul><ul><li>Lower BP targets did not increase adverse effects such as ischemic heart disease or ischemic stroke. </li></ul>

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