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Carl J. Pepine, MD, MACC Division of Cardiovascular Medicine

Morbidity and Mortality in Contemporary CAD Patients With Hypertension Treated With Either a Verapamil/Trandolapril or Beta-Blocker/Diuretic Strategy (INVEST): Main Outcomes, Predictors of Risk, Diabetes, New Diabetes, BP and Depression/QoL Sub-analyses.

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Carl J. Pepine, MD, MACC Division of Cardiovascular Medicine

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  1. Morbidity and Mortality in Contemporary CAD Patients With Hypertension Treated With Either a Verapamil/Trandolapril or Beta-Blocker/Diuretic Strategy (INVEST): Main Outcomes, Predictors of Risk, Diabetes, New Diabetes, BP and Depression/QoL Sub-analyses Carl J. Pepine, MD, MACC Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, Florida

  2. Background Limited data on optimal care of hypertensive CAD patients Design PROBE assessing outcomes (e.g. death, MI, stroke) in hypertensive CAD patients treated w/ either a calcium antagonist (verapamil SR) or noncalcium antagonist (atenolol) -based strategy with addition of trandolapril and/or HTCZ to both strategies for BP control Hypothesis Treatment strategies are equivalent BP Goals <140/<90 or <130/<85 for diabetes and renal dysfunction Recruitment Characteristics Conducted in 862 Sites in 14 Countries in 3 geographic regions Recruitment from 9/97-12/00; 22,576 patients Follow-up complete in 2/03; 61,643 patient years (mean 2.7y/pt) INVEST OVERVIEW

  3. CAS NCAS CAS NCAS CHLOR AML LIS LOS ATEN Overall BP Control at 24 Months --INVEST-- -- ALLHAT-- -- LIFE-- 80 72 71 70 63 63 61 57 60 54 % Patients 48 50 45 40 30 20 10 0 JNC VI <140/<90 mmHg BP Goal

  4. Blood Pressure Control Systolic 24 Months Diastolic Systolic Diastolic Change in BP (mmHg) p = 0.26 8594 7738 7119 8558 8639 7758 7842 5721 3659 8676 7726 7148 8573 8694 7710 7850 5834 3679 CAS (n) 11,267 NCAS (n) 11,309 Time (Months) p = 0.41

  5. Primary and Secondary Outcomes CAS NCAS n = 11267 n = 11309 Outcome No. (%) No. (%) p value First Event 1119 (9.93) 1150 (10.17) 0.57 Death 873 (7.75) 893 (7.90) 0.72 Nonfatal MI 151 (1.34) 153 (1.35) 0.95 Nonfatal Stroke 131 (1.16) 148 (1.31) 0.33 CV Death 431 (3.83) 431 (3.81) 0.68 CV Hospitalization 726 (6.44) 709 (6.27) 0.35 0.80 1.0 1.2 CAS Better NCAS Better Unadjusted Relative Risk with 95% CI Relative Risk Pepine, JAMA 2003;290:2805-16

  6. Factors Independently Associated With Increased Risk of the Primary Outcome (Death, MI or Stroke) Hazard Ratio Estimates From Multivariate Stepwise Model Hazard Ratio Pepine JACC 2006; 47: 547 - 551

  7. HR Reduced Risk Increased Risk Risk of Primary Outcome (Death, MI or Stroke) : High-Risk Subgroups and SBP Achieved on TreatmentPepine JACC 2006; 47: 547 - 551

  8. Risk of Death, MI or Stroke by Selected Doses of Added Therapy: Effect of ACEI and HCTZ 0 0 2 2 4 4 0 0 12.5 12.5 25 25 4/25 4/25 Strategy Added Therapy/ Dose Trandolapril (mg) CAS NCAS HCTZ (mg) CAS NCAS Trand/HCTZ (mg) CAS NCAS Reduced Risk Increased Risk Pepine JACC 2006; 47: 547 - 551

  9. 1.0 1.2 0.80 CAS Better NCAS Better Outcomes in Hypertensive CAD Patients Without Diabetes at Baseline Unadjusted Relative Risk with 95% CI CAS NCAS n = 8101 n = 8082 Outcome No. (%) No. (%) New-Onset Diabetes 569 (7.03) 665 (8.23) Death or New-Onset Diabetes 1050 (12.97) 1177 (14.57) Primary Event or New Onset Diabetes 1185 (14.63) 1313 (16.25) n= patients without diabetes at baseline Pepine JACC 2006; 47: 547 - 551

  10. HR Reduced Risk Increased Risk Predictors of Risk for New Diabetes Multivariate Analysis Factors not contributing to increased risk: Asian race; renal impairment; CHF; PVD; gender, black race; age; smoking; prior MI Cooper-Dehoff Am J Cardiol 2006; 98; 890-894

  11. 2.0 1.5 Hazard Ratio 1.0 0.5 100 110 120 130 140 150 160 170 180 SBP (mm Hg) measured at visit prior to diagnosis SBP and Risk of New Onset Diabetes (Unadjusted) Cooper-Dehoff Am J Cardiol 2006; 98; 890-894

  12. 0 0 2 2 4 4 0 0 12.5 12.5 25 25 4/25 4/25 Risk of New Onset Diabetes by Selected Doses of Added Therapy: Effect of ACEI and HCTZ Strategy Added Therapy/ Dose Trandolapril (mg) Verapamil SR Atenolol HCTZ (mg) Verapamil SR Atenolol Trand/HCTZ (mg) Verapamil SR Atenolol HR Reduced Risk Increased Risk Cooper-Dehoff Am J Cardiol 2006; 98; 890-894

  13. CV Pharmacotherapy and Newly Diagnosed Diabetes CAPPP STOP-2 HOPE ALLHAT ANBP2 LIFE SCOPE CHARM VALUE PEACE INVEST ALPINE ASCOT STOP-2 INSIGHT ALLHAT 0 -10 -20 % Reduction of New Diabetes -30 -100 ACE-I or ARB CA+ACE-I or ARB CA Adapted from Pepine, Cooper-Dehoff JACC 2004;44:509 Randomized active treatment vs. SOC (e.g. β-B+/or diuretic)

  14. SBP <140 SBP 140 HR (95% CI) Incidence and Risk of Primary Outcome 8.1% 14.5% 0.58 (0.53-0.63) Incidence (95% CI) HR ≤110 >110 to ≤120 >120 to ≤130 >130 to ≤140 >140 to ≤150 >150 to ≤160 >160 to ≤170 >170 to ≤180 >180 Patients with primary outcome (n) 57 59 45 196 493 596 437 253 132 266 202 Total patients (N) 234 1709 6859 7216 3737 1663 689 INVEST Results: Overall Population Primary Outcome vs Mean Follow-Up SBP Overall Population (N = 22,576) Mean Follow-Up SBP (mm Hg) 67.5 73.2 Mean DBP (mm Hg) 76.5 78.7 81.1 84.2 87.7 90.7 97.4 Meserli Ann Int Med 2006 in press

  15. 4 3 Estimated Hazard Ratio 2 1 0 INVEST Results: Prior MI Subgroup Primary Outcome vs Mean Follow-Up SBP Patients With Prior MI (N = 7218) 60 Incidence (95% CI) Hazard Ratio* 50 40 Incidence (%) 30 20 10 0 ≤110 >110 to 120 >120 to 130 >130 to 140 >140 to 150 >150 to 160 >160 to 170 >170 to 180 >180 Mean Follow-up SBP (mm Hg) Patients with primary outcome (n) 26 104 237 245 188 108 56 24 24 Total patients (N) 112 647 2133 2171 1226 541 236 82 70 67.0 72.4 Mean DBP (mm Hg) 76.0 78.1 80.4 83.6 87.7 89.3 95.9 Meserli Ann Int Med 2006 in press

  16. 5 Primary Outcome(Death, MI, or stroke) Hazard Ratio 4 3 2 1 0 30 >100 >30 to 35 >35 to 40 >40 to 45 >45 to 50 >50 to 55 >55 to 60 >60 to 65 >65 to 70 >70 to 75 >75 to 80 >80 to 85 >85 to 90 >90 to 95 >95 to 100 INVEST Subanalysis: PP and Risk PP: Risk for Primary Outcome Nadir = 54 mm Hg 40 30 20 Estimated Hazard Ratio Incidence (%) of Primary Outcome 10 0 PP (mm Hg) Total patients 39 94 608 2403 4046 4532 3815 2567 1755 1137 681 375 218 124 87 94 Stepwise Cox proportional hazards model to estimate hazard ratio (HR); HR = 1 set at PP=50 mm Hg Meserli Ann Int Med 2006 in press

  17. INVEST: Predictors of High Depressive Symptoms (CESD  16) Reid, D ISOQOL, Prague 11/13/03

  18. OR • SBP category (1: SBP ≤ 120, 2: 120 < SBP ≤ 130, 3: 130 < SBP ≤ 140, 4: 140 < SBP ≤ 150, 5: 150 < SBP ≤ 160, 6: >160 mmHg ) SBP and OR for Adverse HRQOLBaseline to 2yr 12 wk 18 wk Baseline 6 wk 6 mon 18 mon 24 mon 12 mon Gong AHA Sci Ses 2006

  19. Treatment strategies are equivalent in preventing death, MI or stroke and controlling blood pressure “Strategy concept” requires multiple drugs (trandolapril plus/minus HCTZ) in most patients to achieve JNC VI BP goals Prevention of death and diabetes as well as depression by the calcium antagonist strategy could have important public health implications Summary and Conclusions

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