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. INVEST OVERVIEW 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)

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

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

5. 0.801.21.0 CAS BetterNCAS Better CAS NCAS n = 11267 n = 11309 Outcome No. (%) No. (%) p value First Event1119 (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 Primary and Secondary Outcomes Unadjusted Relative Risk with 95% CI Relative Risk Pepine, JAMA 2003;290:2805-16

6. Factor# Events /# Pts Event Rate HR p value CHF (Class I, II, III) 302/125624%<0.0001 Diabetes 913/640014%<0.0001 US Resident 1999/1713112%<0.0001 Renal Insufficiency 114/42427%<0.0001 Stroke/TIA 322/162920%<0.0001 Smoker 1242/1045412%<0.0001 MI 1012/721814%<0.0001 PVD 440/269916%<0.0001 CABG/PCI 877/616614%<0.0001 Black 352/302912%0.0780 Age (By Year) <0.0001 Hazard Ratio Factors Independently Associated With Increased Risk of the Primary Outcome ( Death, MI or Stroke) Hazard Ratio Estimates From Multivariate Stepwise Model Pepine JACC 2006; 47: 547 - 551

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

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

9. 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 Diabetes1185 (14.63)1313 (16.25) 1.0 0.80 1.2 CAS BetterNCAS Better n= patients without diabetes at baseline Outcomes in Hypertensive CAD Patients Without Diabetes at Baseline Unadjusted Relative Risk with 95% CI Pepine JACC 2006; 47: 547 - 551

10. 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 Increased RiskReduced Risk HR Cooper-Dehoff Am J Cardiol 2006; 98; 890-894

11. SBP and Risk of New Onset Diabetes (Unadjusted) SBP (mm Hg) measured at visit prior to diagnosis 0.5 1.0 1.5 2.0 100110120130140150160170180 Hazard Ratio Cooper-Dehoff Am J Cardiol 2006; 98; 890-894

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

13. -100 -30 -20 -10 0 STOP-2INSIGHTALLHAT % Reduction of New Diabetes ACE-I or ARB CA+ACE-I or ARB CA INVESTALPINESCOPECHARMANBP2LIFEHOPEALLHATCAPPPSTOP-2VALUEPEACEASCOT CV Pharmacotherapy and Newly Diagnosed Diabetes Adapted from Pepine, Cooper-Dehoff JACC 2004;44:509 Randomized active treatment vs. SOC (e.g. β-B+/or diuretic)

14. Primary Outcome vs Mean Follow-Up SBP Overall Population (N = 22,576) Mean Follow-Up SBP (mm Hg) 16633737721668591709234Total patients (N)689 13225343759649319645 Patients with primary outcome (n) 266 57 202 59 >120 to ≤130 >110 to ≤120 ≤110>130 to ≤140 >140 to ≤150 >150 to ≤160 >180>170 to ≤180 >160 to ≤170 Incidence (95% CI)HR INVEST Results: Overall Population SBP <140 8.1% 14.5% SBP  140 HR (95% CI) 0.58 (0.53-0.63) Incidence and Risk of Primary Outcome Mean DBP (mm Hg)76.5 73.267.5 87.784.281.178.790.797.4 Meserli Ann Int Med 2006 in press

15. INVEST Results: Prior MI Subgroup Mean Follow-up SBP (mm Hg) 236541122621712133647112Total patients (N)82 5610818824523710426 Patients with primary outcome (n) 24 70 24 Patients With Prior MI (N = 7218) Primary Outcome vs Mean Follow-Up SBP >120 to  130 >110 to  120 ≤110>130 to  140 >140 to  150 >150 to  160 >180 Incidence (95% CI)Hazard Ratio* Estimated Hazard Ratio 4 3 2 1 0 Incidence (%) 50 40 30 20 10 0 60 >160 to  170 >170 to  180 Mean DBP (mm Hg)76.0 72.467.0 87.783.680.478.189.395.9 Meserli Ann Int Med 2006 in press

16. 12494218873756811137256738151755453240462403 PP: Risk for Primary Outcome INVEST Subanalysis: PP and Risk PP (mm Hg) Incidence (%) of Primary Outcome Nadir = 54 mm Hg 0 1 2 3 4 5 >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 >100 3030 6089439 Total patients Primary Outcome (Death, MI, or stroke) Hazard Ratio Stepwise Cox proportional hazards model to estimate hazard ratio (HR); HR = 1 set at PP=50 mm Hg Estimated Hazard Ratio 40 30 20 10 0 Meserli Ann Int Med 2006 in press

17. INVEST: Predictors of High Depressive Symptoms ( CESD  16) Predictor Std coeff t-statisticp-value Baseline CESD Score0.71227.4<.001 Stroke at baseline0.0652.560.01 Assignment to NCAS0.0552.220.03 Not significant: Age Race Gender Angina Abnormal angiogram Myocardial infarction CABG/PCI Cancer PVD LVH CHF Smoking Reid, D ISOQOL, Prague 11/13/03

18. SBP and OR for Adverse HRQOL Baseline to 2yr SBP category (1: SBP ≤ 120, 2: 120 160 mmHg ) O R Baseline6 wk 12 wk18 wk 6 mon 12 mon 18 mon24 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