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

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)

Overall BP Control at 24 Months % Patients BP Goal <140/<90 mmHg --INVEST---- ALLHAT LIFE -- CAS NCAS CAS NCAS CHLOR AML LIS LOS ATEN JNC VI

Time (Months) Diastolic Systolic CAS (n) 11,267 NCAS (n) 11, Blood Pressure Control p = 0.26 p = 0.41 Change in BP (mmHg) Systolic Diastolic 24 Months

CAS BetterNCAS Better CAS NCAS n = n = 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:

Factor# Events /# Pts Event Rate HR p value CHF (Class I, II, III) 302/125624%< Diabetes 913/640014%< US Resident 1999/ %< Renal Insufficiency 114/42427%< Stroke/TIA 322/162920%< Smoker 1242/ %< MI 1012/721814%< PVD 440/269916%< CABG/PCI 877/616614%< Black 352/302912% Age (By Year) < 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:

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

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

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) 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:

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;

SBP and Risk of New Onset Diabetes (Unadjusted) SBP (mm Hg) measured at visit prior to diagnosis Hazard Ratio Cooper-Dehoff Am J Cardiol 2006; 98;

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

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)

Primary Outcome vs Mean Follow-Up SBP Overall Population (N = 22,576) Mean Follow-Up SBP (mm Hg) Total patients (N) Patients with primary outcome (n) >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 < % 14.5% SBP  140 HR (95% CI) 0.58 ( ) Incidence and Risk of Primary Outcome Mean DBP (mm Hg) Meserli Ann Int Med 2006 in press

INVEST Results: Prior MI Subgroup Mean Follow-up SBP (mm Hg) Total patients (N) Patients with primary outcome (n) 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 Incidence (%) >160 to  170 >170 to  180 Mean DBP (mm Hg) Meserli Ann Int Med 2006 in press

PP: Risk for Primary Outcome INVEST Subanalysis: PP and Risk PP (mm Hg) Incidence (%) of Primary Outcome Nadir = 54 mm Hg >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 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 Meserli Ann Int Med 2006 in press

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

SBP and OR for Adverse HRQOL Baseline to 2yr SBP category (1: SBP ≤ 120, 2: mmHg ) O R Baseline6 wk 12 wk18 wk 6 mon 12 mon 18 mon24 mon Gong AHA Sci Ses 2006

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