1. Rethinking Lower Blood Pressure Goals for Diabetic Patients with Coronary Artery Disease – Findings from the INternational VErapamil SR – Trandolapril STudy (INVEST) Rhonda M. Cooper-DeHoff, Yan Gong, Eileen M. Handberg, Anthony A. Bavry, Scott J. Denardo, George L. Bakris and Carl J. Pepine on behalf of the INVEST Investigators University of Florida Gainesville, FL

2. Disclosures INVEST conduct and analysis was funded by Abbott Laboratories through 12/2008 Cooper-DeHoff: research grant NHLBI (K23HL086558) Handberg: unrestricted educational grants AstraZeneca, AtCor Medical, Daiichi Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and Schering-Plough Bakris: research grants Juvenile Diabetes Research Foundation, Glaxo Smith Kline, Forest Laboratories and CVRx; consultant Glaxo Smith Kline, Merck, Novartis, Boehringer-Ingelheim, Takeda, Abbott Laboratories, Walgreens, Bristol Meyer Squibb/Sanofi, Gilead, Forest Labs and CVRx. Pepine: research grants NHLBI, Baxter, Pfizer, GlaxoSmithKline, and Bioheart, Inc; consultant Abbott Laboratories, Forest Labs, Novartis/Cleveland Clinic, NicOx, Angioblast, Sanofi-Aventis, NIH, Medtelligence, and SLACK Inc; unrestricted educational grants AstraZeneca, AtCor Medical, Daiichi Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and Schering-Plough. Gong, Bavry and Denardo: None

3. Background DIABETIC PATIENTS: current HTN treatment guidelines SBP <130 mm Hg P O S I T I O N S T A T E M E N T there is no threshold value for BP, and risk continues to decrease well into the normal range Evidence supporting SBP <130 mm Hg is lacking, particularly in diabetic patients with CAD Diabetes Care. 2010;33 Suppl 1:S11-61, Hypertension. 2003;42(6):1206-1252, Diabetes Care. 2002;25(1):199-201

4. Objective To determine the effect of level of SBP reduction on adverse CV outcomes in a cohort of patients with diabetes and CAD

5. Hypothesis Diabetic patients who achieved SBP <130 mm Hg would have reduced CV outcomes compared with diabetic patients who achieved SBP 130-<140 mm Hg

6. INVEST Trial Design International trial in 22,576 patients with CAD and hypertension Randomized to multi-drug treatment strategies verapamil SR + trandolapril + HCTZ atenolol + HCTZ + trandolapril Trandolapril recommended for all patients with diabetes Primary Outcome: First occurrence of all- cause mortality, nonfatal MI or nonfatal stroke Secondary Outcomes: All-cause mortality, nonfatal MI, nonfatal stroke, total MI and total stroke Main finding: risk for CV adverse outcomes was equivalent comparing the strategies Pepine et al. JAMA. 2003:290:2805-2816

7. Methods Patients with diabetes at baseline grouped according to mean on-treatment SBP Sep 97- Mar 03 INVEST follow up – Evaluated time to primary and secondary outcomes according to group Apr 03- Nov 08 Extended follow up (US Cohort) - National Death Index search to evaluate long term effect on mortality <130 mm Hg Tight Control 130-<140 mm Hg Usual Control 140 mm Hg Not Controlled Tight Control Further categorized on-treatment SBP in 5 mm Hg segments to evaluate effect of very low SBP

8. Results: Flow Diagram INVEST 22,576 (17,131 US) Diabetes 6,400 (5,077 US) Tight Control 2,255 (35%) Usual Control 1,970 (31%) Not Controlled 2,175 (34%) INVEST Follow Up 16,893 pt years Extended Follow Up 22,700 pt years Alive 2,010 Dead 248 Alive 1,769 Dead 201 Alive 1,841 Dead 334 Alive, US 1,558 Alive 1,188 Dead 370 Alive, US 1,423 Dead 259 Alive 1,164 Alive, US 1,389 Dead 270 Alive 1,119 39,593 pt yrs

9. Results: Baseline Characteristics Tight Control n=2,255 Usual Control n=1,970 Not Controlled n=2,175 Mean age (yr) (SD)65 (9)66 (9)67 (9) Age > 70 yr (%)293236 Mean BMI (kg/m 2 ) (SD)30 (6)31 (6) Beta Blocker Strategy (%)49 52 Women (%)515459 Race/Ethnicity (%) Caucasian Non-Caucasian 41 59 46 54 46 54 Chronic Angina (%)726665 Prior MI (%)363334 Prior Stroke/TIA (%)8.48.511 Smoking History (%)494544 Renal Impairment (%)3.62.45.0 Hypercholesterolemia646261

10. Results – BP Reduction No difference comparing the two treatment strategies in terms of BP reduction achieved in any of the groups

11. Results – Antihypertensive Drug Use Mean Number of Study + Nonstudy Antihypertenisve Drugs

12. Results: Outcome Rates INVEST Follow Up n=6400 Tight Control n=2,255 Usual Control n=1,970 Not Controlled n=2,175 p value Outcome# of Events (Event Rate %) Primary Outcome286 (12.7)249 (12.6)431 (19.8)< 0.0001 Nonfatal MI29 (1.3)33 (1.7)67 (3.1)0.008 Nonfatal Stroke22 (1.0)26 (1.3)52 (2.4)0.001 Total MI108 (4.8)100 (5.0)185 (8.5)< 0.0001 Total Stroke34 (1.5)33 (1.7)70 (3.2)0.0001 All Cause Mortality248 (11.0)201 (10.2)334 (15.4)< 0.0001 Extended Follow Up n=4370 Tight Control n=1,389 Usual Control n=1,423 Not Controlled n=1,558 p value Outcome# of Events (Event Rate %) All Cause Mortality270 (19.4)259 (18.2)370 (23.7)0.01

13. Results: Outcomes During INVEST Tight Control vs Usual Control Log Rank p=0.49 Nonfatal MI Tight Control vs Usual Control Log Rank p=0.38 Nonfatal Stroke

14. 0 2 4 6 8 10 12 Results: Outcomes – US Cohort Adj. HR 1.15, 95% CI 1.01-1.32, p=0.036 Other significant variables in Cox regression model: age, race, PAD, MI, CHF, renal impairment, hyperchol, smoking hx, revasc, TIA/stroke

15. (n=2,255) Reference Results: Outcomes – Tight Control Group Other significant variables in Cox regression model: age, race, PAD, MI, CHF, US residency, renal impairment, LVH, TIA/stroke

16. Limitations Pre-specified secondary analysis, representing observational data from an RCT Patients were not randomized to SBP groups BP during extended follow up unknown Data may not be generalized to all patients with diabetes

17. Summary As expected, diabetic patients with SBP not controlled (140 mm Hg) had the worst outcomes Tight Control (<130 mm Hg) of SBP was not associated with improved CV outcomes compared with Usual Control (130-< 140 mmHg) There was increased risk for mortality in the Tight Control group which persisted during extended follow up SBP <115 mm Hg was associated with an increase in risk for mortality

18. Conclusion Is it time to rethink lower BP goals in patients with diabetes and CAD?

20. Mortality – DBP US Diabetics

21. Mortality – Tight DBP Group Reference Diastolic Blood Pressure (mm Hg)