1. on behalf of the INVEST Investigators
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, Walgreen’s, 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. DIABETIC PATIENTS: current HTN treatment guidelines
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): , Diabetes Care. 2002;25(1):

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:

7. Methods
Patients with diabetes at baseline grouped according to mean on-treatment SBP
Tight Control
<130 mm Hg
Usual Control
≥130-<140 mm Hg
Not Controlled
≥140 mm Hg
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
Tight Control
Further categorized on-treatment SBP in 5 mm Hg segments to evaluate effect of very low SBP

8. Results: Flow Diagram 39,593 pt yrs Alive 2,010 Dead 248 1,769 201
1,841
334
INVEST
22,576
(17,131 US)
Diabetes
6,400 (5,077 US)
Tight
Control
2,255 (35%)
Usual Control 1,970 (31%)
Alive, US
1,558
Alive
1,188
Dead
370
1,423
259
1,164
1,389
270
1,119
Not Controlled
2,175 (34%)
INVEST Follow Up
16,893 pt years
Extended Follow Up
22,700 pt years
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 (%) 29 32 36
Mean BMI (kg/m2) (SD)
30 (6)
31 (6)
Beta Blocker Strategy (%) 49 52
Women (%) 51 54 59
Race/Ethnicity (%)
Caucasian
Non-Caucasian 41 46
Chronic Angina (%) 72 66 65
Prior MI (%) 33 34
Prior Stroke/TIA (%)
8.4
8.5 11
Smoking History (%) 45 44
Renal Impairment (%)
3.6
2.4
5.0
Hypercholesterolemia 64 62 61

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 Outcome
286 (12.7)
249 (12.6)
431 (19.8)
<
Nonfatal MI
29 (1.3)
33 (1.7)
67 (3.1)
0.008
Nonfatal Stroke
22 (1.0)
26 (1.3)
52 (2.4)
0.001
Total MI
108 (4.8)
100 (5.0)
185 (8.5)
Total Stroke
34 (1.5)
70 (3.2)
0.0001
All Cause Mortality
248 (11.0)
201 (10.2)
334 (15.4)
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 Mortality
270 (19.4)
259 (18.2)
370 (23.7)
0.01

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

14. Results: Outcomes – US Cohort2 4 6 8 10 12
Adj. HR 1.15, 95% CI , p=0.036
Other significant variables in Cox regression model:
age, race, PAD, MI, CHF, renal impairment, hyperchol, smoking hx, revasc, TIA/stroke

15. Results: Outcomes – Tight Control Group
Reference
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?