Rethinking Lower Blood Pressure Goals for Diabetic Patients with Coronary Artery Disease – Findings from the INternational VErapamil SR – Trandolapril STudy (INVEST)

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

DisclosuresDisclosures

• 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

BackgroundBackground

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

ObjectiveObjective

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

HypothesisHypothesis

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

INVEST Trial DesignINVEST Trial Design

International trial in 22,576 patients with CAD and hypertension

Randomized to multi-drug treatment strategies• v

erapamil 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

MethodsMethods

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 HgTight 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

Results: Flow DiagramResults: Flow Diagram

INVEST22,576

(17,131 US)

Diabetes6,400

(5,077 US)

Tight Control

2,255 (35%)

Usual Control

1,970 (31%)

Not Controlled

2,175 (34%)

INVEST Follow Up16,893 pt years

Extended Follow Up22,700 pt years

Alive2,010

Dead248

Alive1,769

Dead201

Alive1,841

Dead334

Alive, US

1,558 Alive1,188

Dead370

Alive, US

1,423

Dead259

Alive1,164

Alive, US

1,389

Dead270

Alive1,119

39,593 pt yrs

Results: Baseline CharacteristicsResults: Baseline CharacteristicsTight Control

n=2,255Usual Control

n=1,970Not 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) 31 (6)

Beta Blocker Strategy (%) 49 49 52

Women (%) 51 54 59

Race/Ethnicity (%) Caucasian Non-Caucasian

4159

4654

4654

Chronic Angina (%) 72 66 65

Prior MI (%) 36 33 34

Prior Stroke/TIA (%) 8.4 8.5 11

Smoking History (%) 49 45 44

Renal Impairment (%) 3.6 2.4 5.0

Hypercholesterolemia 64 62 61

Results – BP ReductionResults – BP Reduction

No difference comparing the two treatment strategies in terms of BP reduction achieved in any of the groups

Results – Antihypertensive Drug UseResults – Antihypertensive Drug Use

0%

20%

40%

60%

80%

100%

Tight Control Usual Control Not Controlled

0 1 2 3 or more

Mean Number of Study + Nonstudy Antihypertenisve Drugs

Results: Outcome Rates Results: Outcome Rates

INVEST Follow Upn=6400

Tight Controln=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) < 0.0001

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) < 0.0001

Total Stroke 34 (1.5) 33 (1.7) 70 (3.2) 0.0001

All Cause Mortality 248 (11.0) 201 (10.2) 334 (15.4) < 0.0001

Extended Follow Upn=4370

Tight Controln=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

Results: Outcomes During INVEST Results: Outcomes During INVEST

•Tight Control vs Usual Control Log Rank p=0.49Nonfatal MI

•Tight Control vs Usual Control Log Rank p=0.38

Nonfatal Stroke

0 2 4 6 8 10 12

Results: Outcomes – US CohortResults: 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

(n=2,255)

Reference

Results: Outcomes – Tight Control GroupResults: Outcomes – Tight Control Group

Other significant variables in Cox regression model:

age, race, PAD, MI, CHF, US residency, renal impairment, LVH,

TIA/stroke

LimitationsLimitations

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

SummarySummary

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

ConclusionConclusion

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