rethinking lower blood pressure goals for diabetic patients with coronary artery disease –...
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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?