STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone

Similar presentations


Presentation on theme: "STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone"— Presentation transcript:

1 STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone
Eva M. Lonn, MD, MSc, FRCPC, FACC Professor of Medicine McMaster University Hamilton, Ontario, Canada

2 Study of Atherosclerosis with Ramipril and Rosiglitazone
STARR Study of Atherosclerosis with Ramipril and Rosiglitazone Eva M. Lonn, Hertzel C. Gerstein, Jackie Bosch, Gilles Dagenais, Rafael Diaz, Patrick Sheridan, Salim Yusuf The STARR Investigators

3 Background and Rationale
Blood pressure and glucose are risk factors for vascular disease and increase the risk for CV events People with prediabetes defined as impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are at increased long-term risk for CVD and frequently exhibit a cluster of cardiometabolic risk factors Dysglycemia Atherogenic lipid abnormalities Hypertension or prehypertension Abdominal obesity Atherogenic lifestyle habits

4 Background and Rationale
ACE-I block the RAAS and decrease the breakdown of bradykinin Lower blood pressure Favourable effects on glucose metabolism Vascular protective effects Decrease inflammation Improve endothelial function Randomized controlled trials reported reduced carotid IMT progression and CV risk reduction in high-risk people with vascular disease and/or diabetes treated with ACE-I Thiazolidinediones bind to PPAR  receptors Increase insulin sensitivity Lower glucose Decrease inflammation Lower blood pressure Improve lipids (HDL, LDL density,  or  TG, FFA)  Adiponectin Improve endothelial function Several previous trials reported reduced rates of carotid IMT progression in people with diabetes treated with TZDs; one small trial in CAD

5 The STARR Trial Objectives Design Eligibility Recruitment Organization
To evaluate the effect of Ramipril 15 mg/day on subclinical vascular disease progression To evaluate the effect of Rosiglitazone 8 mg/day on subclinical vascular disease progression Design Double-blind placebo controlled parallel group RCT 2 x 2 factorial; Substudy of DREAM Average 3 years of follow-up Eligibility Men and women ≥ 30 years with IGT (FPG < 7 and 2 hr PG mmol/L) and/or IFG (FPG= mmol/L); no CVD; no DM; Adequate baseline carotid ultrasound exam Recruitment Organization 1425 subjects from 32 centers in 10 countries Coordination: PHRI, McMaster University, Canada Sponsored by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, GlaxoSmithKline, sanofi-aventis, King Pharmaceuticals Outcome Annualized progression slope of the aggregate carotid intima-media thickness

6 Study Outcomes Primary CIMT Measurement:
Aggregate IMT1 = ∑ Segment Max IMT / Nr. of visualized segments Secondary CIMT Measurement: CCF IMT = ∑ Average CCF IMT/2 Other CIMT Measurements: Single Max IMT = Single Segment Maximum IMT Aggregate IMT2 = ∑ Segment Max IMT CCA+BIF / Nr. of visualized segments

7 Statistical Analysis Sample size Primary Analysis
Double placebo primary CIMT slope = mm/year; SD of the slope=0.025; 30% treatment effect at the margins; no interaction; 5% attrition rate; α=0.05 Amendment:  Sample Size to 1400 (for primary CIMT slope=0.012) Allow baseline CUS to be done up to maximum 6 months post randomization Primary Analysis Population: Participants with ≥ 2 adequate CUS exams after the baseline CUS Annualized slopes of the primary, secondary and other CIMT measurements computed for each participant from all serial CUS data by least-squares regression and compared between treatment groups Confirmatory Analysis Regression analysis using repeated mixed effect linear models with IMT as the dependent variable (fixed effects: treatment, time, time*treatment interaction term; unstructured covariance matrix) Sensitivity Analysis All participants with ≥ 1 CUS after baseline

8 STARR – Study Population
Total Rami Plac Rosi Clinical Eligibility + Adequate Baseline CUS 1425 715 710 709 716 Died Lost to Follow-up 13 7 6 3 4 9 Baseline + ≥ 1 CUS exam Sensitivity Analysis 1347 681 666 670 677 Baseline + ≥ 2 CUS exams Primary Analysis 1256 637 619 621 635

9 STARR: 2 x 2 Factorial Design
N = 1256 subjects with IGT and/or IFG and baseline + ≥ 2 adequate CUS examinations Rosiglitazone N=621 Placebo N=635 Ramipril N= 637 Ramipril Active + Rosiglitazone Active n=316 Ramipril Active + Rosiglitazone Placebo n=321 DREAM: 2 x 2 factorial design Placebo N=619 Rosiglitazone Active + Ramipril Placebo n=305 Rosiglitazone Placebo + Ramipril Placebo n=314 Ramipril: 5 mg/day x 2 months; 10 mg X 10 months; 15 mg after 1 year Rosiglitazone: 4 mg X 2 months; 8 mg thereafter

10 Baseline Characteristics
Active Rami N=637 Plac Rami N=619 Active Rosi N=621 Plac Rosi N=635 Age (yrs) 54.6 ± 10.9 54.5 ± 10.6 54.3 ± 10.7 54.8 ± 10.8 Women 373 (58.6%) 320 (51.7%)* 335 (54.0%) 358 (56.4%) IIGT 383 (60.1%) 378 (61.1%) 374 (60.2%) 387 (60.9%) IIFG 92 (14.4%) 81 (13.1%) 88 (14.2%) 85 (13.4%) IGT+IFG 162 (25.4%) 160 (25.9%) 159 (25.6%) 163 (25.7%) Hypertension 246 (38.6%) 265 (42.8%) 259 (41.7%) 252 (39.7%) Hyperchol. 204 (32.0%) 203 (32.8%) 194 (31.2%) 213 (33.5%) Smoking (curr) 62 (9.7%) 74 (12.0%) 68 (11.0%) Sedentary 190 (29.8%) 182 (29.4%) 178 (28.7%) 194 (30.6%)

11 Baseline Characteristics
Active Rami N=637 Plac Rami N=619 Active Rosi N=621 Plac Rosi N=635 North America 243 (38.2%) 229 (37.0%) 240 (38.7%) 232 (36.5%) South America 187 (29.4%) 182 (29.4%) 183 (29.5%) 186 (29.3%) Europe/Australia 73 (11.4%) 75(12.1%) 68 (11.0%) 80 (12.6%) India 134 (21.0%) 133 (21.5%) 130 (20.9%) 137 (21.6%) ASA/Antiplatelet 76 (11.9%) 65 (10.5%) 76 (12.2%) 65 (10.2%) Statin 57 (9.0%) 75 (12.1%) 71 (11.4%) 61 (9.6%) Fibrate 14 (2.2%) 13 (2.1%) 17 (2.7%) 10 (1.6%) Thiazide diuretic 66 (10.6%) Beta-blocker 106 (16.6%) 102 (16.5%) 109 (17.6%) 99 (15.6%) CaChannel Blocker 55 (8.6%) 58 (9.3%) ARB 42 (6.8%) 33 (5.2%)

12 Baseline Characteristics
Active Rami N=637 Plac Rami N=619 Active Rosi N=621 Plac Rosi N=635 BMI (kg /m2) 30.0 ± 5.1 30.4 ± 5.5 30.5 ± 5.4 30.0 ± 5.2 WHR (M) 0.96 ± 0.07 0.96 ± 0.06 0.97 ± 0.07 WHR (F) 0.86 ± 0.07 SBP (mmHg) 134.5 ± 19.1 135.5 ± 19.1 134.7 ± 18.5 135.3 ± 19.7 DBP (mmHg) 81.5 ± 11.3 82.1 ± 11.7 81.8 ± 11.3 81.7 ± 11.7 ABI 1.2 ± 0.2 FPG (mmol/L) 5.75 ± 0.7 5.77 ± 0.7 2 Hr PG (mmol/L) 8.68 ± 1.4 8.77 ± 1.4 8.72 ± 1.3 8.72 ± 1.4 LVH on ECG 25 (3.9%) 26 (4.2%) 21 (3.4%) 30 (4.7%)

13 Baseline CIMT Univariate Associations with Aggregate IMT1:
CIMT (mm) Ramipril (n=637) Rami Placebo (n=619) Rosiglitazone (n=621) Rosi Placebo (n=635) Aggregate IMT1 0.75 ± 0.19 0.76 ± 0.19 0.75 ± 0.20 0.76 ±0.19 CCF IMT 0.66 ± 0.16 0.67 ± 0.16 Single Max IMT 1.23 ± 0.53 1.25 ± 0.54 1.23 ± 0.52 1.25 ± 0.55 Aggregate IMT2 0.78 ± 0.19 0.79 ±0.19 0.79 ± 0.20 Univariate Associations with Aggregate IMT1: Age (p<0.0001) Sex (p<0.0001) Systolic BP (p<0.0001) Diastolic BP (p<0.0001) FPG (p<0.0001) Region (p<0.0001)

14 Ramipril: Adherence/Adverse Effects
Placebo On Study Drug at 1 year 94.0% 95.5% at 2 years 90.7% 93.0% at 3 years at Final visit Non – Study ACE-I at Final Visit 83.9% 83.6% 1.3% 91.9% 88.6% 3.6% Reasons for Stopping Study Drug Participant Refusal 6.3% 6.5% MD advice 1.7% 1.9% Cough 7.4% 1.6% Fatigue 1.3 % 0.3% Hypotension 1.1% 0.5% UPDATED SEPT Note – Ps/JP given groupings for compliance as individual list indicates categories are not grouped. Updated Sept 6/06

15 Ramipril Effect on Blood Pressure
Systolic BP (mmHg) Mean Final Systolic BP (mmHg) Ramipril Placebo p 126.1± ± <0.0001 Placebo Ramipril Diastolic BP (mmHg) Mean Final Diastolic BP (mmHg) Ramipril Placebo p 75.5 ± ±11.1 <0.0001 Placebo Ramipril

16 Ramipril Effect on Glucose
Fasting PG (mM) 2 Hour PG (mM) Placebo Placebo Ramipril Ramipril UPDATED SEPT Mean Final Ramipril Placebo p Fasting PG (mmol/L) 5.80 ± 1.0 5.88 ± 1.2 0.26 2 Hr PG (mmol/L) 7.37 ± 2.3 7.59 ± 2.7 0.24

17 Ramipril Effect on Carotid IMT
Primary Analysis IMT Slope (mm/year) Ramipril (n=637) Mean ± SE Placebo (n=619) p Aggregate IMT1* ± ± 0.45 CCF IMT ± ± 0.36 Single Max IMT ± ) ± 0.38 Aggregate IMT2 ± ± 0.66 *No significant interaction between ramipril and rosiglitazone (p=0.28) Multivariate Adjusted Analysis: No significant treatment effects Confirmatory Analysis: No significant treatment effects Sensitivity Analysis: No significant treatment effects

18 Ramipril Effect on Carotid IMT
Primary Analysis Confirmatory Analysis Aggregate IMT1 Slope Year IMT(mm) 0.72 0.74 0.76 0.78 0.8 1 2 3 4 5 Aggregate IMT1 Progression 0.012 p=0.45 p=0.37 0.010 0.008 Placebo mm/year 0.006 Ramipril 0.004 0.002 Ramipril Placebo

19 Rosiglitazone Adherence/Adverse Effects
Placebo On Study Drug at 1 year 95.8% 97.5% at 2 years 94.5% 94.8% at 3 years at Final Visit Non study TZD at Final Visit 89.0% 87.7% 91.2% 89.9% 0.3% Reasons for Stopping Study Drug Participant Refusal 7.1% 6.8% Edema 1.8% 1.3% MD advice 1.9% 1.5% Weight Gain 0.9% MD Advice 1.1% UPDATED SEPT Note – Ps/JP given groupings for compliance as individual list indicates categories are not grouped. Updated Sept 6/06

20 Rosiglitazone Effect on Blood Pressure
Systolic BP (mmHg) Mean Final Systolic BP (mmHg) Rosiglitazone Placebo p 128.4 ± ± Placebo Rosiglitazone Diastolic BP (mmHg) Mean Final Diastolic BP (mmHg) Rosiglitazone Placebo p 76.7 ± ± Placebo Rosiglitazone

21 Rosiglitazone Effect on Glucose
Fasting PG (mM) 2 Hour PG (mM) Placebo Placebo Rosiglitazone Rosiglitazone UPDATED SEPT Mean Final Ramipril Placebo p Fasting PG (mmol/L) 5.66 ± 1.1 6.01 ± <0.0001 2 Hr PG (mmol/L) 7.04 ± 2.5 8.00 ± <0.0001

22 Rosiglitazone Effect on Carotid IMT
Primary Analysis CIMT Slope (mm/year) Rosiglitazone (n=621) Placebo (n=635) p Aggregate IMT1 ± ± 0.1747 CCF IMT ± ± 0.0171 Single Max IMT ± ± 0.2772 Aggregate IMT2 ± ± 0.0296 All additional analyses including the confirmatory analysis (mixed models), the sensitivity analysis (in 1347 subjects) and multivariate adjusted analyses showed similar results – trend toward lower CIMT progression with rosiglitazone compared to placebo for the primary measurement (Aggregate IMT1 ) and significant reduction in CIMT progression for the secondary measurement (CCF IMT) and for the Aggregate IMT2 progression

23 Rosiglitazone Effect on Carotid IMT
Primary Analysis Primary Outcome Secondary Outcome Rosiglitazone Placebo 0.002 0.004 0.006 0.008 0.010 0.012 Aggregate IMT1 Slope mm/year CCF IMT Slope 0.008 p=0.017 p=0.174 0.006 mm/year 0.004 0.002 Rosiglitazone Placebo Difference Active-Placebo (mm/year): ± ±

24 Rosiglitazine Effect on Carotid IMT
Confirmatory Analysis Primary CIMT Measurement Secondary CIMT Measurement Aggregate IMT1 Progression CCF IMT Progression 0.8 p=0.08 0.7 p=0.01 Placebo Placebo 0.78 0.68 IMT (mm) IMT (mm) 0.76 0.66 Rosiglitazone Rosiglitazone 0.74 0.64 0.72 0.62 1 2 3 4 5 1 2 3 4 5 Year Difference Active-Placebo: ± ± Year

25 Rosiglitazone Subgroup Analysis
Mean Primary CIMT Slope Difference: Active-Placebo p - interaction 0.36 0.76 0.44 0.59 Age<=54 (n=646) Age>54 (n=610) Women (n=693) Men (n=563) North America (n=472) South America (n=369) Europe/Australia (n=148) India (n=267) Baseline CUS at: Randomization (n=460) Within 3 months from Rand (n=337) 3-6 months from Rand (n=459) -0.014 0.0 0.010

26 Cardiovascular Events
Rami Plac Rosi Major CV Events 10 11 12 9 CV Death 1 MI Stroke New Angina 7 6 Revasc 4 CHF 2 Low Short-term CV Risk

27 Conclusions STARR is the largest RCT of the effects of ACE-I and TZD on carotid IMT Participants with prediabetes without CVD and generally well controlled CV risk factors Low short-term risk for CV events Slow rates of subclinical vascular disease progression Ramipril 15 mg/day was well tolerated, lowered BP by 5.5/2.7 mmHg and resulted in modest trends towards improved glycemia, but had no significant effect on carotid IMT Study population Asymptomatic subjects without over-activated RAAS Low carotid IMT progression - study power

28 Conclusions The results of STARR for the ramipril arm are consistent within the trial and are also in general consistent with previous studies The findings of STARR do not challenge the role of ACE-I in higher risk populations, such as people with CVD, diabetes or uncontrolled hypertension

29 Conclusions Rosiglitazone 8 mg/day was well tolerated, lowered FPG by 0.4 (7.2 mg/dl) mmol/L, 2 hr PG by 1.0 mmol/L (18.0 mg/dl) and BP by 1.1/1.1 mmHg Rosiglitazone - trend towards lower carotid IMT progression for the primary CIMT measurement and significant reductions in the secondary carotid IMT measurement and the additional aggregate carotid IMT measurement Results for rosiglitazone were consistent within the trial and are also consistent with previous studies of TZDs on carotid IMT in people with diabetes Further trials of the long-term effects of TZDs on CV events are warranted

30 Question & Answer


Download ppt "STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone"

Similar presentations


Ads by Google