1. Uncontrolled Hypertension, Systolic and Diastolic Blood Pressure and Development of Symptomatic Peripheral Arterial Disease in the Women’s Health Study (WHS) Tiffany M. Powell, Robert J. Glynn, Mark A. Creager, Paul M. Ridker, Aruna D. Pradhan Harvard Medical School Brigham and Women’s Hospital The authors have no conflicts of interest related to this research.

2. Peripheral Arterial Disease Increasing but under-diagnosed cardiovascular health issue Affects up to 29% of Americans Hypertension linked to PAD development Lacking data on PAD risk prediction related to: – Systolic blood pressure (SBP) – Diastolic blood pressure (DBP) Criqui,M.H. et al. Vasc Med 2001, Murabito,J.M. et al. Am Heart J 2002

3. Uncontrolled Hypertension Up to two-thirds of Americans with hypertension are: – Untreated – Undertreated Control of hypertension to current guidelines reduces coronary artery disease by 57% How does blood pressure and control status relate to PAD risk? Wang,T.J. et al., Circulation 2005

4. Systolic Blood Pressure and Diastolic Blood Pressure Peripheral Arterial Disease Coronary Artery Disease Cerebrovascular Disease Control Status ? ?

5. Women’s Health Study (WHS) Randomized, double-blind, placebo controlled trial of low-dose aspirin and Vitamin E for the primary prevention of cardiovascular disease and cancer 39,876 U.S. female health professionals aged 45 years and older without prior history of CVD Self-reported systolic and diastolic blood pressure categories as well as treatment status obtained at baseline

6. Study Population 39,261 Women with Complete exposure Data 39,876 Women 515 Women Missing Baseline SBP 534 Women Missing Baseline DBP 51 Women Missing History and Treatment of HTN

7. 39,261 Women Free of Symptomatic PAD with Complete Data on Blood Pressure Without HTN N = 30300 Treated and Controlled N = 2679 Untreated and Uncontrolled N = 3494 Undertreated and Uncontrolled N = 2788 Women with HTN Uncontrolled HTN defined as reported SBP > 140 mmHg and/or DBP > 90 mmHg, or on anti- hypertensive therapy

8. PAD Events in WHS Sept 2005 – 482 self-reported cases of symptomatic PAD Symptomatic PAD defined as: – Intermittent claudication based on Edinburgh Claudication Questionnaire – Documented peripheral arterial surgery inclusive of peripheral angioplasty or stenting 116 confirmed cases of PAD

9. Statistical Analysis Continuous BP values assigned using mid-point of reported BP category. Cox Proportional Hazards Regression Hazard Ratios for incident PAD: – According to treatment and BP control status – SBP, DBP, Mean Arterial Pressure (MAP), Pulse Pressure (PP) per 10 mmHg and BP categories Global model fit assessed by model log-likelihood statistics.

10. Models of PAD Risk Multivariate models adjusted for: – Age (logage) – Smoking (never/past/current) – Diabetes (no/yes) – BMI (continuous) – History of Elevated Cholesterol (no/yes cholesterol > 240 mg/dl) – Postmenopausal HT – Randomized treatment assignment with ASA/Vit E

11. Baseline Characteristics No HTN (N=30300) Treated and Controlled (N=2679) Hypertensive (untreated) (N=3494) Hypertensive (undertreated) (N=2788) p-value for Trend Age, yrs 53.8  6.656.7  7.457.2  7.858.2  7.8 <0.0001 BMI, kg/m 2 25.3  4.528.0  5.728.5  5.929.2  6.0 <0.0001 Hyperlipidemia, %7731 (25.5)1203 (44.9)1306 (37.4)1373 (49.3)0.04 Diabetes, %496 (1.6)191 (7.1)182 (5.2)305 (10.9)0.003 Smoker, %4097 (13.4)310 (11.6)447 (12.8)323 (11.6)<0.0001

12. Baseline Characteristics Normotensive (untreated) (N=30300) Normotensive (treated) (N=2679) Hypertensive (untreated) (N=3494) Hypertensive (undertreated) (N=2788) p-value for Trend SBP, mmHg 117.0  12.8129.6  7.2144.9  11.4147.5  9.8 <0.0001 DBP, mmHg 73.8  8.981.7  5.988.0  7.489.2  6.9 <0.0001 MAP, mmHg 88.2  9.297.7  5.3107.0  5.8108.6  5.8 <0.0001 PP, mmHg 43.2  10.047.9  7.556.9  14.258.3  11.7 <0.0001 Values are mean  SD

13. PAD Risk by Treatment and Control Status Hazard Ratio P for trend < 0.0001

14. SBP LRT: 184.23 df : DBP 0 0.5 1.0 1.5 2.0 SBP and DBP 169.61 184.31 PP 177.50 MAP 178.21 PP and MAP 184.31 HR for PAD Per 10 mmHg increase in BP variable 10 10 11 10 10 11 Multivariable HRs According to 10mmHg Increase in BP

15. Categories of Systolic Blood Pressure P for linear trend < 0.0001 Hazard Ratio

16. Categories of Blood Pressure Both Systolic and Diastolic Blood Pressure SBP Categories Age-AdjustedMultivariable-Adjusted <120 mm Hg1.00 (reference) 120 – 139 mm Hg1.66 (0.97–2.84)1.66 (0.95-2.89) 140 – 159 mm Hg2.67 (1.36-5.28)2.73 (1.35-5.51)  160 mm Hg 4.06 (1.35-12.20)3.84 (1.25-11.82) P, linear trend0.0020.003 DBP categories < 75 mm Hg1.00 (reference) 75 – 84 mm Hg0.98 (0.59-1.62)0.96 (0.57-1.61) 85 – 89 mm Hg0.87 (0.46-1.67)0.95 (0.49-1.84)  90 mm Hg 1.10 (0.53-2.28)1.16 (0.55-2.44) P, linear trend0.960.76

17. Limitations Self-reported blood pressure subject to missclassification Findings limited to symptomatic disease Study population exclusively comprised of women

18. Conclusions Uncontrolled hypertension is associated with incident symptomatic PAD in women. While all blood pressure variables assessed were associated with PAD incidence, SBP was the best single predictor in this analysis.

19. Implications These data support a strong prognostic role for systolic blood pressure in the development of PAD in women. Identifies women with uncontrolled hypertension as a high-risk population.

20. Questions ?