Center for Clinical Trials Seminar Series Presentation, September 2, 2009

1. Trials of diet and lifestyle modification: Food fights and other battles Lawrence J. Appel, MD, MPH Professor of Medicine, Epidemiology and International Health (Human Nutrition) Johns Hopkins Medical Institutions Sept 2, 2009

8. Stroke Mortality by Level of Usual Systolic BP* *Source: Prospective Studies Collaboration, Lancet, 2002: Meta-analysis of 61 prospective studies with 2.7m person-yrs, 11.9k deaths Definition of Hypertension

9. Blood Pressure Classification (JNC VII) Category Systolic BP Diastolic BP Normal < 120 and < 80 Pre-hypertension 120-139 or 80–89 Hypertension Stage 1 Stage 2 140–159 > 160 or or 90–99 > 100

10. Distribution of BP Levels in US Adults, Ages 18 and Older (NHANESIII) “ Normal” <120/80 Prehypertension SBP 120-39 or DBP 80-89 Hypertension SBP > 140 or DBP > 90 Source: Wang, Hypertension, 2004 42% 27% 31%

11. Prevalence of High Blood Pressure by Age and Race/Ethnicity, Women, Age 18 and Older * Extimate is based on sample size not meeting requirement of NHANES III design or relative standard error is greater than 30 percent. 100 30 20 10 0 Percent 40 Black (excludes Hispanic Blacks) 80 70 60 50 90 White (excludes Hispanic Whites) Mexican American 18-29 2.0* 1.0* 0.6* 30-39 11.3 6.2 4.6* 40-49 30.5 10.6 12.7 50-59 47.9 33.5 36.8 60-69 77.8 59.3 50.9 70-79 72.6 67.0 66.9 80 + 80.5* 71.0* 74.3 Source: Burt V, et al. Hypertension, 1995

12. Mean SBP and DBP by Age and Race/Ethnicity for Women, Age 18 Years and Older 150 140 130 120 110 100 90 80 70 mm Hg 18-29 30-39 40-49 50-59 60-69 70-79 80+ Diastolic Systolic Source: Burt V, et al. Hypertension, 1995 SBP Rise with Age = ~0.6 mmHg per year Age Black White Mexican-American

14. Effects of Population-Based BP Reduction (Shifting SBP Distribution Downward) Stamler R. Hypertension 1991;17:I-16–I-20. % Reduction in Mortality Reduction in BP After Intervention Before Intervention Stroke CHD Total -6 -4 -3 -8 -5 -4 -14 -9 -7 Reduction in SBP mmHg 2 3 5

15. Completed Trials

16. Types of Trials Type of Trial Research Question Examples Feeding Studies Effects of Diet Change on Blood Pressure and Other Risk Factors DASH DASH-Na OmniHeart Behavioral Intervention Studies Feasibility and Effects of Lifestyle Change in Free-Living Individuals TOHP1 TOHP2 TONE PREMIER Wt Loss Maintenance

17. D ietary A pproaches to S top H ypertension

18. DASH Centers Hopkins Pennington Brigham NHLBI Duke CHR

20. Run-in and Intervention Periods 3 wks 8 weeks Run-in Intervention Control Diet Control F & V Combination Randomization

24. The DASH diet

25. Weekly BP by Diet During Intervention Feeding WEEKS B 1 2 3 4 5 6 7,8 DIASTOLIC SYSTOLIC Appel, NEJM 1997;336:1117

26. Effect of DASH Diet by BP Status Hypertensives Non-Hypertensives * † * * * * p< 0.05 (main effect) † p< 0.05 (BP status interaction)

27. The DASH diet: Can it be improved?

29. Participant Flow Period 1 6 weeks Period 2 6 weeks Period 3 6 weeks Randomization to 1 of 6 sequences Washout Period 2–4 wk Washout Period 2-4 wk BP, Lipids: Run-In 6 days Participants Ate Study Food Screening / Baseline Participants Ate Their Own Food

30. Macronutrient Goals, % kcal *Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d CARB* Carbohydrate 58 Protein 15 Fat 27 Monounsaturated 13 Polyunsaturated 8 Saturated 6

31. Macronutrient Goals, % kcal *Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d CARB* PROT Carbohydrate 58 48 Protein 15 25 Fat 27 27 Monounsaturated 13 13 Polyunsaturated 8 8 Saturated 6 6

32. Macronutrient Goals, % kcal *Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d CARB* PROT UNSAT Carbohydrate 58 48 48 Protein 15 25 15 Fat 27 27 37 Monounsaturated 13 13 21 Polyunsaturated 8 8 10 Saturated 6 6 6

33. Systolic Blood Pressure CARB* PROT UNSAT CARB* PROT UNSAT All (n = 164) Baseline mean = 131.2 mmHg Hypertension (n = 32) Baseline mean = 146.5 mmHg p = 0.002 -1.4 -1.3 p = 0.005 -2.9 p = 0.02 -3.5 p = 0.006 * CARB similar to DASH diet Appel, JAMA 2005;294:2455

34. LDL Cholesterol CARB* PROT UNSAT CARB* PROT UNSAT All (n = 161) Baseline mean = 129.2 mg/dL LDL ≥ 130 mg/dL (n = 75) Baseline mean = 156.7 mg/dL p = 0.01 -3.3 +1.5 p = 0.24 -1.5 p = 0.22 -2.1 p = 0.33 +1.7 p = 0.45 -3.9 p = 0.09 * CARB similar to DASH diet

35. Effects of Reducing (Substituting) Carbohydate on BP in Hypertensives 1 He, Ann Int Med, 2005; 2 Appel, JAMA, 2005; 3 Hodgson, AJCN, 2006 Partially Substituting Carbohydrate with: Carb (% kcal) Reduction Net SBP Net DBP Soy Protein 1 -3.7% -7.9 -5.3 Mixed Protein 2 -10% -3.5 -2.4 Lean Red Meat 3 -5.3% -5.2 +0.2 Monounsat Fat 2 -10% -2.9 -1.9

36. Salt Matters

37. Key Studies Supporting the Role of Sodium Reduction as a Means to Lower BP Non-Hypertensives Study Reduce BP DASH-Na Prevent hypertension TOHP 2 Prevent age-related rise in BP INTERSALT Prevent CVD events TOHP 3 Hypertensives Initial therapy DASH-Na Adjunct to drug therapy TONE Substitute for medication TONE

38. Incident Hypertension in TOHP2

39. Percent Reduction in Incident Hypertension over 36-48 Months from Weight Loss and Sodium Reduction Interventions in TOHP2 6 Months 18 Months End of Study * * * * * * * * * P <0.05

40. Control Diet Randomization Run-in: (11-14 days) Intervention (Three 30-day periods, random order) Intermediate Sodium Higher Sodium Lower Sodium Higher Sodium Intermediate Sodium Lower Sodium Study Design Control Diet, N = 204 DASH Diet, N = 208 N = 412

41. Effect of Sodium Level on Systolic Blood Pressure Systolic Blood Pressure Control Diet DASH Diet Higher Intermed Lower Sodium Level (mmol/d) - 6.7 p<.0001 - 3.0 P<.0001 Sacks, NEJM 2001;344:3 (143) (106) (65) - 2.1 - 1.3 - 1.7 - 4.6

42. Systolic Blood Pressure Control Diet DASH Diet Higher Intermed Lower Sodium Level Effect of DASH Diet on Systolic Blood Pressure -2.2 p=.02 -5.0 p=.0003 -5.9 p<0.0001

43. Interactive Effects of Reduced Na and DASH Diet on Systolic BP Systolic Blood Pressure Higher Lower Sodium Level Na Effect in Control Diet = - 6.7 DASH Effect - 5.7 Combined* Effects Actual = - 8.9 Predicted = - 12.4 * P < 0.001, Strict Additivity

44. Effects of Reduced Na on CVD Events: Results from 3 Randomized Trials INTERVENTION OUTCOME FU TONE (2001) 639 Elderly ↓ Na 21% ↓ CVD events 2.3 yrs Taiwan Veterans (2006) 1,981 Elderly ↓ Na /↑ K Salt 41%* ↓ CVD Mortality 2.6 yrs TOHP Follow-up [abs] 3,126 Prehypertensives ↓ Na 30%* ↓ CVD events 10-15 yrs *p<0.05

45. Effects of Reduced Na Intake on CVD: Longterm Results from the Trials of Hypertension Prevention (Cook et al, BMJ, 2007) Adj RR = 0.70 p=0.02

46. Opportunities to Reduce Racial Disparities in BP

47. Effect of Na Reduction (Higher to Lower) in African-Americans and Non-African-Americans on Typical American Diet African-Americans Non-African-Americans - 8.0 † P<.001 - 4.5 † P<.001 - 5.1 P<.001 - 2.2 P<.001 0 † P-interaction < 0.05

48. Effect of DASH Diet By Race African-Americans Non-African-Americans * † * * * * p< 0.05 (main effect) † p< 0.05 (race interaction)

49. Older-aged individuals can make and sustain lifestyle changes that control BP

50. Mean Change in Weight (kg) by Randomized Group in Older-Aged Persons (TONE) 0 9 18 30 Whelton JAMA 1998;279:839.

51. Mean Change in Urinary Sodium Excretion (mmol/24hr) in Older-Aged Persons (TONE) 0 9 18 30 Whelton JAMA 1998;279:839.

53. Design Randomization Primary Outcomes (6 months) End of Intervention (18 months) = Data Visit ADVICE ONLY EST EST + DASH

54. Change in Weight (kg) (Baseline Wt = 97 kg) * * *p<0.001 vs Advice Change in Wt (Kg)

55. Change in Fitness* (Baseline = 130 beats/min) * *p<0.05 vs Advice Change in HR (Beats/min) * Heart Rate (beats/min at Stage 2 of exercise test)

56. Change in Urine Na Excretion (Baseline=170 mmol/24 hr) * * * p < 0.05 vs Advice Change in Urine Na (mmol/24 hr)

57. Fruit and Vegetable Intake (servings/day) * p <.001 EST+ DASH vs Advice + p <.001 EST + DASH vs EST * + Fruit and Veg (serv/day)

58. Saturated Fat Intake (% kcal) ** p <.05 vs Advice * p <.0001 vs Advice + p <.0001 EST+DASH vs EST * + ** Sat Fat Intake (%kcal)

59. Hypertension Prevalence (Among Those with Hypertension at Baseline) + p <.01 vs Advice % with Hypertension + + + +

60. 10-Year Probability of CHD Event RR = 0.89 (0.84-0.94), P <0.001 RR = 0.87 (0.82-0.92), P <0.001

61. 2005 Dietary Guidelines for Americans JNC VII – Hypertension Prevention and Treatment Guidelines 2006 American Heart Association Guidelines

62. Ongoing Trials

64. Design Self-Directed (SD) – comparison group Call-Center Directed (CCD) In-Person Directed (IPD) Randomization Last visits: 24 – 36 m after randomization = Data Collection Points, every 6 months during follow-up

65. Description of Groups Randomized Groups Self-Directed (SD) Call-Center Directed (CCD) In-Person Directed (IPD) Counselor: None Healthways Coach Hopkins Coach Static Website: √ Interactive Web-site: √ √ Sessions: Telephone Only Group Mtgs Individual Telephone PCP Reinforcement √ √

66. CCD and IPD Intervention Goals Weight Goal Minimum 5% weight loss, individually tailored Behaviors Calories 1200 kcal/d if ≤ 170 lb; 1500 kcal/d if > 170 lb and < 220 lb; 1800 kcal/d if > 220 lb and < 270 lb; 2200 kcal/d if > 270 lb Diet DASH diet 7-12 services of fruits/vegetables 2-3 servings of low fat dairy low sodium ≤ 25% of calories from fat Exercise Build to ≥ 180 minutes/wk of moderate intensity physical activity in bouts ≥ 10 minutes in length

70. Lessons and Battles (Food Fights)

78. Costs of Lifestyle Intervention Trials Sample Size Duration of Intervention Total Costs Per Participant Costs POWER 415 2 yr $5.9 m $14.2k

79. Costs of Feeding Studies Sample Size Duration of Feeding Total Costs Per Participant Costs DASH 459 11wk $7.8 m $17k DASH-Sodium 412 14 wk $11.8 m $29k Omni Heart 160 19 wk $6.2 m $39k Omni Carb 160 21 wk $10.3 m $64k

80. Costs of Mass Mailing in Feeding Studies DASH DASH-Sodium OmniHeart # Brochures Sent 115,000 265,000 393,000 # Enrolled from Mass Mailing 90 69 72 Yield/ 10k Brochures 7.8 2.6 1.8 Mailing Costs Per Enrolled $486 $1,459 $2,074 Total Mailing Costs $43,700 $100,700 $149,340

90. MI, CHD Death, or Revascularization (all participants) Stroke Effects of WHI Dietary Modification Intervention on Total CVD and Stroke Time, y HR, 0.97 (95% CI, 0.90-1.06) Comparison Intervention Time, y HR,1.02 (95% CI, 0.90-1.15) Comparison Intervention

91. Comparison of Lipids, Blood Pressure, and Framingham Risk Score Effects of WHI Diet and OMNI-Heart* Diets *OMNI-Heart = Optimal Macronutrient Intake Trial to Prevent Heart Disease Source: Appel LJ, et al. JAMA 2005; 294:2455-64 OMNI-Heart WHI Carb Protein Unsat Fat (yr 3) Total Chol (mg/dl) -3.3 -12.4 -19.9 -15.4 LDL-C -3.6 -11.6 -14.2 -13.1 HDL-C -0.4 -1.4 -2.6 -0.3 Triglycerides 0 0.1 -16.4 -9.3 SBP (mmHg) -0.2 -8.2 -9.5 -9.3 DBP (mmHg) -0.3 -4.1 -5.2 -4.8 Framingham Estimated 10-Yr Risk  3-4%  16%  21%  20%