1. TROPHY TRial Of Preventing HYpertension

2. High-normal BP increases CV risk Vasan RS et al. N Engl J Med. 2001;345:1291-7. Incidence of CV events in women Cumulative incidence (%) and 95% CI High-normal BP 130–139/85–89 mm Hg Normal BP 120–129/80–84 mm Hg Optimal BP <120/<80 mm Hg 10 8 6 4 2 0 02468 12 Time (years) Framingham Heart Study

3. TROPHY: Background Framingham, MRFIT, and other studies indicate that prehypertension is a strong predictor of excessive cardiovascular risk These data illustrate the need to identify and potentially treat patients with prehypertension Hypertension (HTN) is a progressive and self- accelerating condition Vascular abnormalities occur long before the onset of clinical disease Julius S et al. N Engl J Med. 2006;354:1685-97.

4. TROPHY: Study objectives TROPHY evaluated 2 years of treatment with candesartan in individuals with prehypertension* Primary objective: –Determine if the incidence of HTN can be reduced for up to 2 years after discontinuation of active treatment Secondary objective: –Evaluate the incidence of HTN during 2 years of treatment with candesartan or placebo Julius S et al. N Engl J Med. 2006;354:1685-97. *Average BP 130–139/≤89 mm Hg; or ≤139/85–89 mm Hg

5. TROPHY: Study design Julius S et al. N Engl J Med. 2006;354:1685-97. Candesartan 16 mg qd n = 391 Patients with untreated prehypertension Ages 30–65 years N = 772 Placebo n = 381 Placebo Years 3 & 4 Study end points: Development of HTN at years 2 and 4 Randomized Double-blind Years 1 & 2

6. TROPHY: Baseline characteristics Candesartan n = 391 Placebo n = 381 Age (years)48.648.3 Male (%)59.160.1 Race (%) White79.884.3 Black12.38.1 Other7.97.6 BMI (kg/m 2 )29.930.0 N = 772 Julius S et al. N Engl J Med. 2006;354:1685-97.

7. Candesartan n = 391 Placebo n = 381 Blood pressure (mm Hg)133.9/84.8134.1/84.8 Total-C (mg/dL)202.9205.7 Triglycerides (mg/dL)145.8159.8 HDL-C (mg/dL)48.949.2 Glucose (mg/dL)95.595.9 TROPHY: Baseline laboratory values N = 772 Julius S et al. N Engl J Med. 2006;354:1685-97.

8. TROPHY: Reduction in new-onset hypertension  66%*  16%* Candesartan vs PlaceboPlacebo only *Relative risk reduction † P < 0.001; ‡ P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97. † ‡ N = 772

9. TROPHY: Reduction in new-onset hypertension N = 772 Cumulative incidence (%) Julius S et al. N Engl J Med. 2006;354:1685-97. RRR 16% HR = 0.84 (0.75–0.95) P = 0.007 RRR 66% HR = 0.34 (0.25–0.44) P < 0.001 Number of patients without HTN 391 381 356 269 309 184 191 118 Candesartan Placebo 127 85 PlaceboCandesartan 16 mg qd Candesartan vs placebo Placebo only 100 80 60 40 20 0 01234 Study year

10. TROPHY: Blood pressure by treatment group After 2 years: ↓SBP ~10 mm Hg At study end: ↓SBP 2.0 mm Hg (P = 0.037) Julius S et al. N Engl J Med. 2006;354:1685-97. Placebo Candesartan SBP (mm Hg) Difference (mm Hg) 0 0612182430364248 Time (months) 140 130 120 90 30 0 -10 -20 Candesartan vs PlaceboPlacebo only SBP difference

11. TROPHY: Incidence of adverse events Adverse events (AE) Candesartan n = 396 (%) Placebo n = 391 (%) Any serious AE14 (3.5)23 (5.9) Cardiovascular1 (0.3)6 (1.5) Gastrointestinal4 (1.0)2 (0.5) Headache85 (21.5)74 (18.9) Dizziness41 (10.4)33 (8.4) Hypotension4 (1.0)2 (0.5) Angioedema01 (0.3) Julius S et al. N Engl J Med. 2006;354:1685-97.

12. TROPHY: Summary Efficacy –Candesartan significantly delayed new-onset HTN vs placebo: Relative risk reduction: 66% (year 2); 16% (year 4) Absolute reduction of new-onset HTN: 26.8% (year 2); 9.8% (year 4) New-onset HTN at 2 years: 13.6% vs 40.4% Safety –Candesartan was safe and well tolerated –Serious AE rates: 3.5% (candesartan) vs 5.9% (placebo) Julius S et al. N Engl J Med. 2006;354:1685-97.

13. TROPHY: Implications Vascular abnormalities occur long before the onset of clinical disease Aggressive BP-lowering with candesartan can reduce the incidence of HTN in prehypertensive patients at risk for CV disease Julius S et al. N Engl J Med. 2006;354:1685-97.