DECLARATION OF CONFLICT OF INTEREST. Nothing to disclose

DECLARATION OF CONFLICT OF INTEREST Nothing to disclose

Four-Year Clinical Outcomes of the OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis; evaluation by IntraVascular UltraSound ) trial; - OLIVUS Extended - Atsushi Hirohata, Keizo Yamamoto, Yoshihiro Imai, Keitaro Senoh, Eiki Hirose, Yuhei Kobayashi, Hiroya Takafuji, Fumihiko Sano, Minako Ohara, Keisuke Ohkawa, Yuko Toyama, Kazumasa Nosaka, Junji Yoshida, Yuzuru Iino and Tohru Ohe, Japan

Atsushi Hirohata Keizo Yamamoto Toru Miyoshi Kunihiko Hatanaka Yoshihiro Imai Keitaro Senoh Yuhei Kobayashi Hiroya Takafuji Eiki Hirose Fumihiko Sano Keisuke Ohkawa Yuko Toyama Yuzuru Iino Kazumasa Nosaka Junji Yoshida Tohru Ohe

Background (1) Extensive cardiovascular disease is the major cause of morbidity and mortality in patients with ischemic heart disease. Optimal plaque management is a key strategy for preventing subsequent cardiovascular events. The OLIVUS trial, using serial volumetric IVUS, reported a positive role in achieving lower rated of coronary atheroma progression through the administration of Olmesartan, an ARB, for stable angina patients requiring percutaneous coronary intervention (PCI) 1). Hirohata A,et al.:j Am Coll Cardiol 2010;55(10):976-982

Background (2) However, the direct benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear.

Purpose OLIVUS Extended; To examine the 4-year clinical outcomes from OLIVUS trial according to treatment strategy with Olmesartan.

OLIVUS; Methods Prospective, randomized, multicenter trial Two hundreds forty-seven stable angina pectoris patients with hypertension undergoing percutaneous coronary intervention (PCI) were selected. After PCI for their culprit lesions, intravascular ultrasound (IVUS) was performed in their non-culprit vessels (without angiographically documented coronary stenosis [<50%]) to determine atheroma volume at baseline.

247 patients randomized Baseline PCI, IVUS Control (n=121) Olmesartan (10-40mg, n=126) β-blockers, CCB glycemic control agents OLIVUS trial -12-16months CAG, IVUS - MACCE statins 102 completed serial IVUS 103 completed serial IVUS 48months Clinical Follow-up OLIVUS Extended: Major adverse cerebro- and cardiovascular events during 4-years

Changes in Atheroma Volume ( Baseline 14-months, OLIVUS Primary Endpoint ) Control (%) (%) 10 P =0.016 P =0.038 5 Olmesartan 5.4 * (2.4 to 8.5) 3.1 * (0.7 to 5.6) 0.6 (-1.9 to 3.1) 0 0-0.7 (-3.4 to 2.0) -10 Atheroma Volume -5 Percent Atheroma Volume ( * p<0.05 from baseline to follow-up) Hirohata A,et al.:j Am Coll Cardiol 2010;55(10):976-982

247 patients randomized Baseline PCI, IVUS Control (n=121) Olmesartan (10-40mg, n=126) β-blockers, CCB glycemic control agents OLIVUS trial -12-16months CAG, IVUS - MACCE statins 102 completed serial IVUS 103 completed serial IVUS 48months Clinical Follow-up OLIVUS Extended: Major adverse cerebro- and cardiovascular events during 4-years (233/247=93%)

OLIVUS Extended; Major Adverse Cerebro and Cardiovascular Event (MACCE) Death from cardiac or cerebral causes Myocardial infarction Stroke (neurologic deficit confirmed by CT or MRI) Unstable or progressive angina (according to the Braunwald unstable angina classification and the CCS angina classification) Deterioration of heart function or renal failure

Baseline Patient Characteristics Control (n=121) Olmesartan (n=126) P-value Male (%) 68 76 NS Age(years) 68.4 ± 8.8 67.8 ± 8.7 NS Smoking (%) 31 34 NS Diabetes (%) 35 31 NS Oral Diabetic Agents (%) 17 20 NS Insulin (%) 7.1 5.6 NS History of Coronary Artery Disease (%) 13 15 NS Anti-hypertensive Agents (%) 39 40 NS β-blocker (%) 13 13 NS Calcium Channel Blockers (%) 50 41 NS Statins (%) 74 71 NS

Blood parameters at Baseline and 4-years follow-up Baseline Follow-up Control Olmesartan P- value Control Olmesartan P- value Total cholesterol(mg/dl) 185.9±34.3 183.3±29.6 0.554 183.8±37.0 181.4±30.4 0.941 HDL-C(mg/dl) 50.4±12.6 * 47.1±12.7 * 0.073 56.1±15.2 * 52.6±13.3 * 0.084 Triglyceride(mg/dl) 142.4±64.6 163.9±126.4 0.131 140.4±73.9 158.7±81.0 0.093 LDL-C(mg/dl) 108.0±30.2 106.8±24.8 0.405 101.7±30.8 101.2±26.2 0.915 Body Mass Index (kg/m2) 23.9±3.5 24.7±3.2 0.091 23.7±3.0 24.3±4.3 0.270 Creatinine (mg/dl) 1.00±0.41 0.99±0.25 0.844 0.92±0.44 0.97±0.29 0.153 e-gfr (ml/min/1.73m2) 57.9±19.2 59.6±17.5 0.517 HbA1c (%) 5.9±1.2 6.1±1.1 0.358 5.7±0.9 5.9±0.9 0.242 BNP (pg/dl) 49.8±47.2 45.1±29.7 0.482 46.9±67.9 37.4±32.3 0.211 ( * P<0.01, P,0.05 between baseline to follow-up)

(mmhg) 180 Serial Changes of Blood Pressure 1 6 0 142.4±24.3 144.4±23.6 138.4±21.4 137.9±25.3 133.1±20.5 135.4±26.1 1 4 0 1 2 0 Olmesartan 1 0 0 79.2±10.8 81.1±12.9 74.7±14.6 77.4±11.3 Control 73.6±14.6 74.9±12.8 8 0 Baseline 14-months 4-years ( P<0.05, P<0.01, between baseline to follow-up)

Adjudicated Major Cerebro and Cardiovascular Events during 4-years Composite of Cardio or Cerebrovascular death, MI, stroke, angina, or heart / renal failure Control (n=121) Olmesartan (n=126) 17.4 8.0 0.04 Death (All cause) 3.3 3.2 0.95 Cardio or Cerebrovascular death 1.7 0.8 0.51 Nonfatal myocardial infarction 0.8 1.6 0.59 Nonfatal stroke 1.7 0 0.15 Unstable angina 10.7 4.8 0.10 (Culprit related / new de novo coronary lesions) 5.0/5.7 3.2/1.4 Deterioration of Heart / Renal Failure 2.5 0.8 0.30 p

(%) 100 Cumulative Event-free from Cerebro or Cardiovascular death, MI, stroke, angina, or heart / renal failure 90 P=0.04 (log-rank test) 80 70 Control Olmesartan 60 200 400 600 800 1000 1200 1400 (Days)

OLIVUS-extended Hazards Ratio for Major Cerebro and Cardiovascular Events (Adjusted model, 95% CI) Age >70 2.85(0.69-6.01) Olmesartan 0.76 (0.45-0.89) Statins 0.84 (0.68-1.10) Hx of IHD Annual %ATV progression > 20% 3-Vessel Disease HbA1c>7.5% (Baseline) 2.25 (0.71-3.27) 1.91 (0.83-2.88) 3.41 (1.58-6.72) 3.08 (1.33-5.14) 0.1 1 10 (IHD; Ischemic Heart Disease, %ATV; Percent Atheroma Volume)

% Atheroma Volume Changes (Baseline 14-months) Annual Atheroma Progression with or without MACCE (%) 30 23.8±18.7 20 P < 0.001 10 2.1±13.8 0 MACCE (+) (n=31) MACCE (-) (n=216)

Serial Changes of Biomarkers Control Olmesartan (mg/l) 0 (μg/ml) 4 -. 0 5. 1 3 2 P=0.0007 -.15 1. 2 -. 2 5 P=0.0183 0-1 -. 3 hs-crp (FU-Baseline) - 2 Adiponectin (F/U-Baseline)

Summary Composite rate of MACCE and cumulative event-free survival for 4-years were significantly better in the Olmesartan group than in the control group. By adjusting for validated prognosticators, Olmesartan administration was identified as a good predictor of MACCE. Patients with adverse events had larger annual atheroma progression than the rest of the population.

Limitation Enrolled small number of stable angina patients In the current study, high proportion of patients (previously taking >40%, and >70% from beginning of trial) were already being treated with optimal lipidlowering therapy, therefore, it may be difficult to show an effect in addition to that treatment.

Conclusions Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cerebro- and cardiovascular events in this study cohort.