The OPTImal CArdiac REhabilitation (OPTICARE) trial: a randomized, controlled superiority trial of two extended educational and behavioral intervention programs Ron T van Domburg and Madoka Sunamura on behalf of the OPTICARE investigators Erasmus Medical Center and Capri Cardiac Rehabilitation Rotterdam

No conflict of interests

Background Currently, most patients with Acute Coronary Syndromes (ACS) undergo PCI in the acute phase and are under optimal medical treatment. As a result, the prognosis of ACS patients increased significantly. However, cardiac rehabilitation (CR) programs have barely changed since the 1980s. Few data are available on the optimal CR format in ACS patients.

Objectives To determine the effects of two extended CR programs designed to stimulate permanent adaption of a heart-healthy lifestyle, compared with current standard CR, in ACS patients.

Outcome parameters Systematic COronary Risk Evaluation (SCORE) at 18 Months Individual SCORE risk function parameters: Systolic blood pressure, total cholesterol and smoking behavior Quality of life Anxiety Daily physical activity

In- and exclusion criteria Inclusion Patients with a documented ACS who were referred for CR. Exclusion Heart failure, LVEF<40%, psychological or cognitive impairments which may limit cardiac rehabilitation, COPD, renal failure.

Treatment allocation CR-only CR+G CR+T T0 3M 12M 18M standard CR Fup Face-to-Face CR+T Telephone standard CR 3 group sessions including fitness training and lifestyle counseling 5-6 telephonic lifestyle counseling sessions 3 physical activity counseling sessions Fup T0 3M 12M 18M

Randomization ITT analysis PP analysis OPTICARE trial N=914 CR+G Face-to-Face N=309 CR+T Telephone N=299 CR-only N=306 262 completed standard CR (85.1%) 250 completed standard CR (83.6%) 306 completed standard CR (82.7%) PP analysis 187 completed CR+G (60.5%) 170 completed CR+T (56.8%) 306 completed CR-only (82.7%) CR+G: standard CR extended with face-to-face group counseling sessions CR+T: standard CR extended with telephone counseling sessions CR-only: standard CR

Baseline characteristics CR+G CR+T CR-only N=309 N=299 N=306 Age, years 57 57 57 Male, % 79 83 80 Intervention at baseline PCI, % 81 75 78 CABG, % 12 15 14 No revascularization, n (%) 7 10 8 Prior MI, % 7 10 9 Prior PCI, % 8 10 11 Prior CABG, % 1 1 2 Diabetes, % 14 11 14 Dyslipidemia, % 29 33 40 Current smoking (pre-ACS), % 45 43 42 Hypertension, % 44 40 39

Cardiac medication at randomization (6 weeks post-ACS) Acetylsalicylic acids 97% Thienopyridines 86% Statins 97% Beta blockers 84% ACE inhibitors 70% 20 40 60 80 100 Percentage

Primary outcome: Score risk function Intention-to-Treat Per-Protocol 3.50 3.50 p=0.48 p=0.41 p=0.22 CR-only 3.25 3.25 CR-only CR+G p=0.39 CR+T median SCORE risk function 3.00 median SCORE risk function 3.00 CR+G CR+T 2.75 2.75 2.50 2.50 3 Months 18 3 Months 18 CR+G: standard CR, extended with group counseling sessions CR+T: standard CR, extended with telephone counseling sessions

Smoking Intention-to-Treat Smoking Per-Protocol Total cholesterol 50% 50% 40% 40% CR+G Percentage smoking 30% CR-only 30% p=ns Percentage smoking CR-only 20% CR+T 20% CR+G p<0.05 p<0.05 10% 10% CR+T preACS 3 Months 18 preACS 3 Months 18 Total cholesterol Intention-to-Treat Total cholesterol Per-Protocol 4.4 CR-only 4.4 p=ns CR-only 4.2 CR+T p<0.001 p<0.05 4.2 p<0.001 Total cholesterol CR+T Total cholesterol 4.0 CR+G 4.0 3.8 CR+G 3.8 3.6 3.6 3 Months 18 3 Months 18

Metabolic parameters SBP (mmHg) Intention-to-Treat SBP (mmHg) Per-Protocol 140 140 135 p<0.05 135 p<0.05 p=ns p=ns Systollic blood pressure 130 Systolic blood pressure 130 125 125 120 120 3 Months 18 3 Months 18 Waist circumference Intention-to-Treat Waist circumference Per-Protocol 105 105 p=ns CR+T CR p=ns Waist circumference (cm) Waist circumference (cm) 100 100 CR+G 95 95 3 Months 18 3 Months 18

At least 6 of the 9 risk factors on target at 18M 0% 10% 20% 30% Intention-to-Treat Per-Protocol CR+G CR CR+T 16.8 13.7 24.5 16.9 21.8 p=0.56 p=0.87 p=0.004 p=0.33 At least 6 of the 9 risk factors on target at 18M Percentage of patients% Systolic blood pressure≤140 mmHg Diastolic blood pressure≤90 mmHg BMI≤25 Waist circumference (m≤94cm;f≤80cm) LDL<1.8mmol/L Total cholesterol≤4.5 mmol/L Quit smoking No anxiety No depression

Number of steps per day Intention-to-Treat Per-Protocol 7282 7183 6709 8000 8000 p<0.05 CR+G 7500 CR+G 7500 7282 7183 CR-only CR-only 7000 p=0.11 7000 p=0.08 Steps per day 6709 Steps per day 6679 6500 6641 6500 CR+T 6545 CR+T 6000 6000 5500 5500 3 Months 18 3 Months 18

Quality of Life Quality of Life Intention-to-Treat Per-Protocol 6.0 6.0 Intention-to-Treat Per-Protocol CR+G 5.8 CR+T 5.8 p=ns p=0.004 CR+G CR+T p=0.04 5.6 5.6 Quality of Life Quality of Life 5.4 CR 5.4 CR 5.2 5.2 5.0 5.0 3 Months 18 3 Months 18 Anxiety % Anxiety % 15% 15% Intention-to-Treat Per-Protocol 10% CR 10% CR p=ns CR+T p=ns Anxiety % Anxiety % CR+T p=0.036 CR+G 5% 5% CR+G 0% 0% 3 Months 18 3 Months 18

Cardiac events at 18 months CR+G CR+T CR-only Pvalue N=309 N=299 N=306 Total number of events 83 (27%) 79 (26%) 70 (22%) 0.44 Mortality, n (%) 1 (0) 1 (0) 0 (0) 0.56 Readmissions for ACS STEMI, n (%) 1 (0) 5 (2) 2 (1) 0.24 NSTEMI, n (%) 5 (2) 3 (1) 3 (1) 0.98 Unstable angina, n (%) 4 (1) 3 (1) 2 (1) 0.64 Other CVD admissions Stable angina, n (%) 14 (4) 13 (4) 9 (3) 0.64 Chest pain, n (%) 16 (5) 12 (4) 11 (4) 0.53 Arrhythmias, n (%) 6 (2) 4 (1) 2 (1) 0.65 Interventions CAG, n (%) 8 (3) 5 (2) 7 (2) 0.59 PCI, n (%) 9 (3) 9 (3) 12 (3) 0.85 CABG, n (%) 1 (0) 0 (0) 2 (1) 0.16 Cardiac ER, n (%) 18 (6) 24 (8) 20 (7) 0.90 17

Conclusions Both extended CR programs (face-to-face group and telephone counseling sessions on top of standard CR) as compared with standard CR-only Were not beneficial with respect to the SCORE risk function. Factually, most patients largely reached the target levels of the modifiable SCORE risk factors (Systolic BP, total cholesterol and smoking) already at randomization (6 weeks post-ACS), which made it almost impossible to achieve an additional benefit (“ceiling effect”).

Conclusions Extended CR with telephone counseling sessions on top of standard CR as compared with standard CR-only showed PP analyses (motivated patients) Less smoking Lower cholesterol level Improved quality of life No benefit for the other end points in the ITT and PP analyses

Conclusions Extended CR with face-to-face group counseling sessions on top of standard CR as compared with standard CR-only showed ITT analyses Lower cholesterol levels PP analyses (motivated patients) Less smoking More risk factors on target Less anxiety Lower cholesterol levels Higher quality of life Trend to more steps/day

Acknowledgements OPTICARE team Nienke ter Hoeve (leadership), Myrna van Geffen, Verena van Marrewijk, Saskia Versluis and all Capri personnel Scientific Board Rita van den Berg-Emons, Eric Boersma, Marcel Geleijnse, Henk Stam CEC committee Mattie Lenzen, Arend Schinkel In collaboration with Medical Service Center of the health insurance company “Zilveren Kruis” Referral hospitals