We randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2–4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat.

• heart rate under 50 beats per minute (bpm);
• second or third degree heart block;
• asthma;
• receiving a β blocker or their physician planned to start one perioperatively;
• prior adverse reaction to a β blocker;
• coronary artery bypass graft surgery in the preceding 5 years and no cardiac ischaemia since;
• low-risk surgical procedure (based on individual physician's judgment);
• on verapamil;
• or previous enrolment in POISE.

In POISE, patients received the first dose of the study drug (ie, oral extended-release metoprolol 100 mg or matching placebo) 2–4 h before surgery. Study drug administration required a heart rate of 50 bpm or more and a systolic blood pressure of 100 mm Hg or greater; these haemodynamics were checked before each administration. If, at any time during the first 6 h after surgery, heart rate was 80 bpm or more and systolic blood pressure was 100 mm Hg or higher, patients received their first postoperative dose (extended-release metoprolol 100 mg or matched placebo) orally. If the study drug was not given during the first 6 h, patients received their first postoperative dose at 6 h after surgery. 12 h after the first postoperative dose, patients started taking oral extended-release metoprolol 200 mg or placebo every day for 30 days. If a patient's heart rate was consistently below 45 bpm or their systolic blood pressure dropped below 100 mm Hg, study drug was withheld until their heart rate or systolic blood pressure recovered; the study drug was then restarted at 100 mg once daily. Patients whose heart rate was consistently 45–49 bpm and systolic blood pressure exceeded 100 mm Hg delayed taking the study drug for 12 h.

Patients who were unable to take medications orally received the study drug by slow or rapid intravenous infusion every 6 h until they could resume oral medications. The slow infusion consisted of 15 mg of the study drug in 25 mL normal saline infused over 60 min; heart rates and blood pressures were checked at 10, 30, and 60 min into the infusion. If a patient's heart rate dropped below 50 bpm or systolic blood pressure dropped to below 100 mm Hg the infusion was stopped and subsequent infusions had 10 mg of study drug. The rapid intravenous infusion consisted of 5 mg of the study drug infused over 2 min and repeated—as long as haemodynamic criteria were met—every 5 min for a total of 15 mg. Investigators were allowed to select either the slow or rapid intravenous infusion for any participant who was unable to take medications orally.

An electrocardiograph (ECG) was recorded 6–12 h postoperatively and on the first, second, and 30th days after surgery. We obtained a measurement of troponin or, if unavailable, a creatine kinase-MB measurement 6–12 h postoperatively and on the first, second, and third days after surgery. These measurements were recorded on the case report forms and forwarded to the POISE project office. All measurements were reviewed centrally. If a patient's biomarkers or cardiac enzymes were raised but a myocardial infarction case report form was not submitted, we asked the centre to review the case to ensure that a myocardial infarction was not missed. Centres were encouraged to obtain more frequent ECGs and cardiac biomarkers if they suspected a myocardial infarction.

All 8351 patients were included in analyses; 8331 (99·8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5·8%] patients in the metoprolol group vs 290 [6·9%] in the placebo group; hazard ratio 0·84, 95% CI 0·70–0·99; p=0·0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4·2%] vs 239 [5·7%] patients; 0·73, 0·60–0·89; p=0·0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3·1%] vs 97 [2·3%] patients; 1·33, 1·03–1·74; p=0·0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1·0%] vs 19 [0·5%] patients; 2·17, 1·26–3·74; p=0·0053).