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The ultra-short-acting beta-blockers esmolol and landiolol have the theoretical advantages of very fast onset of effects and short halflives. Notably, landiolol may lower BP to a lower extent than esmolol. Evidence of prevention of AF with landiolol after NCS is less robust and inconsistent than in the context of cardiac surgery.202–205 The timing of the initiation of beta-blockers to prevent AF remains unclear, with most prophylactic regimens using shortacting agents being started intra-operatively.187

5.2.2 Amiodarone

Amiodarone is the most frequently used agent for prevention of post-operative AF,206 with a risk reduction of 58% in NCS in a meta-analysis evaluating different antiarrhythmic drugs (AADs), but may induce relevant non-cardiac side effects.201 In another meta-analysis, amiodarone (oral or intravenous [i.v.]) and betablockers were equally effective in reducing post-operative AF.207 In another prospective RCT, a combination of beta-blocker plus amiodarone outperformed beta-blockers alone in reducing postoperative AF.208 It should be noted that the two latter studies were undertaken in patients undergoing cardiac surgery. Overall, while preventive amiodarone seems to reduce the incidence of AF, the clinical benefits associated with its routine use are unclear.

5.2.3 Statins

Despite the wide-ranging use of statins in patients undergoing surgery, RCTs assessing the effects of initiating statin therapy during the peri-operative period are scarce. This should be viewed separately from patients already on statin therapy. The long-term use of statins in patients with CVD or high risk of CVD is well-established.40 Observational data suggest a potential benefit of statins in the peri-operative phase. In a large, retrospective, and observational cohort, which included 180 000 veterans undergoing NCS, the use of statins on the day of or the day after surgery was associated with a reduction in mortality (RR, 0.82; 95% CI, 0.75–0.89).209 Similar results were seen in a retrospective cohort study using hospital discharge and pharmacy records.210 Although both studies used propensity matching to reduce bias, these analyses are prone to confounding, especially when discharge and pharmacy records are used. As such, RCTs give a more reliable effect estimation, for example: the Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) trial studied 648 statin-naïve patients, of whom 24% had a history of CVD and 49% had diabetes.211 In this randomized, placebo-controlled trial, patients received a loading dose of atorvastatin 80 mg within 18 h before surgery followed by 40 mg daily for 7 days. Use of atorvastatin did not reduce the risk of major events (all-cause mortality, non-fatal MI, or stroke at 30 days [HR, 0.87; 95% CI, 0.60–1.26; P = 0.46]). However, the trial was underpowered to draw definite conclusions. In addition, several meta-analyses have shown ambiguous results and most studies are of a limited size with less than 100 patients.212,213 Therefore, routine peri-operative initiation of statin therapy is not recommended. However, in patients in whom statin use is already indicated, treatment should be considered peri-operatively, particularly in patients scheduled for high-risk surgery (e.g. vascular surgery). 5.2.4 Renin–angiotensin–aldosterone system

inhibitors Data on peri-operative use of renin–angiotensin–aldosterone system (RAAS) inhibitors are inconclusive. The majority of studies suggest that continued use of RAAS inhibitors is associated with a higher risk of peri-operative hypotension and, as a consequence, higher use of vasopressors and inotropes. Furthermore, intra-operative hypotension and its duration is associated with end-organ damage, including kidney injury, myocardial damage, and stroke.214 In a small trial of 275 subjects, randomized to either continuation of their angiotensin-converting-enzyme inhibitors (ACEIs) or omission of the final pre-operative ACEI dose, patients randomized to omission of the last dose before surgery experienced intra-operative hypotension less frequently (76/137 [55%] vs. 95/138 [69%]) and vasopressor use was less likely.215 On the other hand, post-operative hypertension was more frequent in the omission group. Furthermore, in an observational cohort study consisting of 4802 patients undergoing NCS and using an ACEI or angiotensin receptor blocker (ARB), discontinuation of these drugs in the 24 h before surgery was associated with a lower risk of intra-operative hypotension (adjusted RR, 0.80; 95% CI, 0.72–0.93; P , 0.001), and associated with a reduction in the composite end-point consisting of all-cause mortality, stroke, and MI (adjusted RR, 0.82; 95% CI, 0.70–0.96; P = 0.01);216 8% of the patients in this cohort were diagnosed with HF, in whom RAAS inhibitors are the cornerstone of medical therapy. A systematic review, including nine studies (five RCTs and four cohort studies), revealed that withholding ACEI/ARB on the morning of surgery was not associated with mortality or MACE;217 however, it did confirm that withholding therapy was associated with less intra-operative hypotension (OR, 0.63; 95% CI, 0.47–0.85). If an ACEI/ARB is withheld prior to NCS, it should be restarted as soon as possible in order to prevent unintended long-term omission. No data on peri-operative effects of angiotensin receptor neprilysin inhibitors (ARNI) exist, but hypotension is more common compared with patients on ACEI.218 Some important RCTs in this field are ongoing: the impact of renin– angiotensin system inhibitors continuation vs. discontinuation on outcome after major surgery trial STOPorNOT219 (NCT03374449), and the POISE-3 trial (NCT03505723) are both assessing a hypotension-avoidance strategy vs. a hypertension-avoidance strategy on the risk of vascular death and major vascular events in patients who are followed for 30 days after NCS.

5.2.5 Calcium channel blockers

The effects of calcium channel blockers (CCBs) on the balance between myocardial oxygen supply and demand makes them theoretically suitable for risk-reduction strategies. The relevance of randomized trials assessing the peri-operative effects of CCBs is limited by their small size, lack of risk stratification, and the absence of systematic reporting of cardiac death and MI. A meta-analysis pooled 11 randomized trials totalling 1007 patients.220 Treatment with CCBs significantly reduced the number of episodes of myocardial ischaemia and supraventricular tachycardia (SVT) in the pooled analyses. However, the decrease in mortality and MI reached statistical significance only when both end-points were combined (RR, 0.35; 95% CI, 0.08–0.83; P = 0.02). In contrast, a matched casecontrol study of 1000 patients undergoing acute or elective

ESC Guidelines                                                                                                                                                                                     3855

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