PREVENT MINS Trial Protocol Version 2.1 March 10, 2022
Sponsor: Jagiellonian University Medical College
Principal Investigator: Wojciech Szczeklik, MD, PhD
Trial Chair: P.J. Devereaux, MD, PhD
| Title: | Ivabradine for PREVENTion of Myocardial Injury after Noncardiac Surgery (MINS) - PREVENT-MINS Trial. |
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| Study Design: | Multicentre, randomised, placebo-controlled trial of ivabradine as add-on therapy to standard medical treatment. |
| Sample size: | 2500 patients. |
| Primary Objectives: | To determine the effect of perioperative administration of ivabradine in patients with, or at risk of, atherosclerotic disease who are undergoing noncardiac surgery. The primary outcome is myocardial injury after non-cardiac surgery (MINS) defined as any myocardial infarction and any elevated postoperative cardiac troponin judged as resulting from myocardial ischaemia during or within 30 days after noncardiac surgery. |
| Secondary Objectives: | To determine the impact of ivabradine on the following outcomes at 30 days after surgery: a composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest; vascular death; MINS not fulfilling the criteria of myocardial infarction; myocardial infarction; peak troponin concentration; area under the curve troponin; days alive and at home; stroke; all-cause mortality; health-related quality of life; cancellation/postponement of surgery on the day of surgery due to HR concerns; clinically important atrial fibrillation; safety outcomes including clinically significant bradycardia, clinically significant hypotension and phosphenes. |
| Tertiary Objectives: | To determine the impact of ivabradine on outcomes including: 1) at 30 days after surgery: cardiac revascularization; re-hospitalization for vascular reasons; acute myocardial injury according to the Fourth Universal Definition of Myocardial Infarction; non-fatal cardiac arrest; acute congestive heart failure; deep vein thrombosis/pulmonary embolism; major bleeding according to ISTH definition; bleeding independently associated with mortality after noncardiac surgery; sepsis; acute kidney injury fulfilling KDIGO criteria; acute kidney injury requiring dialysis; amputation; days outside the Intensive Care Unit; length of hospital stay; length of ICU stay; discharge destination 2) at 1 year after surgery: all-cause mortality; vascular death; myocardial infarction; non-fatal cardiac arrest; stroke; health-related quality of life; amputation; cardiac revascularization; re-hospitalization for vascular reasons. |
| Inclusion criteria: | Patients are eligible if they fulfil all of the following criteria: 1. ≥45 years of age; 2. Expected to require at least an overnight hospital admission after noncardiac surgery; 3. Provide written informed consent to participate in the PREVENT-MINS Trial AND fulfil ≥1 of the following 5 criteria (A-E): A. Current or prior history of coronary artery disease; B. Current or prior history of peripheral arterial disease; C. History of stroke; D. Undergoing major vascular surgery OR E. Any 3 of the following 9 risk criteria: i.) Undergoing major surgery (i.e. intraperitoneal, intrathoracic, retroperitoneal, major orthopedic); ii. History of congestive heart failure; iii. History of a transient ischaemic attack; iv. History of diabetes; v. Age ≥70 years; vi. History of hypertension; vii. Serum creatinine ≥175 μmol/L (≥2.0 mg/dl); viii. History of smoking within 2 years of surgery; ix. Undergoing emergent/urgent surgery. |
| Treatment regimen: | Patients fulfilling hemodynamic requirements will receive 5mg of oral ivabradine or matching placebo as an add on to the standard treatment twice daily starting ≥1 hour before surgery and continued for up to seven days after surgery. |
| Follow-up: | 30 days and 1 year. |
More than 230 million major noncardiac surgeries are performed worldwide each year and this number is increasing (1-3). The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) prospective cohort study - which enrolled a representative sample of 40,000 adults ≥45 years from 28 centres in 14 countries - demonstrated that 1.8% of patients having inpatient noncardiac surgery died within 30 days of the procedure (4). In the VISION Study, ischaemic myocardial injury after noncardiac surgery accounted for 13% of all postoperative deaths (5). Patients with myocardial injury after noncardiac surgery have a poor long-term prognosis, with 1 in 7 patients suffering a major vascular complication at a mean time of 16 months of follow-up (6).
There is evidence that perioperative tachycardia is associated with an increased risk of myocardial ischaemia and death after noncardiac surgery (7-10). Randomised controlled trials have shown that beta-blockers reduce heart rate and decrease the risk of perioperative myocardial ischaemia at the expense of increasing the risk of clinically important hypotension, stroke, and mortality (11). Ivabradine is a pure heart rate lowering drug which in contrast to beta-blockers decreases myocardial oxygen demand without affecting blood pressure or ventricular contractility (12). Ivabradine has proven efficacy and safety in patients at risk of major cardiovascular complications in the non-surgical setting. The most common side-effects associated with the administration of ivabradine include bradycardia and phosphenes, which are a transiently enhanced brightness in a limited area of the visual field. Preliminary data on the perioperative use of ivabradine are promising, yet inconclusive (13, 14).
We will conduct a multicentre randomised controlled trial (i.e. PREVENT-MINS) of ivabradine versus placebo in patients with, or at risk of, atherosclerotic disease who are undergoing noncardiac surgery.
PREVENT-MINS will address the following question: is ivabradine superior to placebo for the prevention of myocardial injury after noncardiac surgery (MINS) in patients with or at risk of atherosclerotic disease having noncardiac surgery?
Multiple studies have shown that perioperative tachycardia is associated with an increased risk of cardiac complications and death (7-9, 15-19). Tachycardia causes myocardial oxygen supply-demand mismatch by reducing the duration of diastole and may lead to rupture of unstable atherosclerotic plaques with subsequent occlusion of coronary arteries (15, 20, 21).
The VISION study demonstrated that myocardial injury after noncardiac surgery (MINS) defined as a troponin elevation within 30 days after noncardiac surgery judged to be due to ischaemia is associated with poor prognosis regardless of the presence of ischaemic features (i.e. ischemic symptoms or ECG findings) (4). Periprocedural myocardial injury has been recognized in the Fourth Universal Definition of Myocardial Infarction as a distinct clinical diagnosis (22). Both preoperative and intraoperative tachycardia have been shown to be associated with an increased risk of MINS, with a linear increase in the risk of MINS with increasing values of heart rate (7, 8).
There is evidence that rigorous heart rate control may prevent perioperative myocardial infarctions (23). Results of two large randomised controlled trials which evaluated the efficacy of metoprolol (POISE) and clonidine (POISE-2) in preventing major cardiac complications after noncardiac surgery suggest that substantial heart rate reduction is a promising cardioprotective strategy provided that it does not result in hypotension (11, 24). Ivabradine is a selective heart rate lowering agent that both reduces myocardial oxygen demand and improves oxygen supply without significant adverse haemodynamic effects (25). Small observational and interventional studies provide encouraging but not definitive evidence on the utility of ivabradine in surgical settings (13, 14, 26). Therefore, the efficacy and safety of ivabradine in noncardiac surgery has not yet been established.
Association between preoperative heart rate and perioperative complications has been evaluated in several studies. Data from the largest report, the VISION study, suggested a significant association between increased preoperative heart rate (>96 beats/min) and incidence of MINS (OR 1.48, 95% CI 1.23–1.77), MI (OR 1.71, 95%CI 1.34–2.18) and mortality (OR 3.16, 95%CI 2.45–4.07). At the same time low preoperative heart rate (<60 beats/min) was found to be related to decreased mortality (OR 0.50, 95%CI 0.29–0.88). Data from the POISE trial also demonstrated that every 10-beats/min increase in pre-randomisation heart rate was associated with a 31% relative increase in the odds of perioperative MI (adjusted OR, 1.31; 95% CI, 1.12-1.52).
Ivabradine acts on the mixed Na+/K+ inward ion current called If, which is one of the most important ionic currents involved in the pacemaker activity of the sinoatrial node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner, thus reducing heart rate and increasing time for blood to flow to the myocardium. In contrast to other heart rate reducing medications (e.g. beta-blockers and calcium channel blockers), ivabradine does not significantly decrease blood pressure.
Hellenbart and colleagues performed a scoping review of the literature and identified two small randomised controlled trials evaluating preoperative administration of ivabradine (14, 27, 28). We found two additional experimental studies which used ivabradine to attenuate haemodynamic response to laryngoscopy and endotracheal intubation (26, 29). Periprocedural heart rate was lower in the group of patients receiving ivabradine than in the control group in all four trials. One study showed that 5 mg of ivabradine administered in the evening before surgery and repeated 1 hour before the induction of anaesthesia provided better control of the heart rate than 10 mg of propranolol (14). Mathur and colleagues performed a randomised controlled trial in patients having nasal and laryngeal surgeries and found that 5 mg of ivabradine lowers the heart rate and blood pressure to a lesser degree than 50 mg of metoprolol tartrate (29). Out of the total of 105 patients randomly allocated to receive ivabradine shortly before surgery, no patient experienced bradycardia or hypotension.
The majority of participants enrolled in previous trials were healthy adults. None of the identified experimental studies assessed the incidence of major cardiac complications after noncardiac surgery. The only study evaluating the role of ivabradine administered both before and after surgery in preventing cardiac complications in patients at high risk of perioperative myocardial ischaemia was a non-randomised one and had few events available for analysis (13).
In summary, results of small trials performed in relatively healthy patients suggest that a 5 mg dose of ivabradine initiated shortly before surgery lowers heart rate in the perioperative period without causing hypotension. There is insufficient evidence to assess the risk and benefit profile of ivabradine in patients with or at risk of atherosclerotic disease scheduled for noncardiac surgery.
Borer and colleagues randomly assigned 360 patients with a ≥3-month history of chronic coronary syndrome (CCS) to receive ivabradine (2.5 mg, 5 mg or 10mg twice a day) or placebo for 2 weeks and later switched all participants to 10 mg of ivabradine twice a day in an open label extension of the trial followed by a 1-week randomised withdrawal of the study drug (30). In a per-protocol analysis of 257 patients, the time to 1-mm-ST-segment depression at through of drug activity at day 14 increased by 9.0 (63.6) seconds (s) with placebo and 32.0 (74.3), 44.1 (80.1), and 46.2 (78.2) s with ivabradine 2.5 mg, 5 mg, and 10 mg respectively, with the difference being statistically significant in case of the 5 mg and 10 mg dose. Time to limiting angina was significantly higher in patients receiving the 10 mg dose compared to placebo (69.4 [74.8] s vs 24.7 [64.2] s) and numerically higher with lower doses of ivabradine than with placebo. Three patients withdrew from the study due to transient visual symptoms, which occurred in 1 patient in each of the lower dosage groups and 13 patients receiving 10 mg of ivabradine twice a day. No cardiac adverse events were observed after withdrawal of the study drug, which suggests that stopping treatment with ivabradine is safe and does not result in rebound phenomena.
The INITIATIVE trial randomised 939 patients with CCS to receive ivabradine 5 mg or atenolol 50 mg, up titrated to (7.5 or 10 mg) and (100 mg), respectively after 4 weeks (31). The total exercise duration after one month of treatment was similar in both groups, with a 6.7 s (95% CI from -7.4 to 20.8) difference in favour of ivabradine. Ivabradine induced a similar or greater improvement in exercise capacity than atenolol for a comparatively smaller reduction in the heart rate and rate pressure product at peak exercise. Ivabradine was non-inferior to atenolol in terms of all studied endpoints regardless of the dose and reduced the number of angina attacks by two-thirds. Ivabradine was well tolerated, with only 2 out of 315 patients withdrawing from the treatment due to transient visual symptoms and 7 out of 315 patients experiencing sinus bradycardia in the group allocated to receive 7.5 mg dose of ivabradine.
Ruzyllo and colleagues compared the antianginal efficacy and safety of ivabradine and amlodipine in a randomised trial of 1195 patients with CCS (32). The total exercise duration at 3 months was improved by 27.6 (91.7), 21.7 (94.5), and 31.2 (92.0) seconds with ivabradine 7.5 mg, 10 mg, and amlodipine 10 mg respectively. Ivabradine was non-inferior to amlodipine in terms of time to angina onset and 1 mm ST-segment depression. Ivabradine was superior to amlodipine for reducing myocardial workload and significantly decreased heart rate at rest as well as at peak exercise by 11-13 and 12-15 beats per minute respectively. Less than 1% of the patients withdrew from treatment due to visual symptoms. Sinus bradycardia was the cause of withdrawal of treatment in only 0.4% of the patients.
In the ASSOCIATE trial (n=889), the addition of ivabradine 5 mg (later titrated to 7.5 mg) to 50 mg of atenolol in patients with CCS resulted in an increase in the total exercise time of 24.3 s (65.3) compared to 7.7 s (63.8) with placebo (33). Ivabradine was superior to placebo for all of the prespecified exercise test criteria, reduced the heart rate as well as rate-pressure product at the peak of exercise, and ivabradine was well tolerated with only 1.1% of patients allocated to the intervention arm withdrawing due to sinus bradycardia.
The BEAUTIFUL (If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction) trial enrolled 10 917 patients with CCS and left-ventricular systolic dysfunction (ejection fraction <40%) to evaluate the impact of ivabradine (5 mg, with the intention of increasing to the target dose of 7.5 mg twice a day) on cardiac outcomes (34). The trial did not demonstrate evidence of benefit with ivabradine compared to placebo in terms of the primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure, with a hazard ratio of 1.00 (95% CI 0.91-1.1).
In a prespecified subgroup of patients with heart rate of 70 beats per minute or greater, the hazard ratio for the primary outcome was equal to 0.91 (95% CI 0.81-1.04) when comparing ivabradine to placebo. Ivabradine reduced admissions to hospital for fatal and non-fatal myocardial infarction (hazard ratio of 0.64, 95% CI 0.49-0.84) and coronary revascularization (hazard ratio 0.70, 95% CI 0.52-0.93) in this subgroup, despite the fact that 84% of patients with heart rate ≥70 beats per minute were treated with beta-blockers. The mean difference between the placebo and ivabradine groups in change from baseline resting heart rate at 6 months was equal to 7.2 beats per minute (95% CI 6.8–7.5). Bradycardia was more common in the ivabradine group than in the placebo group (13% vs 2%), but only 146 (21%) patients receiving ivabradine who withdrew from treatment due to bradycardia were symptomatic. Bradycardia was less common in the subgroup of patients with a baseline heart rate of ≥70 beats per minute in both the ivabradine and placebo group (reason for discontinuation of treatment in 6% vs 1% of patients respectively). Visual symptoms such as phosphenes were transient and led to withdrawal from treatment in 37 (0.3%) of patients. The authors concluded that ivabradine is safe in patients with coronary artery disease and reduced ejection fraction, and that it can be safely combined with beta-blockers.
The SIGNIFY trial randomised 19 102 patients who had CCS with a heart rate ≥70 beats per minute to receive ivabradine at a starting dose of 7.5 mg twice daily (except for patients ≥75 years old, who received a reduced dose of 5.0 mg twice a day) or matching placebo on top of guideline-based medical treatment (35). After three months of treatment, the mean heart rate was reduced to 60.7 (9.0) and 70.6 (10.1) beats per minute in the ivabradine and placebo groups respectively. The trial did not provide sufficient evidence to reject the null hypothesis of no difference between ivabradine and placebo in terms of the primary composite outcome of death from cardiovascular causes or nonfatal myocardial infarction with a hazard ratio of 1.08 (95% CI 0.96-1.20).
Unexpectedly, ivabradine was associated with an increase in the incidence of the primary end point in the subgroup of patients who had angina classified as Canadian Cardiovascular Society class 2 or higher with a hazard ratio of 1.18 (95% CI 1.03-1.35). Among patients without angina or those classified as Canadian Cardiovascular Society class 1, the hazard ratio for the primary outcome when comparing ivabradine to placebo was 0.89 (95% CI 0.74-1.08). In SIGNIFY, drug withdrawal was more common in the ivabradine group than in the placebo group (13.2% vs 7.4%), with symptomatic and asymptomatic bradycardia leading to withdrawal of treatment in 1.9% and 2.1% of patients receiving ivabradine and 0.3% and 0.2% of patients in the placebo group respectively. The overall incidence of symptomatic and asymptomatic bradycardia in the ivabradine group was 7.9% and 11.0%, respectively, compared to 1.2% and 1.3%, respectively, in the placebo group. Phosphenes led to study-drug withdrawal in 0.6% of patients receiving ivabradine and 0.1% of those receiving placebo. The authors indicated that the relatively high incidence of bradycardia in SIGNIFY was due to the higher than recommended initiation and maintenance doses of ivabradine.
A systematic review by Ferrari and colleagues which identified 13 blinded randomised trials with a sample size of at least 100 patients comparing different anti-anginal drugs in patients with CCS concluded that no anti-anginal drug is superior to another, with equivalence demonstrated only between beta-blockers, calcium channel blockers and ivabradine (36). The authors deemed pooling of the trials’ results inappropriate due to methodological differences.
One systematic review summarising safety outcomes in the three largest ivabradine trials conducted to date showed that phosphenes occurred in 601/12,771 (4.7%) of patients treated with ivabradine and 69/12,804 (0.5%) patients receiving placebo (37). Symptomatic bradycardia was reported in 907/12,771 (7.1%) patients from the ivabradine groups compared to 142/12,804 (1.1%) in the placebo groups. Atrial fibrillation was more common with ivabradine than with placebo (814/12771 [6.3%] vs 613/12804 [4.7%]) with an odds ratio equal to 1.35 (95% CI 1.21–1.51). The increase in the risk of atrial fibrillation due to ivabradine, though smaller than previously estimated, was confirmed in yet another systematic review which included over 40,000 participants (5.34% vs 4.56%) (38).
The SHIFT trial randomised 6558 patients with symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, in sinus rhythm, with a heart rate of ≥70 beats per minute who had been hospitalized for heart failure within the previous 12 months to receive ivabradine (5 mg twice daily starting dose with the possibility of later up titration to 7.5 mg twice daily) or placebo on top of optimal medical therapy (39). Treatment with ivabradine was associated with an average reduction in heart rate of 15 beats per minute from a baseline heart rate of 80 beats per minute. The primary endpoint (i.e. a composite of cardiovascular death or hospital admission for worsening heart failure) occurred in 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo, resulting in a hazard ratio of 0.82 (95% CI 0.75–0.90). Both individual components of the primary outcome were significantly less common in patients receiving ivabradine compared to placebo. In a post-hoc analysis, ivabradine reduced the incidence of cardiovascular death or hospitalisation for worsening heart failure regardless of the presence of angina at baseline (40). Serious adverse events were less common in the ivabradine group than in the placebo group, but the incidence of symptomatic bradycardia (5% vs 1%) and phosphenes (3% vs 1%) was higher with ivabradine than with placebo.
Data from the SHIFT trial suggest that ivabradine is more effective in the subgroup of patients with a baseline heart rate ≥75 beats per minute, the threshold at which ivabradine was registered for use in patients with chronic heart failure New York Heart Association class II to IV with systolic dysfunction by the European Medicines Agency (41). A pooled analysis of individual patient data from the SHIFT and BEAUTIFUL trials demonstrated that ivabradine reduces the risk of major outcomes in a broad population of patients with left ventricular systolic dysfunction and a heart rate ≥70 beats per minute regardless of the primary clinical presentation (i.e. coronary artery disease or heart failure), severity of disease (i.e. New York Heart Association class or ejection fraction), and background dose of beta-blockers (42). The hazard ratio for cardiovascular mortality, hospital admission for heart failure or hospital admission for myocardial infarction in 11,897 patients randomised to ivabradine or placebo in either of the two trials was equal to 0.85 (95% CI 0.79-0.91).
The use of ivabradine has also been actively investigated in other populations (e.g. patients with conduction abnormalities or left ventricular dysfunction undergoing cardiac surgery, critically ill patients, patients with mitral stenosis), with many trials conducted on relatively small groups of patients and yielding inconclusive results. We summarised these additional studies in APPENDIX I.
Based on the available evidence, the European Society of Cardiology currently recommends ivabradine as a second-line (class IIa recommendation) or first line (in combination with a beta-blocker or a calcium channel blocker; class IIb recommendation) anti-ischaemic treatment in patients with CCS who are in sinus rhythm (43). Ivabradine has received a class IIa recommendation to reduce the risk of hospitalization for worsening heart failure or cardiovascular death in symptomatic patients with left ventricular ejection fraction ≤35%, in sinus rhythm and a resting heart rate ≥70 beats per minute, despite optimal medical treatment (including an evidence-based dose of a beta-blocker or as a substitute for a beta-blocker in patients who are unable to tolerate or have contra-indications for beta-blockers) (44). In patients with CCS and symptomatic heart failure (New York Heart Association class II-IV) with systolic dysfunction and a resting heart rate ≥70 bpm, ivabradine has a class IIa recommendation as an add-on anti-anginal drug on top of a beta-blocker or as a substitution for a beta-blocker in patients who do not tolerate beta-blockers.
Evidence summary
Ivabradine has been used in the European Union since 2005 and safety data have been established from trials enrolling thousands of participants in the non-operative setting. Two specific adverse events are known to be related to the pharmacological action of ivabradine: sinus bradycardia and transient visual disturbances known as phosphenes, which occur in approximately 7% (symptomatic cases) and 5% of patients treated with ivabradine in the largest clinical trials conducted to date respectively. Phosphenes are benign and transient phenomena, which rarely lead to withdrawal of treatment and bradycardia is less common with higher baseline heart rates. Ivabradine is associated with an approximately 1% absolute increase in the risk of detected atrial fibrillation according to a recent meta-analysis. Treatment with ivabradine, either alone or in combination with beta-blockers, is currently considered both effective and safe in patients with CCS and heart failure.
Results of randomised controlled trials suggest that ivabradine could prevent perioperative myocardial ischaemia on par with beta-blockers with less side effects, particularly hypotension. A meta-analysis of randomised trials in patients undergoing noncardiac surgery showed a substantial reduction in the incidence of perioperative myocardial infarction with beta-blockers, but this benefit was considered to be outweighed by the increased risk of clinically relevant hypotension, stroke, and death resulting from perioperative beta-blockade. Therefore, we need to establish the efficacy of ivabradine in patients having noncardiac surgery.
Data regarding the influence of ivabradine on cardiac complications after surgery in patients at high risk of perioperative myocardial ischaemia are inconclusive (13). Results of small trials performed in relatively healthy patients suggest that a 5 mg dose of ivabradine initiated shortly before surgery lowers heart rate in the perioperative period without causing hypotension (14, 29), but does not provide sufficient evidence to assess the risk and benefit profile of different doses of ivabradine in patients with or at risk of atherosclerotic disease scheduled for noncardiac surgery. According to results of two large trials evaluating ivabradine in non-operative clinical settings, the use of ivabradine 5-7.5 mg twice daily increased the incidence of bradycardia compared to placebo, but most of these events were asymptomatic (34, 39). The relatively high incidence of bradycardia in the SIGNIFY trial was attributed to the higher than recommended initiation and maintenance doses of ivabradine. Based on these data, in the PREVENT-MINS trial we will use a 5mg dose of Ivabradine twice daily, initiated ≥1 hour before surgery and continued for up to 7 days after surgery.
Several RCTs assessed the impact of perioperative administration of beta blockers, among which the largest study (POISE trial) showed that perioperative administration of metoprolol decreased the incidence of myocardial infarction (HR 0.84, 95% CI 0.70 to 0.99) but simultaneously increased mortality (HR 1.33, 1.03 to 1.74) and rate of stroke (HR 2.17, 95% CI 1.26 to 3.74). Adverse events were predominantly attributed to the increased incidence of clinically important hypotension. Meta-analysis of nine RCTs of perioperative beta-blockers administration, encompassing 10 529 patients, showed a reduction of nonfatal MI (RR 0.73, 95% CI 0.61 to 0.88) but an increased 30-day mortality (RR 1.27, 95% CI 1.01 to 1.60) as well as a higher incidence of stroke (RR 1.73, 95% CI 1.00 to 2.99) and hypotension (RR 1.51, 95%CI 1.37 to 1.67). These results were mainly driven by the POISE trial, but the results are consistent even when the POISE trial was not included.
The potential benefit associated with perioperative heart rate decrease was also an element of the rationale for the POISE-2 trial in which a different HR-reducing medication, clonidine, was administered perioperatively to reduce the incidence of perioperative cardiovascular complications. Clonidine mechanism of action is multidirectional - it not only lowers blood pressure by stimulating presynaptic α2-receptors and imidazoline-1 receptors in the brain, but also reduces heart rate, most probably by its action through the vagus nerve. POISE-2 trial failed to show a difference between clonidine and placebo groups in terms of the primary outcome (i.e. a composite of death and non-fatal myocardial infarction) with a HR of 1.08 (95% CI 0.93 to 1.26; P=0.29). Similar to the first POISE trial, there was an increase in the incidence of clinically important hypotension in the intervention arm compared to placebo (HR 1.32; 95% CI, 1.24 to 1.40). Moreover, patients receiving clonidine more often suffered nonfatal cardiac arrest (HR 3.20; 95% CI, 1.17 to 8.73). The authors reported that the less pronounced cardioprotective effect of clonidine compared to metoprolol may have been due to the less pronounced impact on heart rate with clonidine; clinically significant bradycardia had a HR of 2.74 (95% CI, 2.19–3.43) in POISE-1, whereas it was only 1.49 (95% CI,1.32–1.69) in POISE-2.
The entire body of evidence suggests that an ideal drug in prevention of cardiovascular complications after surgery would be one that slows down the heart rate and does not cause substantial hypotension, hence ivabradine is a promising intervention to study in this setting.
Our group has collectively participated in several large perioperative studies including VISION, VISION-CTA, MANAGE, HIP ATTACK, POISE 3 and OPTIMIZE II. These studies enabled us to establish the incidence of MINS in the Polish population of patients undergoing surgery (with active troponin screening of more than 2000 patients), to evaluate the population at risk (information about comorbidities, tachycardia, hypotension during surgery etc.), and to establish a broad network of cooperating centres with experience in clinical trials.
The study was designed to stay in line with the real-life scenario of perioperative care. The drug/placebo will be administered orally over a relatively short period of time during hospitalisation, which will increase compliance and safety.
Perioperative tachycardia is associated with an increased risk of cardiac complications and death within 30-days after surgery. Data from randomised trials suggests that reducing patients’ heart rate in the perioperative period prevents myocardial ischaemia. Preliminary evidence suggests that ivabradine is as potent as beta-blockers in preventing myocardial ischaemia and has a more favourable safety profile than beta-blockers concerning the risk of hypotension and stroke in the perioperative period. There is a need for an adequately powered trial to establish the efficacy of ivabradine in preventing myocardial injury after noncardiac surgery and to guide clinical practice in a population of patients with or at risk of atherosclerotic disease undergoing noncardiac surgery.
The study aims to determine whether perioperative administration of ivabradine is superior to placebo for the occurrence of myocardial injury after noncardiac surgery (MINS) within 30 days after randomisation in patients with or at risk of atherosclerotic disease having noncardiac surgery.
The PREVENT-MINS trial is a multicentre RCT of 2500 patients with or at risk of cardiovascular disease randomised to receive either oral ivabradine or placebo in the perioperative period. Patients, health care providers, data collectors, outcome adjudicators, and investigators will all be blinded to patients’ allocation to either arm of the trial. The PREVENT-MINS trial will use a parallel-group design with an equal allocation ratio (see Trial Flow Chart).
Pooled data from the VISION prospective cohort study that employed active high-sensitivity troponin screening during the first 3 days after surgery and other prospective observational studies using routine troponin measurement indicate that 18% of the control group in the PREVENT-MINS trial will suffer the primary outcome within 30 days (45). Based on results of a meta-analysis that included data from the POISE trial and several RCTs that concluded that ivabradine is likely to exert similar anti-ischaemic effects as beta-blockers, we estimate that 13.5% of the patients in the experimental group will suffer MINS (11). Based on a group sequential design with 2 interim analyses conducted when 50% and 75% outcomes were collected, enrolling 2500 patients will allow us to detect a 25% relative risk reduction with 86.4% power with the overall two-sided type I error rate of α=0.05 guaranteed by using the Lan-DeMets (O’Brien-Fleming) alpha spending function (46).
Patients are eligible for the study if they fulfil the following criteria for inclusion:
AND
A. Current or prior history of coronary artery disease as defined by any one of the following 7 criteria:
History of angina;
History of acute coronary syndrome;
History of a segmental cardiac wall motion abnormality on echocardiography or a segmental fixed defect on radionuclide imaging;
History of a positive radionuclide exercise, echocardiographic exercise, or pharmacological cardiovascular stress test demonstrating cardiac ischaemia;
History of a coronary angiographic or CT coronary angiographic evidence of atherosclerotic stenosis ≥50% of the diameter of any coronary artery;
ECG with pathological Q waves in at least two contiguous leads; OR
Previous coronary artery revascularization, (i.e. percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]);
B. Peripheral arterial disease as defined by a physician diagnosis of a current, or prior history of any of the following 4 criteria:
Intermittent claudication;
Vascular surgery OR percutaneous transluminal angioplasty (PTA) for atherosclerotic disease;
An ankle/brachial systolic blood pressure ratio <0.90 in either leg at rest; OR
Angiographic, CT angiographic or doppler findings demonstrating >70% stenosis in a noncardiac artery;
C. History of stroke as defined by any one of the following 2 criteria
A physician diagnosis of stroke; OR
CT or MRI evidence of a prior stroke;
D. Undergoing major vascular surgery defined as all vascular surgeries (including any above foot amputation) with the exception of arteriovenous shunt, vein stripping procedures (varicose vein surgery), carotid endarterectomies, endovascular abdominal aortic aneurysm repair (EVAR); OR
E. Any 3 of 9 risk criteria:
Undergoing major surgery defined as: intraperitoneal, intrathoracic, retroperitoneal, or major orthopaedic;
History of congestive heart failure defined as a physician diagnosis of a current or prior episode of congestive heart failure OR prior radiographic evidence of vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary oedema;
History of a transient ischaemic attack;
Diabetes diagnosis and currently taking hypoglycemic agent;
Age ≥70 years;
History of hypertension;
Serum creatinine >175 μmol/L (>2.0 mg/dl) based on the most recent values before randomisation;
History of smoking within 2 years of surgery; and
Undergoing emergent/urgent surgery, defined as surgery that a surgeon schedules to go to the operating room within 48 hours from an acute presentation to the hospital.
Patients with any of the following criteria will not be included in the study:
PATIENT RECRUITMENT AND INFORMED CONSENT
PREVENT-MINS Trial will enrol patients from more than 20 centres located in Poland. In most centres, study personnel will screen the patient list in the preoperative assessment clinic to identify eligible patients. Study personnel will use a variety of screening approaches to capture patients who do not attend the preoperative assessment clinic, including screening the daily surgical list in the operating room, patients on surgical wards and ICUs, and patients in the preoperative holding area. At each centre, the services of anaesthesia, surgery, and medicine will be asked to notify the study personnel regarding all surgical admissions through the emergency department and ward patients requiring surgery. Study personnel will approach all eligible patients to obtain informed consent before surgery. Whenever possible, patients will be approached in preoperative clinics to inform them about the trial. Patients who were not identified or approached in the preoperative clinic will be contacted before surgery to discuss the trial and their potential participation.
Randomisation will be performed before surgery after a patient is deemed eligible and written informed consent is obtained. Study personnel will randomise patients via an Interactive Web Randomisation System (IWRS). The computerized randomisation process will use random permuted blocks of sizes 4 or 6 and stratification by centre. Study personnel will not know the block size. Patients will be randomised to receive study drug or matching placebo according to a 1:1 ratio. IWRS will be available 24h a day and will ensure full anonymity and security of the data.
Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a HR ≥65 bpm) will receive 5mg of oral ivabradine or matching placebo as an add on to the standard treatment at least 1 hour before surgery and the first postoperative dose in the evening or in the morning post-op, at least 12 hours after the preoperative dose provided that HR is ≥65bpm with systolic blood pressure ≥90 mm Hg. Starting on the day after surgery, patients will receive 5mg oral ivabradine or matching placebo twice a day (BID). The administration of the study drug will be stopped after the final dose (i.e. postoperative day 7) or at discharge from the hospital. If the patient develops atrial fibrillation or atrial flutter, the study drug will be held until the patient returns to sinus rhythm. Placebo tablets will have similar appearance as the active drug administered to participants in the intervention group (ivabradine 5mg). Patients, treating physicians, healthcare providers, data collectors, study investigators and statisticians will be blind to treatment allocation.
Safety aspects of the intervention:
We established safety parameters to hold the drug (e.g. bradycardia, systolic blood pressure <90 mm Hg, onset of atrial fibrillation). Patients with known sensitivity to ivabradine and those deemed to be at an increased risk of adverse events from the study drug (e.g. patients treated with verapamil/diltiazem) based on existing data and statements of regulatory bodies will be excluded from the trial. Investigators and other members of the treatment team will not break the treatment code unless it is absolutely necessary to ascertain the type of treatment received (ivabradine or placebo) by a given patient in order to choose between crucial therapeutic options (please see emergency unblinding section).
None of the Project Office nor Steering Committee members will have access to the list of treatments allocated to patients, except the authorised persons of the data management committee (DMC), who will be responsible for supervising all safety aspects of the study. The unblinded documentation will remain confidential and will not be made available to anyone outside the DMC.
Preparation and shipment of the study drug/placebo:
Both active drug and placebo will be manufactured and packaged at the same pharmaceutical company according to Good Pharmacological Practice rules. Placebo tablets will be manufactured by pharmaceutical company with drug production facilities located in Poland and will meet all standards of study placebo.
We have incorporated design features into PREVENT-MINS trial to minimize ivabradine side effects risks. First, we will require patients to have SBP ≥90mmHg with a preoperative heart rate of ≥65 beats per minute (bpm) to be eligible for the trial and to receive the study drug. Second, the exclusion criteria in the study were carefully designed to minimize drug interactions with known substances and patients’ conditions. Furthermore, the study drug will only be used for up to 7 days after surgery, which in comparison to other studies in non-surgical settings is a very short period, and the amount of possible ivabradine complications should be relatively smaller. Ivabradine will be administered during hospitalization which will enable careful observation and side effects detection.
Perioperative bradycardia can occur for many reasons. It is a known complication during general anaesthesia, as a side effect of inhaled anaesthetics, opioids or agents used to reverse effects of nondepolarizing neuromuscular blocking agents (acetylcholinesterase inhibitors, sugammadex). It can be triggered by surgical intervention. Bradycardia can also occur during neuraxial blockade, when high thoracic level is involved. Fortunately, in most cases bradycardia is transient and resolves spontaneously or after administration of an anticholinergic agent (e.g. atropine) without any further complications. Patients receiving medications that slow the heart rate are at higher risk of developing bradycardia.
We will exclude patients receiving nondihydropyridine calcium channel blockers and class I or III antiarrhythmic drugs from the trial to minimize the risk of serious bradyarrhythmias. We will encourage physicians to closely monitor patients, especially ones on beta-blockers, participating in the trial. In case of bradycardia detection, we recommend general management according to the site’s local guidelines. The decision regarding withholding or discontinuing the oral study drug will rest with the attending physician. They will be encouraged to continue the oral study drug unless the patient has clinically important bradycardia or other side effects (e.g. hypotension). If so, physicians may temporarily interrupt or permanently discontinue the study drug.
After hospital admission, patients will be randomly allocated to the treatment strategy: ivabradine or placebo. Administration of all medications that are not contraindicated to be used together with ivabradine is permitted during the study. Patients selected for the study should receive optimal medical therapy appropriate to their cardiovascular condition including all heart rate reducing drugs except nondihydropyridine calcium channel blockers and class I or III antiarrhythmic drugs. Patients unable to tolerate beta-blockers and receiving nondihydropyridine calcium channel blockers due to coronary artery disease or hypertension will be excluded from the study. Concomitant treatments received by patients (and their respective doses) will not be modified during the study unless it is recommended according to current clinical practice. Patients with myocardial infarction (according to the universal definition) will receive treatment according to the current guidelines.
Study personnel will follow patients throughout their time in hospital after surgery. They will be evaluating the patients, reviewing their medical records, and recording any outcomes.
Troponins will be measured in hospital after surgery on postoperative days 1, 2, and 3. An ECG will be obtained whenever an elevated troponin is detected, as per routine practice. The heart ultrasound and/or cardiologist consult will be ordered when needed. Blood pressure and heart rate will be monitored according to routine clinical practice.
The personnel will assess outcome occurrence 30 days after randomisation by telephone or approach participants during in-person visits scheduled at the enrolling site according to the postoperative care plan, with a uniform and standardised collection of outcome data in both cases. The personnel will contact all patients by telephone at 1 year after randomisation to assess outcome occurrence. Investigators can appoint unscheduled visits for any conditions if medically justified according to their knowledge.
Patient outcomes are determined throughout the trial and at the completion of the follow-up. APPENDIX II provides definitions for all outcomes.
The primary outcome is myocardial injury after non-cardiac surgery (MINS) defined as any myocardial infarction and any elevated postoperative cardiac troponin judged as resulting from myocardial ischaemia during or within 30 days after noncardiac surgery. In centres routinely using Roche’s fifth generation Elecsys hsTnT, we will use an established cut-off of 20 ng/L combined with an absolute change of ≥5 ng/L (judged as due to ischemia) to diagnose MINS. The optimal change criteria for other troponin assays will be individualized based on the cTn assay characteristics, absolute cTn concentration, the timing of measurement, and pretest probability of an acute versus chronic insult.
As of the time of writing the current version of the protocol, the above-mentioned criteria represent an up-to-date state of knowledge on what constitutes a prognostically important change in troponin concentrations measured using different commercially available high sensitivity troponin assays. Myocardial injury after noncardiac surgery (MINS) is a relatively newly established diagnosis and acute myocardial injury has only recently been recognized in the most recent guidelines as a separate clinical entity (22). Given the dynamically changing landscape of evidence in this field, the definition of MINS may be refined during the conduct of the trial. If this happens, a protocol amendment may be necessary to warrant adherence to the universal definition of MINS currently in force at the time of termination of the trial. Any potential changes in the definition will be made before unblinding of data with the aim of improving the trial’s results applicability to clinical practice.
Secondary outcomes at 30 days include: a composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest; vascular death; MINS not fulfilling the criteria of myocardial infarction; myocardial infarction; peak troponin concentration; area under the curve troponin; days alive and at home; stroke; all-cause mortality; health-related quality of life; cancellation/postponement of surgery on the day of surgery due to HR concerns; clinically important atrial fibrillation; safety outcomes including clinically significant bradycardia, clinically significant hypotension and phosphenes.
Tertiary outcomes at 30 days include: cardiac revascularization; re-hospitalization for vascular reasons; acute myocardial injury according to Fourth Universal Definition of Myocardial Infarction; non-fatal cardiac arrest; acute congestive heart failure; deep vein thrombosis/pulmonary embolism; major bleeding according to ISTH definition; bleeding independently associated with mortality after noncardiac surgery; sepsis; acute kidney injury fulfilling KDIGO criteria; acute kidney injury requiring dialysis; amputation; days outside the Intensive Care Unit; length of hospital stay; length of ICU stay; discharge destination.
Tertiary outcomes at 1 year include: all-cause mortality; vascular death; myocardial infarction; non-fatal cardiac arrest; stroke; health-related quality of life; amputation; cardiac revascularization; cardiac revascularization, re-hospitalization for vascular reasons.
The Event Adjudication Committee consisting of physicians and researchers with expertise in perioperative medicine who are blinded to treatment allocation and who will adjudicate the primary outcome. An event adjudication plan will be developed and govern all details, definitions, and processes. We will use the decisions of the adjudication committee for all statistical analyses.
We will analyse patients in the treatment group to which they are allocated, according to the intention-to-treat principle. A statistical analysis plan will be developed and finalised before any investigator is unblinded. A per-protocol analysis based on data from study subjects who completed the entire study period with outcome measurements available will serve as a sensitivity analysis to assess whether conclusions are sensitive to assumptions regarding the pattern of missing outcome information.
Patients’ demographics, clinical characteristics, and all outcome measurements will be summarized by median with inter-quartile range (IQR, continuous measurements) and frequency with percentage (categorical measurements). These descriptive statistics will be reported separately by study arm. For efficacy outcomes, both unadjusted and multivariable-adjusted results will be reported. All analyses will be conducted with R software.
We will use generalized mixed-effects logistic models to compare the odds of MINS between the ivabradine group and placebo group. These models will account for the stratification by centre and include prespecified prognostically important covariates (age, chronic coronary syndrome, chronic heart failure, baseline NT-proBNP concentration, estimated GFR, peripheral artery disease, diabetes mellitus on insulin therapy) to increase the power and precision of the estimate. This adjusted analysis will be considered the primary analysis. The result will be presented as an odds ratio (OR) with 95% CI. We will infer statistical significance if the computed 2-sided p-value is less than ɑ=0.05.
For dichotomized endpoints, the same approach as described in the primary endpoint section will be used. For quantitative endpoints, we will use mixed-effects models (linear, Poisson, or negative binomial, depending on the distribution of data for a particular endpoint) according to the prespecified statistical analysis plan. All these models will account for the stratification by centre and include prespecified prognostically important covariates (see above) to increase the power and precision of the estimate. We will infer statistical significance if the computed 2-sided p-value is less than ɑ=0.05.
A Data Monitoring Committee (DMC) will meet approximately every 12 months to review safety, protocol compliance and deviation, recruitment, and follow-up rates.
The type I error probability for multiple tests of superiority will be controlled by using a Lan-DeMets (O’Brien-Fleming) alpha spending function with the two-sided type I error of α=0.05 (46). We will perform the interim formal testing at the following time points: 50% of the outcomes are observed, 75% of the outcomes are observed, and the final analysis of all observed outcomes. Two-sided tests of significance will be assumed.
The conditional power based on the method of stochastic curtailment will be used for the early stopping for futility (47). This procedure evaluates the conditional probability that a particular statistical comparison will be significant at the end of the trial at the α level used in the design, given the hypothesized treatment difference and the endpoint data accumulated to date. Conditional power for the primary endpoint will be computed and provided to the DMC as part of the interim study reports and will include calculations based on the originally hypothesized treatment difference as well as the observed treatment difference up to that point in the trial. Discussion about termination of the trial will be triggered by a conditional power < 0.2.
All the missing covariates will be imputed using the MICE (Multiple imputation using chained equations) multiple imputation procedure (48). Thirty iterations with 5 burn-in will be used for all analyses.
Six planned subgroup analyses will be conducted. All subgroups will be analysed using both ITT and PP populations:
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: is life-threatening; or requires inpatient hospitalization or prolongation of existing hospitalization; or results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect; or is a medically important event.
Suspected unexpected serious adverse reactions (SUSARs) are events that meet the following criteria: 1) suspected to be causally associated with ivabradine; 2) unexpected if the nature, severity, or outcome of the reaction(s) is not consistent with the reference information (i.e. product monograph for ivabradine); 3) serious (as defined above for an SAE); and 4) not an efficacy outcome as defined in Section regarding Trial Outcomes.
Efficacy and safety outcomes will be recorded separately and not as SAEs, except if, because of the course or severity or any other feature of such events, the investigator, according to his/her best medical judgment, considers these events as exceptional in this medical condition. Hospitalizations, which were planned before inclusion in the study (e.g. elective or scheduled surgery or other interventions), will not be regarded as SAEs. This pertains also to hospitalizations which are part of the normal treatment or monitoring of the studied disease or another disease present before inclusion in the study (e.g. patient returning to the hospital for chemotherapy), and which did not result in a worsening of the disease.
All SAEs need to be reported within 24 hours of knowledge of the event to the Project Office. For such events, research personnel will complete an SAE CRF in the database. The Project Office will then inform regulatory authorities in a timely manner, as necessary, according to the applicable regulations.
The independent DMC will provide oversight of patients’ safety throughout the trial by reviewing unblinded aggregate data (including all reported study outcome events and SAEs) by treatment group at regular intervals throughout the duration of the trial and ensure that the study adheres to the highest ethical standards. At any time during the trial if safety concerns arise the DMC chairperson will assemble a formal meeting of the full committee. The DMC will make their recommendations to the Steering Committee after considering all the available data.
Substudies may be added at a later date based on the recommendation of the Project Office. A local biorepository will be established to store biological material from blood samples collected during the main project for possible substudies. We will investigate several prognostic factors (e.g. frailty, natriuretic peptide concentration, heart rate) in the context of perioperative complications and externally validate existing cardiac risk prediction tools in our sample. We also plan to evaluate the potential genetic heterogeneity of ivabradine’s treatment effect (e.g. HCN2 gene). These substudies will not be part of the main protocol and the analysis and reporting of these substudies will be separate from the main study.
The National Sponsor of the trial is Jagiellonian University Medical College (JUMC). The trial is financed by the Medical Research Agency (funds obtained as a grant for research and development activities in the field of non-commercial clinical trials no. ABM/2019/1). The trial will be conducted in partnership with the Hamilton Health Sciences Corporation (“HHSC”), through its Population Health Research Institute (PHRI) in Ontario, Canada. PHRI has extensive experience in methodology and conduct of clinical trials. Professor P.J. Devereaux (PHRI, Senior Scientist) will hold the position of the Trial Chair.
Project Office
The Principal Investigator, Principal Co-investigators, Project Manager, Research Assistant, and Project Coordinator are responsible for the activities of the Project Office. The PREVENT-MINS Project Office, part of Jagiellonian University Medical College, is the coordinating centre for this trial and is primarily responsible for the development of the trial protocol, organization of the trial, development of the randomisation scheme, trial database, data internal consistency checks, data analyses, coordination of the trial centres, and conducting the trial.
Throughout the trial, the Project Office will be in contact with all the sites. Periodic teleconferences with sites to discuss topics such as recruitment status, data quality, and outcome event reporting will be organized. Recruitment reports and periodic newsletters will be distributed among sites to keep them informed of the trial status and progress. Recruitment, drug dispensing, follow-ups and eCRF completion will be tracked by the web systems. The due-date reminder notifications and delay reminder calls will be provided to avoid any timeline disturbances. The eCRF database and IWRS will be maintained throughout the whole study. The data manager, as a part of the Project Office, will keep constant surveillance over central data consistency.
Logistic issues, like drug shipments, drug disposal, biobank samples’ cryogenic transportation, all travel and meeting issues will be managed by specialized companies contracted by the Project Office. The University will aid in the management of human resources and financial issues.
The Steering Committee and Data Monitoring Committee will be formed. The Steering Committee will include:Project Principal Investigator, a representative of the Project Leader (JUMC) and a representative of the Project Partner (HHS). The Steering Committee meetings will be held on a quarterly basis. The Data Monitoring Committee will include external biostatisticians and experienced scientists. A schedule of regular (at least once a year) committee meetings will be established.
All participating centres will have a site Principal Investigator (PI), and this individual is responsible for ensuring compliance with respect to the intervention, visit schedule and procedures required by the protocol. The site PI will provide all information requested in the Case Report Forms (CRFs) in an accurate and timely manner according to instructions provided. The site PI will maintain patient confidentiality with respect to all information accumulated in the course of the trial, other than that information to be disclosed by law.
All investigators will be recruited among surgeons, anaesthetists, internal medicine practitioners and cardiologists who are familiar with the perioperative area and its specificity. All local PIs and co-investigators are accustomed to the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable regulations of the Polish law.
This trial will be conducted in compliance with the protocol, the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable regulations of the Polish law. Before study initiation, the Investigator must have written and dated Central Regulatory Approval from the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych, URPL) and Jagiellonian University Bioethics Committee’s approval for the study. Following the approval by the URPL and Ethics Board, Principal Investigators from all participating sites must have: written and dated approval/favourable opinion from the Institutional Review Board (IRB; signed by director of the site or representative); Local Ethics Committee (EC) for the protocol, consent form, patients’ informed consent materials; site contract agreement with the Project office before the initiation of the study. Amendments to the protocol will also require IRB/EC and/or URPL approval.
The weighing of the risks and inconveniences against the anticipated benefit to the individual trial subjects and society supports conducting the PREVENT-MINS Trial. Perioperative increases in the heart rate are common and can lead to myocardial ischaemia which is associated with an increased risk of major cardiovascular complications after surgery. Ivabradine holds substantial promise of preventing ischaemic myocardial injury. Oral administration of ivabradine in the evening prior to the procedure and twice daily for one week after surgery should not pose any significant inconvenience to the patients. Adverse events seen with ivabradine are usually benign and can be relatively easily managed in the perioperative period. There is compelling evidence that the use of ivabradine is safe in patients with chronic coronary syndrome and heart failure in the non-operative setting and preliminary data show that perioperative treatment with ivabradine is feasible and potentially beneficial in surgical patients. Therefore, the risk of experimental evaluation of ivabradine in patients having noncardiac surgery is judged as low and acceptable.
All research personnel will undergo a training session prior to trial commencement to ensure consistency in trial procedures including data collection and reporting safety issues. Study personnel will complete CRFs through an internet platform. Data will be stored on a secure server. Source documentation supporting the information reported on the CRF will be filed at the site and made available for monitoring, IRB/EC review, and regulatory inspections, when required. The Investigator must retain all study records/files in accordance with applicable regulatory requirements. The Data Management Plan will be prepared by the study statistician in adherence to the Good Clinical Data Management Practices from the Society for Clinical Data Management.
All personal data collected from the study will be protected in accordance with the Polish and European data protection legislation such as the Polish Personal Information Protection Act of 10 May 2018 (Dz.U. 2018 poz. 1000) and Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data. Patients will be assigned a unique trial identification number to ensure anonymity. These ID numbers will correspond to allocation data in secure electronic files. Only the DMC and the statistician reporting to the DMC will be aware of the unblinded data until the trial is completed.
Centres will be instructed to store any patient information containing names or other personal identifiers separately and identified by their ID number. Centres will secure all local databases with password-protected access systems. Individual subject medical information obtained as a result of this trial is considered confidential and disclosure to third parties is prohibited except for reasons clearly identified by the law. Medical information may be given to the subject’s personal physician or to other appropriate medical personnel responsible for the subject’s welfare. Data generated as a result of the trial are to be available for inspection on request by the participating physicians, IRB/IEC, and regulatory authorities.
Emergency situations may require unblinding of treatment. As the treating physician (investigator) is responsible for the medical care provided to the trial participant, the decision to break the treatment code in an emergency situation will lie solely with the investigator. Remote access (e.g. by primary or secondary back-up telephone number) will be provided to allow the blind to be broken immediately.
An estimated 100 million adults ≥45 years of age having noncardiac surgery are at risk of perioperative myocardial infarction or injury. Myocardial ischaemic injuries are a leading cause of 30-day mortality after noncardiac surgery. Increased heart rate is considered a modifiable risk factor for myocardial injury after noncardiac surgery. Perioperative beta-blockade has been shown to reduce both the heart rate and the risk of myocardial infarction, yet the potential harm associated with hypotension resulting from the initiation of beta-blockers short before noncardiac surgery precluded the widespread adoption of this strategy in preventing myocardial ischaemia. Ivabradine can be as potent as beta-blockers in slowing down the heart rate without exerting any impact on blood pressure. PREVENT-MINS trial will answer the question whether perioperative administration of ivabradine is superior to placebo in preventing myocardial injury after noncardiac surgery.
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on the conduct of the trial due to various circumstances such as, but not limited to:
In alignment with the COVID-19 guidance documents, issued by the EMA and FDA, appropriate measures for identification and mitigation of the potential risks for the current trial associated with the COVID-19 pandemic have been planned. This guidance does not supersede any local, regional or international requirements or the clinical judgment of the investigator to protect the health and well-being of the trial subjects and site staff. If at any time the Investigator or study Sponsor would assess that the risk of the pandemic on this clinical trial may outweigh the benefits, the same as for any other reasons, study treatment period will be interrupted, and study follow-up will be conducted.
The Sponsor will regularly re-assess the risks associated with the pandemic and, if needed, will take new measures when applicable:
The personnel will assess outcome occurrence 30 days after randomisation by telephone or approach participants during in-person visits scheduled at the enrolling site according to the postoperative care plan, with a uniform and standardised collection of outcome data in both cases. Telephone visit will be conducted to collect 1-year follow-up data.
If any change in subject’s status is identified that may impact the subject’s safety, then study treatment should be interrupted until the subject can be assessed. Any changes in study treatment (frequency, interruption) needs to be clearly documented as “COVID-19-related”.
All deviations from protocol-required assessments should be documented in detail within the subject’s source record and should be clearly designated as “COVID-19-related”.
The sites’ study drug inventory should be closely monitored. Site staff should notify the assigned site monitor if they foresee shortage in the study drug inventory or if there is any interruption in local shipping service. The Sponsor’s assigned Clinical CROs and Study Drug Logistic vendors will continue to monitor inventory of the study drug at study sites.
For trial subjects who are diagnosed with COVID-19 during the active treatment period we encourage the investigators to continue administering the study drug according to the predefined schedule. Such cases should be reported to the Sponsor.
Monitoring visits will be a combination of on-site and remote monitoring methods. In case on-site monitoring visits are not possible, as per institution policies, the sponsor’s site managers may contact the investigator to arrange remote monitoring visits. Additional on-site monitoring visits may be needed in the future to complete source data verification.
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| Time Period | Screening | Baseline | IN HOSPITAL | Follow-up | ||
|---|---|---|---|---|---|---|
| During Hospitalization | At Discharge | 30 days | 1 year | |||
| Eligibility Assessment | x | |||||
| Informed Consent | x | |||||
| Randomisation | x | |||||
| Demographics | x | |||||
| Medical History | x | |||||
| Concomitant Medications | x | x | x | x | x | x |
| Labs | x | x | x | |||
| Biobank | x | x | ||||
| Intervention | x1 | |||||
| Surgery Details | x | x | ||||
| Vitals signs | x | x | x | x | ||
| Troponin | x | x2 | ||||
| QOL3 form | x | x | x | |||
| ASA PS4, DASI5, CFS6 | x | |||||
| Outcome Event | x | x | x | x |
Myocardial injury after non-cardiac injury (MINS) is defined as any myocardial infarction and any acutely elevated postoperative cardiac troponin judged as resulting from myocardial ischaemia during or within 30 days after noncardiac surgery.
In centres routinely using Roche’s fifth-generation Elecsys hsTnT, we will use an established cut-off of 20 ng/L combined with an absolute change of ≥5 ng/L (judged as due to ischaemia) to diagnose MINS. The optimal change criteria for other troponin assays will be individualized based on the cTn assay characteristics, absolute cTn concentration, the timing of measurement, and pretest probability of an acute versus chronic insult.
Vascular death is defined as a death with a vascular cause and includes those deaths following a myocardial infarction, sudden cardiac arrest, stroke, cardiac revascularization procedure (i.e. percutaneous coronary intervention - PCI or coronary artery bypass graft [CABG] surgery), pulmonary embolus, cardiovascular haemorrhage, or deaths due to an unknown cause. Cardiovascular haemorrhage includes a non-stroke intracranial haemorrhage, non- procedural or non-traumatic vascular rupture (e.g. aortic aneurysm), or haemorrhage causing cardiac tamponade.
All-cause mortality includes both vascular and non-vascular death. Non-vascular death is defined as any death due to a clearly documented non-vascular cause (e.g. trauma, infection, malignancy).
Myocardial infarction is defined according to the Fourth Universal Definition of Myocardial Infarction:
Cardiac death in patients with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes before cTn values become available or abnormal.
Coronary intervention-related MI is arbitrarily defined by an elevation of cTn values more than five times the 99th percentile URL in patients with normal baseline values. In patients with elevated pre-procedure cTn in whom the cTn level is stable (< 20% variation) or falling, the post-procedure cTn must rise by >20%. However, the absolute post-procedural value must still be at least five times the 99th percentile URL. In addition, one of the following elements is required: (I) New ischaemic ECG changes; (II) Development of new pathological Q waves; (III) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology; (IV) Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or a side branch occlusion/thrombus, disruption of collateral flow, or distal embolization.
Stent thrombosis associated with myocardial infarction when detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker values with at least one of value above the 99th percentile URL.
CABG-related MI is arbitrarily defined as elevation of cTn values > 10 times the 99th percentile URL in patients with normal baseline cTn values. In patients with elevated pre-procedure cTn in whom cTn levels are stable (≤20% variation) or falling, the postprocedure cTn must rise by > 20%. However, the absolute postprocedural value still must be > 10 times the 99th percentile URL. In addition, one of the following elements is required: (I)Development of new pathological Q waves; (II) Angiographic documented new graft occlusion or new native coronary artery occlusion; (III) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology.
Non-fatal cardiac arrest is defined as successful resuscitation from either documented or presumed ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation, pharmacological therapy, or cardiac defibrillation.
Acute myocardial injury according to the Fourth Universal Definition of Myocardial Infarction is defined according to the Fourth Universal Definition of Myocardial Infarction as a detection of an elevated cTn value above the 99th percentile URL with a rise and/or fall of cTn values.
Peak troponin concentration is defined as a peak cTn concentration measured in the postoperative period.
Area under the curve troponin is defined as total cTn release measured as area under the Troponin-Time curve.
Clinically significant bradycardia is defined as bradycardia that required a pacemaker, sympathomimetic agent, atropine, or study drug discontinuation.
Clinically significant hypotension is defined as systolic blood pressure <90 mm Hg that required fluid resuscitation, intra-aortic balloon pump, a vasoactive agent, or study drug discontinuation.
Phosphene is defined as the phenomenon of seeing light without light actually entering the eye.
Cardiac revascularization includes PCI and CABG surgery.
Re-hospitalization for vascular reasons is defined as a re-hospitalization due to myocardial infarction, nonfatal cardiac arrest, stroke, congestive heart failure, ischaemic symptoms with ST or T wave changes on an ECG, cardiac arrhythmia, cardiac revascularization procedure, amputation, peripheral arterial thrombosis, DVT, pulmonary embolus, any vascular surgery, or cardiovascular haemorrhage.
Acute kidney injury fulfilling KDIGO criteria is defined as an increase in serum creatinine concentration by either an increase of ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours or an increase of ≥50% from baseline within 7 days or urine output <0.5 mL/kg/h for 6 hours.
Acute kidney injury requiring dialysis is defined as an acute kidney injury leading to the use of a haemodialysis machine or peritoneal dialysis apparatus.
Stroke is defined as a new focal neurological deficit thought to be vascular in origin with signs or symptoms lasting more than 24 hours or leading to death. Stroke will be sub-classified into haemorrhagic and non-haemorrhagic stroke.
Health-related quality of life will be evaluated using a validated Polish version of EuroQoL 5 Dimension (EQ-5D; five-level version with visual analogue scale) tool.
Length of hospital stay is defined as the number of nights in the hospital.
Length of ICU stay is defined as the number of nights in the ICU.
Discharge destination is defined as a destination of patient`s discharge from the hospital (i.e. home or long-term care facility or other).
Days outside the Intensive Care Unit is defined as the number of nights outside the Intensive Care Unit within 30 days after the index procedure.
Days alive and at home is defined as the number of days when a patient is alive and out of hospital within 30 days after the index procedure_._
Acute congestive heart failure is defined as an episode characterized by at least one of the following clinical signs (i.e. any of the following signs: elevated jugular venous pressure, respiratory rales/crackles, crepitations, or presence of S3) and at least one of the following: (I) Radiographic findings (i.e. vascular redistribution, interstitial pulmonary oedema, or frank alveolar pulmonary oedema) OR (II) Heart failure treatment implemented with diuretics with documented clinical improvement.
Deep vein thrombosis/pulmonary embolism is defined as a symptomatic or an asymptomatic episode of deep vein thrombosis or pulmonary embolism. The diagnosis of deep vein thrombosis requires evidence of thrombus presence in deep veins of upper or lower extremities defined as any of the following: (I) a persistent intraluminal filling defect on contrast venography (including on computed tomography), (II) noncompressibility of one or more venous segments on B mode compression ultrasonography, or (III) a clearly defined intraluminal filling defect on doppler imaging in a vein that cannot have compressibility assessed (e.g., iliac, inferior vena cava, subclavian). Diagnosis of pulmonary embolism requires any one of the following: (i) A high probability ventilation/ perfusion lung scan (ii) An intraluminal filling defect of segmental or larger artery on a helical CT scan (iii) An intraluminal filling defect on pulmonary angiography (iv) A positive diagnostic test for deep venous thrombosis (e.g. positive compression ultrasound) and one of the following: (a) Non-diagnostic (i.e. low or intermediate probability) ventilation/perfusion lung scan (b) Non-diagnostic (i.e. subsegmental defects or technically inadequate study) helical CT scan.
Major bleeding according to ISTH definition is a bleeding meeting any of the following criteria: (I) Fatal bleeding; (II) Bleeding that is symptomatic and occurs in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, pericardial, in a non-operated joint, or intramuscular with compartment syndrome, assessed in consultation with the surgeon; (III) Extrasurgical site bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells, with temporal association within 24–48 h to the bleeding; (IV) Surgical site bleeding that requires a second intervention - open, arthroscopic, endovascular – or a hemarthrosis of sufficient size as to interfere with rehabilitation by delaying mobilization or delayed wound healing, resulting in prolonged hospitalization or a deep wound infection, or (V) Surgical site bleeding that is unexpected and prolonged and/ or sufficiently large to cause hemodynamic instability, as assessed by the surgeon. There should be an associate fall in hemoglobin level of 20 g/L (1.24 mmol/L), or transfusion, indicated by the bleeding, of at least two units of whole blood or red cells, with temporal association within 24 h to the bleeding.
Bleeding Independently associated with Mortality after noncardiac Surgery (BIMS) is defined as bleeding that leads to a postoperative haemoglobin <70 g/L, leads to blood transfusion, or is judged to be the immediate cause of death.
Clinically important atrial fibrillation is defined as a new onset of atrial fibrillation or atrial flutter of any duration on an ECG or rhythm strip, which results in angina, congestive heart failure, symptomatic hypotension, or requires treatment with a rate controlling drug, antiarrhythmic drug, or electrical cardioversion.
Sepsis is defined as an increase in SOFA score of 2 or more, with evidence of infection. This outcome includes septic shock defined as sepsis with shock (vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mM [>18 mg/dl] in the absence of hypovolaemia). Infection is defined as a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic organisms.
Amputation is defined as an amputation procedure, or auto amputation subsequent to the initial surgery.
Cancellation/postponement of surgery on the day of surgery due to HR concerns is defined as cancellation or postponement of index surgery on the day of the index surgery attributed to concerns about heart rate as assessed by treating physician (anaesthesiologist or surgeon).
Power and sample size estimations were based on a group sequential design with 2 interim analyses conducted when 50% and 75% outcomes were collected. An overall two-sided type I error rate of α=0.05 will be achieved by using the Lan-DeMets (O’Brien-Fleming) alpha spending function. We anticipate that 2500 participants will be recruited, with a 2% dropout rate over the study period. The table below presents the statistical power of the trial for different plausible scenarios of the MINS rate in the control group assuming a 1:1 allocation ratio.
| Dropout Rate (N= Participants retained) | Event rate in control group | 20% Rate reduction in intervention group (RR=0.8) | 25% Rate reduction in intervention group (RR=0.75) |
30% Rate reduction in intervention group (RR=0.7) |
|||
|---|---|---|---|---|---|---|---|
| Event Rate | Power | Event Rate | Power | Event Rate | Power | ||
| 0% (N=2500) | 0.16 | 12.8% | 61.6% | 12.0% | 81.4% | 11.2% | 93.4% |
| 0.18 | 14.4% | 67.6% | 13.5% | 86.4% | 12.6% | 96.1% | |
| 0.2 | 16.0% | 73.1% | 15.0% | 90.3% | 14.0% | 97.7% | |
| 2% (N=2450) | 0.16 | 12.8% | 60.7% | 12.0% | 80.7% | 11.2% | 93.0% |
| 0.18 | 14.4% | 63.0% | 13.5% | 82.7% | 12.6% | 94.1% | |
| 0.2 | 16.0% | 68.6% | 15.0% | 87.1% | 14.0% | 96.4% |
