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Three Part Question

In [cardiac surgical patients], does [preoperative statin reloading in patients on chronic statin therapy] improve [postoperative outcomes]?

Clinical Scenario

A 75-year old man is referred to you for elective cardiac surgery. He has already been taking simvastatin for many years. You know that preoperative statin therapy improves post-operative outcomes in statin-naive surgical patients. You consider whether you should prescribe him additional preoperative statin doses in an attempt to recapture this benefit.

To answer this question, you carry out a literature search for the evidence.

Search Strategy

(Statin*.mp OR Hydroxymethylglutaryl-coa reductase inhibitors/ OR (Simvastatin OR Rosuvastatin OR Fluvastatin OR Cerivastatin OR Lovastatin OR Pravastatin OR Atorvastatin).af) AND (Cardiac Surgery.mp OR Heart Surgery.mp OR Cardiac Surgical Procedures/ OR Coronary Artery Bypass/ OR Heart Valve Prosthesis Implantation/)

MEDLINE to August 2017 using the OVID interface.

Search Outcome

952 papers were found using the reported search. Studies without prior statin use or which failed to perform subgroup analysis based on statin use prior to study entry were excluded. In total, 5 papers were identified that provided the best evidence to answer the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kourliouros et al. 2011 UK	Patients on routine statin treatment. Usual statin discontinued during intervention period. Atorvastatin given for 7 days before and 14 days after surgery, or until discharge. Atorvastatin 10 mg (n = 53); Atorvastatin 80 mg (n = 49)	Single-centre prospective randomised trial (level 1b)	Post-operative atrial fibrillation	Atrial fibrillation occurred in 19 of 53 (36%) in the 10 mg group vs 14 of 49 (29%) in the 80 mg group (p = 0.43)	Single-blinded. Underpowered due to dropouts. Higher rate of β-blocker use in the low dose atorvastatin group (75% vs 53%, p = 0.002) may have attenuated any protective effect of higher dose atorvastatin. Discontinuation of usual statin therapy also represented a statin dose reduction for many patients in the 10 mg atorvastatin group.
Ludman et al. 2011 UK	Patients on >4 weeks statin treatment. Usual statin therapy continued. Atorvastatin 160 mg 2 hours prior to surgery and 24 hours after (n = 23); Control (n = 22). Atorvastatin 160 mg 12 hours prior to surgery and 24 hours after (n = 30); Control (n = 26).	Single-centre prospective randomised trial (level 1b)	Myocardial injury (Troponin T and total creatine kinase (CK) prior to surgery and at 6, 12, 24, 48 and 72 hours), Atrial fibrillation, Duration of intensive care unit stay	No significant difference between groups in all outcomes	Single-blinded.
Castaño et al. 2015 Spain	Patients with dyslipidaemia on >15 days statin treatment. Usual statin dose omitted night before surgery. 2 hours prior to induction: Pravastatin 80 mg (n = 10); Pravastatin 20 mg (n = 10); Placebo control (n = 10).	Single-centre prospective randomised trial (level 1b)	AF, 30 day Mortality, Duration of hospital stay, Duration of ICU stay, Myocardial injury (Troponin I and CK-MB on ICU admission and 4, 8, 16, 24, 32, 40, 48, 96 hours and at 30 days), Total CK, AST, ALT, Creatinine.	Reduction in postoperative concentrations of serum proinflammatory cytokines with statin reload. No significant difference between groups in all other outcomes.	Usual statin therapy included doses as high as 80 mg atorvastatin which is more potent than both 10 and 80 mg pravastatin. As a result, it was unclear whether patients were reloaded or in fact unloaded. Missing data.
Billings et al. 2016 USA	Patients on routine statin treatment. This was discontinued on day of surgery and restarted on postoperative day 2. Atorvastatin 80 mg given on the morning of surgery and 40 mg the morning after. Intervention (n = 206); Placebo control (n = 210).	Single-centre prospective randomised trial (level 1b)	Acute kidney injury, Creatinine peak at 48 hours, Delirium, Myocardial injury (Day 1 CK-MB), AF, Stroke, Pneumonia, Time to extubation, Duration of ICU stay, Hospital mortality	No significant difference between groups in all outcomes	Subsequent continuation of statin therapy was at the discretion of the treating physician.
Chee et al. 2017 Ireland	Patients already on 40mg or less atorvastatin or simvastatin. Usual statin therapy continued. Atorvastatin 80mg for 2 weeks prior to surgery (n = 15) and control (n = 15).	Single-centre prospective randomised trial (level 1b)	White cell count, Neutrophils, Serum creatinine, IL-8, MMP-9, Troponin and urine NGAL	Statin reload associated with lower troponin (p = 0.016) and urine NGAL (p = 0.002). Higher IL-8 and MMP-9 at baseline and 4 hours post cross-clamp removal	Patients on alternative statins other than atorvastatin or simvastatin were excluded. Study powered with a focus on biochemical opposed to clinical end-points.
			Hospital stay, Intensive care unit stay, Acute kidney injury, Transient ischaemic attack, Mortality	No significant difference

Comment(s)

All included studies were small randomised controlled trials consisting of low risk, elective patients. Many were not adequately powered to allow meaningful interpretation of clinical endpoints. Studies included statin regimens of varying potency and duration with a high degree of heterogeneity with baseline chronic statin therapy. In many cases, the control group represented withdrawal of established statin medication. No complications of statin therapy were reported. The available evidence suggests a protective effect of perioperative statin therapy on complications after cardiac surgery in statin-naive patients. Most cardiac surgery patients will already be on statin therapy in line with current clinical guidelines. As a result, this finding has limited applicability in day-to-day clinical practice. Statin reloading prior to percutaneous coronary intervention has been shown to significantly reduce major adverse cardiac events. However, there is little published evidence on this topic in cardiac surgery despite this being a more pragmatic clinical approach.

Clinical Bottom Line

Current best evidence does not support a strategy of preoperative statin reloading in the context of chronic therapy.

References

1. Kourliouros A, Valencia O, Hosseini MT, Mayr M, Sarsam M, Camm J, Jahangiri M. Preoperative high-dose atorvastatin for prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 2011;141: 244-8.
2. Ludman AJ, Hausenloy DJ, Babu G, Hasleton J, Venugopal V, Boston-Griffiths E, Yap J, Lawrence D, Hayward M, Kolvekar S, Bognolo G, Rees P, Yellon DM. Failure to recapture cardioprotection with high-dose atorvastatin in coronary artery bypass surgery: a randomised controlled trial. Basic Res Cardiol 2011;106: 1387-95.
3. Castaño M, González-Santos JM, López J, García B, Centeno JE, Aparicio B, Bueno MJ, Díez R, Sagredo V, Rodriguez JM, García-Criado FJ. Effect of preoperative oral pravastatin reload in systemic inflammatory response and myocardial damage after coronary artery bypass grafting. A pilot double-blind placebo-controlled study. J Cardiovasc Surg (Torino) 2015;56: 617-29.
4. Billings FT, Hendricks PA, Schildcrout JS, Shi Y, Petracek MR, Byrne JG, Brown NJ. High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: a randomized clinical trial. JAMA 2016;315: 877-88.
5. Chee YR, Watson RW, McCarthy J, Chughtai JZ, Nölke L, Healy DG. High dose statin prophylaxis in cardiopulmonary bypass related surgery: clinical utility. J Cardiothorac Surg 2017;12: 20.