April 21, 2016

ARTICLE REVIEW

There has been conflicting evidence about the potential effects of statin initiation, continuation or withdrawal on renal function. This single centre (Vanderbilt University Medical Center, USA), double blind trial, analysed data from 615 patients undergoing cardiac surgery randomised to receive either atorvastatin or placebo. It included 199 patients naïve to statins and 416 already taking them. Those randomised to atorvastatin received 80mg one-day pre-surgery, 40mg on the day of surgery and 40mg one day post-op if they were statin naïve. Alternatively they received 80mg on the day of surgery, 40mg one day post-op and resumed their usual statins on day 2 if they were already prescribed pre-enrollment. The primary outcome was the development of AKI (Acute kidney injury network criteria). (1)

Results

  • Recruitment of patients naïve to statins was halted by the data and safety monitoring board due to increased rates of AKI (9/17 =52.9%) in the subgroup of patients with CKD receiving atorvastatin compared with the placebo group (3/19 =15.8%) (RR, 3.35 [95% CI, 1.12 to 10.05]; P = 0.03).
  • The study was stopped on grounds of futility when there was no significant overall difference in AKI incidence at interim analysis. AKI occurred in 64/308 (20.8%) receiving atorvastatin vs. 60/307 (19.5%) receiving placebo (RR, 1.06 [95%CI, 0.78 to 1.46]; P = 0.75).
  • Among patients naive to statin treatment (n = 199), AKI occurred in 22 of 102 (21.6%) in the atorvastatin group vs. 13 of 97 (13.4%) in the placebo group (RR, 1.61 [0.86 to 3.01]; P = 0.15)
  • Among patients already taking a statin (n = 416), AKI occurred in 42 of 206 (20.4%) in the atorvastatin group vs. 47 of 210 (22.4%) in the placebo group (RR, 0.91 [0.63 to 1.32]; P = 0.63).

Discussion
Acute kidney injury (AKI) is a complex process associated with intra-renal and systemic inflammation including the release of toll-like receptors, the activation and recruitment of resident and infiltrating leucocytes, and increased levels of cytokines such as interleukin-6. (2) There are a number of pleiotropic effects of statins on endothelial function and inflammation that make them a possible candidate to improve outcomes in AKI.

Statins have been an attractive candidate for interventional studies in critical care as they have anti-inflammatory effects, have a good safety profile, are cheap, widely prescribed, and have been associated with positive outcomes in observational studies in a number of settings. However, results in several RCTs in a range of critical care settings have been disappointing. (3-7) In addition, there is evidence that acute high dose statin prescription may be associated with increased rates of AKI (8). AKI is a common complication of cardiac surgery, independently associated with increased complications including mortality and no specific treatments exist. (9)

This study adds important information to the statins story. It is a large, randomised, double blind trial. The recruitment of statin users as well as naïve patients with placebo control allows simultaneous study statin initiation, continuation and withdrawal- interventions which have previously, largely been assessed separately with conflicting results.

Although the numbers are small, the increased rate of AKI in CKD patients initiating high dose statins is striking. Note there was also a trend towards higher AKI in the naïve non-CKD group too. This is despite a very short period of intervention (3 days) and no significant difference in classic statin related side effects (elevated creatinine kinase, liver enzymes) noted. If there is a real risk it is not clear if it only exists for high dose statins.

The statin users randomised to placebo had equivalent outcomes to those that continued. This is reassuring as statins may be omitted in critical care if the enteral route is not available initially.

Conclusions

  • There is no role for the prescription of high-dose statins to prevent AKI in cardiac surgery patients (and highly unlikely to be for any other group).
  • Patients with CKD are at increased risk of AKI with high dose statin initiation in this setting and this may be relevant in other critical care situations.
  • Both the continuation of pre-operative statins and the withdrawal of statins in those assigned to placebo appeared safe.
  • Another negative RCT for the pleiotropic effects of statins makes the pursuit of further trials harder to justify in critical care.

Article review was submitted by ESICM Journal Review Club member Matthiew Varrier on behalf of the AKI section.

References

1.    Billings FTt, Hendricks PA, Schildcrout JS, Shi Y, Petracek MR, Byrne JG, et al. High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomised Clinical Trial. Jama. 2016;315(9):877-88.
2.    Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, et al. Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps. J Am Soc Nephrol. 2016;27(2):371-9.
3.    Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, et al. A multicenter randomised trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013;187(7):743-50.
4.    Papazian L, Roch A, Charles PE, Penot-Ragon C, Perrin G, Roulier P, et al. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomised clinical trial. Jama. 2013;310(16):1692-700.
5.    McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371(18):1695-703.
6.    Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370(23):2191-200.
7.    Wong GK, Chan DY, Siu DY, Zee BC, Poon WS, Chan MT, et al. High-dose simvastatin for aneurysmal subarachnoid haemorrhage: multicenter randomised controlled double-blinded clinical trial. Stroke. 2015;46(2):382-8.
8.    Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, et al. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. Bmj. 2013;346:f880.
9.    Gaffney AM, Sladen RN. Acute kidney injury in cardiac surgery. Curr Opin Anaesthesiol. 2015;28(1):50-9.

 

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