Novel uses for statins in surgical patients

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Novel uses for statins in surgical patients
  Review Novel uses for statins in surgical patients P.R. Gajendragadkar, D.G. Cooper, S.R. Walsh, T.Y. Tang, J.R. Boyle, P.D. Hayes * Department of Vascular Surgery, Addenbrooke’s Hospital, Cambridge University Hospital NHS Trust, Hills Road, Cambridge CB2 0QQ, UK  a r t i c l e i n f o  Article history: Received 25 March 2009Received in revised form25 April 2009Accepted 27 April 2009Available online 9 May 2009 Keywords: StatinsSurgeryVascularReview a b s t r a c t Background:  Aside from their cholesterol-lowering effects statins are known to have a range of other‘pleiotropic’ effects. We present an overview of the basic science behind these effects and then reviewclinical trials and the current role of statins relevant to modern surgical practice. Methods:  A systematic review of the literature was performed using the keywords surgery and the MeSHterm for statins. All clinical studies relating to statin use in surgical patients were evaluated. An overviewof the literature on statin use and cardiac outcomes was performed. Conclusions:  Statins are safe and have a wide range of pleiotropic effects relevant to surgical practice.Strongest evidence for their clinical use comes in primary cardiac risk reduction in many types of vascular surgery. There is a large body of evidence showing their benefit perioperatively in high-riskvascular and cardiac surgery but the picture is less clear for low-risk patients. Further studies are neededto evaluate exact dosage regimes and timing of administration. Novel uses of their anti-inflammatoryproperties in sepsis and vasomotor properties in subarachnoid haemorrhage are being further investi-gated by randomised trials.   2009 Published by Elsevier Ltd on behalf of Surgical Associates Ltd. 1. Introduction Since approval for the treatment of dyslipidaemia in 1987, sta-tins or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors havebecome of the most commonly prescribed medications. 1 Mostevidence for long-term statin use comes from trials aiming toreduce adverse cardiac events. These have shown benefit inpatients for secondary cardiovascular risk reduction regardless of awidevarietyofvariablesincludingbaselinecholesterollevels. 2,3 Itis now well established that statins have a wide range of ‘pleio-tropic effects’ independent of cholesterol-lowering. 4 We reviewedthe current knowledge base on statins from a surgical perspective. 2. Methods A keyword based database search for studies evaluatingoutcomes of statin treatment relevant to surgical areas was con-ducted. This was done by evaluating articles found with thekeyword surgery and the MeSH term for statins – hydrox-ymethylglutaryl-CoA reductase inhibitors. Meta-analyses, rando-mised controlled trials and systematic reviews were used in thefirst instance. Observational studies were used where meta-anal-yses or randomised trials were unavailable or to illustrate the logicbehind the randomised trials. Case reports were not included. Anoverview of the literature on statin use and cardiac outcomes wasperformed. 3. Surgically relevant pleiotropic effects of statins The non-cholesterol linked effects of statins are an area of ongoing research. 4 Of particular surgical relevance are four areas:vasomotor effects, coagulation effects, inflammatory responsemodulation and atherosclerotic plaque stabilisation. These aresummarised in Fig. 1.  3.1. Vasomotor effects Statins prolong endothelial Nitric Oxide Synthase (eNOS)activity producing vasodilatation. 4,5 Animals exhibited bettercoronary relaxation if treated with statins despite no difference incholesterol versus placebo. 6 Atorvastatin improves brachial arteryflow in humans following transient systemic inflammation after Salmonella typhi  vaccination, and, short-term administration of pravastatin increases cerebral blood flow measured by transcranialDoppler in healthy adults. 7,8  3.2. Effects on coagulation Virchowidentifiedvesselwallthrombogenicity,localbloodflowproperties and circulating haemostatic factors as key factors *  Corresponding author. Tel.:  þ 44 (01223) 348190; fax:  þ 44 (01223) 216015. E-mail address: (P.D. Hayes). Contents lists available at ScienceDirect International Journal of Surgery journal homepage: 1743-9191/$ – see front matter    2009 Published by Elsevier Ltd on behalf of Surgical Associates Ltd.doi:10.1016/j.ijsu.2009.04.016 International Journal of Surgery 7 (2009) 285–290  influencing thrombus formation. 9 Statins reduce thrombin andlipopolysaccharide (LPS) induced tissue factor expression byendothelial cells. 10,11 Statins decrease platelet aggregation inde-pendent of levels of low density lipoprotein (LDL-C). 11,12 Statinsincrease tissue plasminogen activator (tPA) and inhibit plasmin-ogen activator inhibitor (PAI)-1, thus favouring fibrinolysis. 10 Asystematic review concluded that fibrinogen levels were affectedby statins in those patients who had high fibrinogen levels to startwith ( > 400 mg/dl). 13 It is increasingly recognised that raised levelsof fibrinogen predict the severity of, and serve as a marker forfuture development of peripheral arterial disease. 14  3.3. Inflammatory response modulation 3.3.1. Acute effects of statin use Intra-peritoneal simvastatin in rat models of acute pancreatitisreduces levels of the pro-inflammatory cytokine interleukin-10. 15 C-reactive protein (CRP) has a short half and is sensitive to ongoinginflammation. 16 The acute effect of statins on the systemicinflammatory response is reflected by CRP reductions within 24 hof high-dose simvastatin. 17 In healthy men, pre-treatment withsimvastatin lowered increases in CRP and other inflammatorymarkers after sepsis-induced inflammation by intravenous endo-toxin (LPS). 18 A rebound increase in CRP and other markers of inflammation within 2 days of discontinuing atorvastatin high-lights the importance of continuing therapy perioperatively. 19  3.3.2. Chronic effects of statin use Higherlevelsof CRP correlatewithcardiovascular risk as well asprogression of carotid artery stenosis. 16,20 In a randomised trial,pravastatin decreased CRP levels by 16.9% (  p < 0.001) over 12weeks independent of LDL-C levels and a variety of other vari-ables. 21 Risk reduction increased in proportion to baseline CRP. 21 The JUPITERtrialsupportsthe importanceof the effectofstatinsonCRP. 22 This multicentre, randomised, placebo-controlled trial of rosuvastatin enrolled 18,000 otherwise healthy patients with‘normal’ LDL-C levels but a highly sensitive CRP of  > 2 mg/l with noobvious cause. The mean hs-CRP was significantly lower in therosuvastatin treated group (  p < 0.001 between groups). Thecombined primary endpoint (myocardial infarction [MI], stroke,coronary revascularisation, hospitalisation for unstable angina andcardiovascular death) was significantly reduced by rosuvastatin(hazard ratio [HR] for rosuvastatin ¼ 0.56; 95% confidence interval[CI]: 0.46–0.69;  p < 0.00001). This correlates to a 5-year numberneeded to treat (NNT) to prevent one primary endpoint of 25. 22  3.4. Atherosclerotic plaque stabilisation/regression Fatal post-operative MIs result from plaque rupture as often asexcessive oxygen demand. 23 Statins dampen the inflammatoryatherosclerotic process, stabilising plaques. 11,24 They reduceinflammatory cells in coronary plaques at the vulnerable fibrouscap and also reduce LDL-C in the lipid core. 24–26 There is an asso-ciation between carotid intimal medial thickening (IMT) andcardiovascular disease. 27–32 Statins decrease mean IMT overa period of years, with the greatest decreases being proportional toLDL-C levels. 33,34 Two years of aggressive lipid lowering with sta-tins produced actual coronary plaque regression (a decrease inatheroma volumes) on intravascular ultrasound. 35 4. Perioperative statin use Making use of the wide range of pleiotropic effects of statinsperioperatively to reduce cardiovascular and other risks is an areaof ongoing research. A systematic review of observational studiesdemonstrated reductions in perioperative death or acute coronarysyndrome(ACS)withstatinuse(summaryoddsratio[OR]fordeathor ACS ¼ 0.70; 95% CI: 0.57–0.87). 36 The two randomised trialsincluded showed promising pooled results (summary OR for deathor ACS ¼ 0.26; 95% CI: 0.07–0.99). 36–38 The randomised DECREASE-IVtrialevaluatedthe effectsofbisoprololand fluvastatin oncardiacoutcomes in ‘intermediate risk’ patients undergoing a variety of elective non-cardiac surgery. 39 The primary endpoint of cardiacdeath and MI 30 days post-operatively was reduced in both Fig. 1.  Summary of some surgically relevant pleiotropic effects of Statins. NO: nitric oxide; eNOS: endothelial nitric oxide synthase; CRP: C-reactive protein; IL-10: interleukin-10;LFA-1: leucocyte function antigen-1; LDL: low density lipoprotein. P.R. Gajendragadkar et al. / International Journal of Surgery 7 (2009) 285–290 286  fluvastatin and bisoprolol randomised subgroups but only reachedstatistical significance in the bisoprolol group. 39 There is enoughevidence to recommend perioperative statin use in high-riskpatients but insufficient yet to recommend routine use for allpatients. 36,40–42 4.1. Use in patients undergoing vascular surgery Many studies using statins for perioperative risk reduction havebeen in vascular surgery. Discounting papers included in thesystematic review by Kapoor et al., 36 we identified studiesregarding both cardiac and renal risk reduction in patients under-going vascular surgery. 4.1.1. Cardiac risk reduction Perioperative myocardial ischaemia and infarction worsenssurvival. 43 The DECREASE-III trial randomised 497 patients under-going non-cardiac vascular surgery. 44 Fluvastatin XL 80 mg orplacebo was administered for a median of 37 days pre-operativelyand continued forat least 1 month afterwards. All patients were on b -blockers. Cholesterol levels fell in the statin group. Fluvastatinproduced a 9% absolute risk reduction in myocardial ischaemia(10.9% versus 19.0%, OR  ¼ 0.53; 95% CI: 0.32–0.88,  p ¼ 0.016). Thecombinedendpointof cardiovascular mortalityor non-fatalMIalsoreduced (4.8% versus 10.1%, OR  ¼ 0.48; 95% CI: 0.24–0.95,  p ¼ 0.039).TheNNTtopreventoneexcessMIwas13.Inflammatorymarkers such as CRP and interleukin-6 were also significantlyreduced in the statin group (  p < 0.001 between groups). 44 Patients who had withdrawal of statins after vascular surgeryhave an increased risk for post-operative troponin release(HR  ¼ 4.6; 95% CI: 2.2–9.6) and the combination of MI and cardio-vascular death (HR  ¼ 7.5; 95% CI: 2.8–20.1), providing evidence forthe rebound effect discussed previously. 45 A pharmaco-economicanalysis using NHS reference costs suggested that perioperativestatin therapy in vascular surgery presents the most cost effectiveuse of statin therapy yet described with an NNTof 15 to prevent anadverse cardiac event. 46 4.1.2. Renal protection Statins are renoprotective in patients undergoing openabdominal aortic aneurysm (AAA) repair. 47 With no difference inpre-operative creatinine levels and glomerular filtration rates, andafter adjustment for aortic cross clamping time and blood loss,creatinine levels are lower 30 days post-operatively in statin userscompared to non-users (102 mmol/l versus 174 mmol/l, analysis-of-variance  p < 0.01). 47 Large observational cohort studies inpatients undergoing lower limb extremity bypass or AAA surgeryhave shown that if kidney function deteriorated, statin use wasassociated with increased odds of complete kidney functionrecovery (OR  ¼ 2.0, 95% CI: 1.0–3.8). 48 Trials with well defined pre-operative statin dosing regimes are increasingly needed to answerinteresting questions posed by observational studies. 5. Use of statins in non-cardiac vascular patients Perioperative risks aside, statins have other surgically relevanteffects in patients with peripheral arterial disease, carotid arterydisease and aneurysmal disease. 5.1. Peripheral vascular disease It is well established that the presence of peripheral vasculardisease alone is linked to increased rates of cardiovascular diseaseand that these risks can be decreased with statins, particularly inthosewith a total cholesterol of  > 3.5 mmol/l. 3,49,50 Statins improveperipheral vascular function. Claudicants randomised to simvasta-tin 40 mg or placebo displayed enhanced ankle-brachial pressureindex at rest and after exercise at 3 and 6 months. The pain-freewalking distance increased 90 m more (95% CI: 64–116 m,  p < 0.005) in the simvastatin group. 51 5.2. Carotid artery disease Each 10% reduction of LDL-C bystatins reduces the risk of strokeby 15.6% (95% CI: 3.7–23.6) and reduces carotid IMT by 0.73% (95%CI: 0.27–1.19). 52 Plaque stabilisation was confirmed histologicallyby examining plaques from carotid endarterectomy (CEA) patientspre-treated with pravastatin compared to placebo. 26 The multi-centre, randomised SPARCL trial in patients with symptomaticcerebrovascular disease, but without known coronary arterydisease found fewer strokes in the statin arm. 53 Subgroup analysisof those with carotid artery stenosis (mean stenosis 51%) showedatorvastatin treated subjects had a 7% absolute reduction (34%relative risk [RR] reduction) in the rate of stroke or transientischaemic attack (HR  ¼ 0.66; 95% CI: 0.50–0.89,  p ¼ 0.005) as wellas a 4% absolute reduction (56% RR reduction) in later rates of CEAcompared with placebo over 5 years (HR  ¼ 0.44; 95% CI: 0.24–0.79,  p ¼ 0.006). 54 5.3. Aneurysmal disease Given the anti-inflammatory effects of statins, their role incontrolling AAA expansion has been investigated. Statin pre-treatment decreases matrix metalloproteinase levels, which arethought to cause proteolysis and aneurysm expansion. 55,56 A recent systematic review of AAA expansion inhibitors identi-fied 13 distinct agents in four categories ( b -blockers, other anti-hypertensives, anti-inflammatory antibiotics and statins). 57 Pooledobservational cohort studies suggested that  b -blockers may reducethe growth rate of AAA but randomised trials did not support thisobservation. 57–59 The evidence for statins meanwhile, is only frompotentially biased cohort studies. 60,61 It will be challenging todesign trials to assess the role of statin therapy in expansion inhi-bition as AAA, coronary artery disease and peripheral vasculardisease share common risk factors, so many patients have firmindications for statin use. However, with the advent of AAAscreening programmes, such trials would be valuable. 6. Use of statins in other surgical patients 6.1. Patients with sepsis A recent systematic review identified 20 studies, mainly retro-spective, of statins use in sepsis or other infections. 62 The studieswere so heterogeneous and the endpoints so diverse thata combined meta-analysis was not attempted by the authors.Within the studies included we identified eight studies poten-tially relevant to surgical practice. 63–70 Six out of seven of thestudies examining the risk of sepsis as the main outcome identifieddecreased odds of sepsis and mortality with pre-hospital statinuse. 62 In the last retrospective study we identified, the authorspostulated whether the anti-inflammatory and anti-coagulanteffects of statins made any difference to post-operative woundcomplications. 70 The study included 10,782 patients undergoinginguinalorventralherniorrhaphyandfoundthatwhilststatinshadno effect on the risk of wound infection or delayed wound healing,they were associated with an increased rate of local post-operativebleeding (  p ¼ 0.01) although this became of borderline significanceafter the type of hernia, age, smoking habits, diabetes status, andbody mass index were taken into account (  p ¼ 0.04). 70 P.R. Gajendragadkar et al. / International Journal of Surgery 7 (2009) 285–290  287  These diverse endpoints and outcomes mean that it is perhapstoo early to look forward to a trial with mortality from sepsis as anendpoint. 71 However, we identified five ongoing randomised trialslooking at the use of statins in sepsis which are relevant froma surgical standpoint. 72–76 Most are investigating safety and levelsof inflammatory cytokines as well as secondary endpoints such aslength of stay and time to shock reversal in patients with sepsis,with one using rosuvastatin in patients with a confirmed diagnosisof ‘broad peritonitis’ post-surgery. 76 The results are awaited withinterest. 6.2. Peritonitis and post-operative adhesion prevention Leukocyte function antigen-1 (LFA-1) has an important role ininflammation. 77 Statins allosterically bind and inhibit LFA-1. MinoralterationsinstatinchemistrytooptimiseLFA-1bindingresultedinpotent, selective and orally active LFA-1 inhibitors which inhibitedneutrophil migration and peritoneal inflammation murine perito-nitis models. 78 LFA-1 inhibitors reduce disease burden in patientswith plaque psoriasis, another inflammatory process. 77 In ratmodels of laparotomy-induced adhesions, intra-peritoneal lova-statin and atorvastatin reduced adhesions by 26% and 58%,respectively (  p < 0.05), possibly via effects on tPA and PAI-1levels. 79 These are earlystudies and to our knowledge no studies of statins or selective LFA-1 inhibitors have taken place in patientswith peritonitis. 6.3. Subarachnoid haemorrhage In rats, statins suppress cerebral aneurysm progression. 80 Therehas been considerable interest in the ability of statins to preventvasospasm and cerebral ischaemia after subarachnoid haemor-rhage(SAH).Thevasospasticmechanismisunclearbutmayincludeleukocyte–endothelial interactions including LFA-1 81 and oxy-haemoglobin induced NO inhibition. 82 As discussed previously,statins bind and inhibit LFA-1 78 and prolong NOS activity. 5 A meta-analysis found statins reduced SAH induced vasospasm(RR  ¼ 0.73; 95% CI: 0.54–0.99), delayed ischaemic deficits(RR  ¼ 0.38; 95% CI: 0.17–0.83), and mortality (RR  ¼ 0.22; 95% CI:0.06–0.82). 83 For these outcomes, NNT of 6.25, 5, and 6.7 applied,respectively. 83 At 6 month follow-up, SAH patients treated with 14days of pravastatin after SAH showed a 73% decrease (  p ¼ 0.041) inthe composite ‘unfavourable outcomes’ endpoint. 84 Subgroupanalysis of statin treated patients who developed vasospasmshowed they had lower LDL-C reductions, suggesting both choles-terol-dependent and -independent mechanisms are involved. 85 AnewmulticentrerandomisedtrialofsimvastatininSAHiscurrentlyrecruiting and is expected to report in 2011. 86 7. Conclusions Statins are safe and well tolerated 87 and have a variety of surgically useful pleiotropic effects beside cholesterol-lowering.Whilst ‘proof of concept’ studies showing other pleiotropic effectsof statins invarious situations arewelcomed, these must be backedup by robust randomised trials in appropriate patient groups tovalidate efficacy and safety before clinical recommendations aboutstatin use can be made.Research into perioperative statin use in many types of vascularsurgery is advanced and such patients should be commenced onastatinpre-operatively, primarilyduetobeinga populationathighriskofcardiovasculareventsandthisshouldbecontinuedlife-long.There is no conclusive data as yet on the acute use of statins peri-operativelyfor other types of surgery in the lowcardiovascular riskpopulation and we do not know if further acute administration of statins in existing users improves outcomes. Existing statin usersshouldnotdiscontinuetheirmedicationintheperioperativeperiodbecause of potential for rebound cardiovascular events. Furtherstudies need to clarify exact dosage regimes and timings of administration of statins for perioperative patients. Additionally,the results of multicentre randomised trials looking at statin use inpatients with sepsis and SAH are also awaited to validate a largebody of retrospective data regarding other clinically significantpleiotropic effects in surgical practice. Conflict of interest  The authors have no conflicts of interest. Sources of funding  None. Ethical approval None. References 1. Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managingcardiovascular risk.  Vasc Health Risk Manag   2008; 4 (2):341–53.2. Randomised trial of cholesterol lowering in 4444 patients with coronary heartdisease: the Scandinavian simvastatin survival study (4S).  Lancet  1994; 344 (8934):1383–9.3. 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