Another Medical Hoax
I was intrigued by Dr London’s report in December 2016 JAMA of decreased peri-operative mortality in statin users.(1) This result does not seem immediately intuitive. Statin drugs inhibit an enzyme in the liver called HMG-CoA reductase involved in cholesterol production, thereby reducing cholesterol levels. Left Image: Surgeons by Reginald Brill 1934 courtesy of Wikimedia Commons.
Higher Cholesterol is Protective of Post Operative Sepsis
Higher cholesterol in the surgical patient is protective of endotoxemia, a dreaded complication of non-cardiac surgery which carries a high mortality rate. According to Dr Wilson writing in Critical Care 2003, ” lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome.” (2)
Severly ILL Patients Have Low Cholesterol
Another observation made by Dr Wilson is that severely ill patients tend to have low cholesterol. If so, then these severely ill patients would not be good candidates for statin drugs in the days prior to their surgical procedure as their cholesterol levels are already low. No need to give a drug to make it lower. On the other hand non-critically ill patients tend to have higher cholesterol values which does make them good candidates for a statin drug.
The Cholesterol Endotoxin Hypothesis
This explains the spurious findings of the JAMA article. The patients not taking statins were sicker with lower cholesterol values, a marker for increased mortality from sepsis.
Low cholesterol is an excellent marker for increased mortality from sepsis. (3-7) Therefore driving down serum cholesterol with a statin drug is not a way to reduce surgical complications, most of which are related to post op sepsis. This Study in JAMA by Dr London is therefore a medical hoax, a result of patient selection bias, not due to any imaginary benefits of statin drugs, which are non-existent.
The damage of this JAMA article could produce is frightening, since some surgeons may actually believe it and give their patients statin drugs. This would be a catastrophe of monumental proportions.
Jeffrey Dach MD
Articles with Related Interest:
Low Level Endotoxemia and Cholesterol
Jeffrey Dach MD
Links and References:
1) Association of Perioperative Statin Use With Mortality and Morbidity After Major Noncardiac Surgery. Martin J London, JAMA Dec 19 2016.
Question Is exposure to a statin in the early perioperative period associated with reduced postoperative complications after noncardiac surgery?
Findings This observational cohort analysis of veterans linked risk and outcome data from the Veterans Affairs Surgical Quality Improvement Program database to statin prescriptions in 180 478 patients and evaluated the associations of early statin exposure on 30-day mortality. After adjustment for risk, other medications used, and potential selection biases, 30-day mortality was significantly reduced in the statin-exposed group.
Meaning Perioperative statin use may be beneficial in reducing 30-day mortality, although the effects of selection biases cannot be excluded.
Importance The efficacy of statins in reducing perioperative cardiovascular and other organ system complications in patients undergoing noncardiac surgery remains controversial. Owing to a paucity of randomized clinical trials, analyses of large databases may facilitate informed hypothesis generation and more efficient trial design.
Objective To evaluate associations of early perioperative statin use with outcomes in a national cohort of veterans undergoing noncardiac surgery.
Design, Setting, and Participants This retrospective, observational cohort analysis included 180 478 veterans undergoing elective or emergent noncardiac surgery (including vascular, general, neurosurgery, orthopedic, thoracic, urologic, and otolaryngologic) who were admitted within 7 days of surgery and sampled by the Veterans Affairs Surgical Quality Improvement Program (VASQIP). Patients were admitted to Department of Veterans Affairs hospitals and underwent 30-day postoperative follow-up. Data were collected from October 1, 2005, to September 30, 2010, and analyzed from November 28, 2013, to October 31, 2016.
Exposure Statin use on the day of or the day after surgery.
Main Outcomes and Measures All-cause 30-day mortality (primary outcome) and standardized 30-day cardiovascular and noncardiovascular outcomes captured by VASQIP. Use of statins and other perioperative cardiovascular medications was ascertained from the Veterans Affairs Pharmacy Benefits Management research database.
Results A total of 180 478 eligible patients (95.6% men and 4.4% women; mean [SD] age, 63.8 [11.6] years) underwent analysis, and 96 486 were included in the propensity score–matched cohort (96.3% men; 3.7% women; mean [SD] age, 65.9 [10.6] years). At the time of hospital admission, 37.8% of patients had an active outpatient prescription for a statin, of whom 80.8% were prescribed simvastatin and 59.5% used moderate-intensity dosing. Exposure to a statin on the day of or the day after surgery based on an inpatient prescription was noted in 31.5% of the cohort. Among 48 243 propensity score–matched pairs of early perioperative statin-exposed and nonexposed patients, 30-day all-cause mortality was significantly reduced in exposed patients (relative risk, 0.82; 95% CI, 0.75-0.89; P < .001; number needed to treat, 244; 95% CI, 170-432). Of the secondary outcomes, a significant association with reduced risk of any complication was noted (relative risk, 0.82; 95% CI, 0.79-0.86; P < .001; number needed to treat, 67; 95% CI, 55-87); all were significant except for the central nervous system and thrombosis categories, with the greatest risk reduction (relative risk, 0.73; 95% CI, 0.64-0.83) for cardiac complications.
Conclusions and Relevance: Early perioperative exposure to a statin was associated with a significant reduction in all-cause perioperative mortality and several cardiovascular and noncardiovascular complications. However, the potential for selection biases in these results must be considered.
2) Wilson, Robert F., Jeffrey F. Barletta, and James G. Tyburski. “Hypocholesterolemia in sepsis and critically ill or injured patients.” Critical Care 7.6 (2003): 1.
3) Leardi, S., et al. “[Blood levels of cholesterol and postoperative septic complications].” Annali italiani di chirurgia 71.2 (1999): 233-237.
Hypocholesterolemia seems to represent a significant predictive factor of morbidity and mortality in critically ill patients. The authors, on the basis of recent literature data, aim to clarify the possible correlation between preoperative hypocholesterolemia and the risk of septic postoperative complications .205 patients undergoing to surgery for gastrointestinal diseases were the object of the study. Patients undergoing “minor” abdominal surgery or video-laparoscopic surgery and classified ASA III-IV were excluded. In all the patients, we considered retrospectively risk factors for postoperative septic complications as follows: preoperative blood concentration of cholesterol, malnutrition, obesity, diabetes, neoplasm, preoperative sepsis, type and duration of operations, antibiotics and regimen of use. Type and incidence of postoperative local or systemic septic complications were recorded. The patients have been stratified according to blood concentration of cholesterol and to the presence or absence of other risk factors. The incidence of postoperative sepsis was 35.1%. The highest incidence of postoperative septic complications (72.7%) was encountered, significantly (X2 = 7.6, p < 0.001), in the patients (11 cases, 5.9%) with cholesterol levels below 105 mg/dl). The results of this study seems to indicate a significant relationship between preoperative hypocholesterolemia and the incidence of septic complications after surgery. Moreover, evaluation of blood cholesterol levels before major surgery might represent a predictive factor of septic risk in the postoperative period.
4) Marik, Paul E. “Dyslipidemia in the critically ill.” Critical care clinics 22.1 (2006): 151-159. Total and HDL cholesterol levels fall at the onset of acute illness and the cholesterol levels normalize as the patient recovers. Hypocholesterolemia may predispose the critically ill patient to sepsis and adrenal failure. Early enteral nutrition and tight glycemic control accelerate the recovery of the cholesterol levels.
5) Chiarla, Carlo, et al. “Severe hypocholesterolemia in surgical patients, sepsis, and critical illness.” Journal of critical care 25.2 (2010): 361-e7.
After surgery, in sepsis and various critical illnesses, factors such as severity of the acute phase response, liver dysfunction, and hemodilution from blood loss have cumulative impacts in decreasing cholesterol; therefore, degree of hypocholesterolemia often reflects severity of illness. The direct correlation between cholesterol and several plasma proteins is mediated by the parallel impact of commonly shared determinants. Cholestasis is associated with a moderation of the degree of hypocholesterolemia. In human sepsis, the poor implications of hypocholesterolemia seem to be aggravated by the simultaneous development of hypertriglyceridemia. Cholesterol and triglyceride levels reflect altered lipoprotein patterns, and the issue is too complex and too poorly understood to be reduced to simple concepts; nevertheless, these simple measurements often represent helpful adjunctive clinical tools.
6) Biller, Katharina, et al. “Cholesterol rather than procalcitonin or C-reactive protein predicts mortality in patients with infection.” Shock 42.2 (2014): 129-132.
Serum cholesterol procalcitonin (PCT) and C-reactive protein (CRP) levels were measured consecutively in 76 critically ill patients at admission to the intensive care unit. The presence of infection was defined according to the CDC (Centers for Disease Control and Prevention) criteria; in-house mortality, underlying diseases, and severity of sepsis were monitored. Nonsurvivors had significantly lower cholesterol levels compared with survivors (69 mg/dL [range, 37-88 mg/dL] vs. 96 mg/dL [range, 71-132 mg/dL], P = 0.006) whereas no significant differences were noted for serum PCT and CRP levels. In a cohort of patients with cholesterol levels of 50 mg/dL or less, 82% did not survive as compared with patients with cholesterol levels of 100 mg/dL or greater (mortality, 21%). In a control group without infection, no difference of cholesterol, PCT, or CRP was found between survivors and nonsurvivors. Our data show that low cholesterol levels in patients with infectious disease have a prognostic value and may be useful markers to identify high-risk patients already at admission.
7) free pdf Thomas Whitney Serum cholesterol Superior Prognostic Marker Sepsis Mortality in ICU 2015 Thomas, Whitney. “Serum cholesterol: A Superior Prognostic Marker of Sepsis Mortality in the ICU Compared to Procalcitonin or C-reactive Protein.” (2015).
Total cholesterol may be a useful and superior prognostic marker of mortality for patients admitted to the ICU with sepsis secondary to infection compared to its CRP and PCT counterparts. Serum cholesterol could provide ICU clinicians a more sensitive screening tool for identifying those patients at highest risk for morbidity and mortality irrespective of other underlying comorbidities, whereas CRP may be more useful for monitoring response to therapy. Cholesterol pathophysiology may also yield insight on experimental therapy including the use of statin medications in septic patients in the ICU.
8) Sandek A., Utchill S, Rauchhaus M. The endotoxin-lipoprotein hypothesis-an update. Arch Med Sci. 2007;3(4A):S81. The endotoxin lipoprotein hypothesis Anja Sandek 2007
9) Pajkrt D, Doran JE, Koster F, et al. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med. 1996;184(5):1601-8.
10) Vreugdenhil AC, Rousseau CH, Hartung T, et al. Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J Immunol. 2003;170(3):1399-405.
11) Statin Drugs Tied to Better Surgery Outcomes By NICHOLAS BAKALARDEC. 21, 2016
12) Shock. 2016 Jan;45(1):10-5. Incidence of Sepsis and Mortality With Prior Exposure of HMG-COA Reductase Inhibitors in a Surgical Intensive Care Population.
Schurr JW1, Wu W, Smith-Hannah A, Smith CJ, Barrera R.
1*Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, Massachusetts †St John’s University College of Pharmacy and Health Sciences, Queens, New York ‡Department of Surgery, North Shore-LIJ Health System Long Island Jewish Medical Center, New Hyde Park, New York.
The anti-inflammatory properties of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may reduce the risk of developing sepsis in surgical intensive care patients and improve outcomes in those who do become septic. The objective of this study was to assess whether surgical intensive care unit (SICU) patients with prior exposure to HMG-CoA reductase inhibitors had a lower incidence of developing sepsis and improved outcomes. A retrospective cohort study was conducted. Patient demographic data, statin use, sequential organ failure assessment (SOFA) scores, vasopressor requirements, ventilator days, length of SICU stay, and mortality in septic patients were collected. Incidence of development of sepsis was determined using systemic inflammatory response syndrome criteria. Patients were grouped into cohorts based on whether they met the sepsis criteria and if they had previously received statins. Cohorts of patients who did and did not become septic with prior statin exposure were compared and an odds ratio was calculated to determine a protective effect. The setting was a SICU. The study comprised of 455 SICU patients and had no interventions. Among the 455 SICU patients, 427 patients were included for the final results. Patients receiving statins verses not receiving statins were similar in demographics. Previous statin exposure had a protective effect in the development of sepsis (9.77% on statins vs. 33.6% without statins; odds ratio 0.203, confidence interval 0.118-0.351). Of those patients who developed sepsis, there was a statistically significant decrease in 28-day mortality in patients with prior statin exposure (P = 0.0341). No statistical difference was noted in length of stay, vasopressor requirements, or days on mechanical ventilation. Prior exposure to statins may have a protective effect on the development of sepsis and decrease mortality in critically ill surgical patients.
13) McAuley, Danny, Pierre-Emmanuel Charles, and Laurent Papazian. “Statins in patients with sepsis and ARDS: is it over? We are not sure.” (2016): 1-3.
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