Statin treatment leads to worse outcome for patients in an intensive care unit

This study was published in Critical Care 2011;15(1):R74

Study title and authors:
Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study.

Terblanche MJ, Pinto R, Whiteley C, Brett S, Beale R, Adhikari NK.
Critical Care & Anaesthesia Research Group, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK. marius.terblanche@kcl.ac.uk

This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/21356051

This 15 day study analysed the effects of statins on ventilated intensive care unit patients. The study included 1,397 mechanically ventilated patients without nonrespiratory organ failure within 24 hours after admission. The overall lengths of intensive care unit and hospital stays were five and 15 days, respectively. Patients receiving statins stayed longer in the intensive care unit by three days.

The study found:
(a) Patients taking statins had a 22% increased risk of organ failure compared to patients not taking statins.
(b) Patients taking statins had a 25% increased risk of liver failure compared to patients not taking statins.
(c) Patients taking statins had an 8% increased risk of liver impairment compared to patients not taking statins.
(d) In the intensive care unit setting, patients taking statins had an 0.7% increased risk of death compared to patients not taking statins.
(e) In the hospital setting, patients taking statins had an 19% increased risk of death compared to patients not taking statins.

Statin treatment leads to worse outcomes for patients in an intensive care unit.

Links to other studiers:
Statins increase the risk of liver damage
Statin users have a 26% increased risk of liver function test abnormalities
Acute hepatitis induced by lovastatin

Statins increase the risk of liver damage

This study was published in the Medical Journal of Basrah University Vol: 25, No: 1 2007

Study title and authors:
Comparative Effects of Lovastatin and Simvastatin on Liver Function tests in Hyperlipidaemic Patients
Zena Sattam, Hamad Al-Jubori, Isam Hamo Mahmood
This study can be accessed at: http://www.iasj.net/iasj?func=fulltext&aId=48121

Drug-induced liver damage has become an important public health problem, contributing to more than 50% of acute liver failure cases, and there have been observations of a large number of liver failure cases on statin therapy. 

In liver function tests, liver damage is confirmed with increased levels of bilirubin and the liver enzymes; Alanine transaminase, aspartate aminotransferase and alkaline phosphatase.

This study measured the effects of statins on liver function tests. The study included: 

(i) 53 patients, aged 35-60 years, took simvastatin therapy. The simvastatin dose ranged from 10 to 20mg a day. Duration of treatment ranged from one month to four years. (Simvastatin group).
(ii) 42 patients, aged 38-60, took lovastatin therapy. The lovastatin dose ranged from 10 to 20mg a day. Duration of treatment ranged from one month to three years. (Lovastatin group).
(iii) A control group of 50 subjects, aged 35-58 who did not take statins. (No-statin group).

The study found:
(a) The alanine transaminase levels of the lovastatin group were 113% higher than the no-statin group.
(b) The aspartate aminotransferase levels of the lovastatin group were 90% higher than the no-statin group.
(c) The alkaline phosphatase levels of the lovastatin group were 11% higher than the no-statin group.(d) The bilirubin levels of the lovastatin group were 40% higher than the no-statin group.
(e) The alanine transaminase levels of the high dose (20 mg a day) lovastatin group were 181% higher than the no-statin group.
(f) The aspartate aminotransferase levels of the high dose (20 mg a day) lovastatin group were 151% higher than the no-statin group.
(g) The alkaline phosphatase levels of the high dose (20 mg a day) lovastatin group were 20% higher than the no-statin group.
(h) The bilirubin levels of the high dose (20 mg a day) lovastatin group were 72% higher than the no-statin group.
(i) The alanine transaminase levels of the long term usage (over 12 months) lovastatin group were 333% higher than the no-statin group.
(j) The aspartate aminotransferase levels of the long term usage (over 12 months) lovastatin group were 321% higher than the no-statin group.
(k) The alkaline phosphatase levels of the long term usage (over 12 months) lovastatin group were 24% higher than the no-statin group.
(l) The bilirubin levels of the long term usage (over 12 months) lovastatin group were 145% higher than the no-statin group.
(m) The alanine transaminase levels of the simvastatin group were 103% higher than the no-statin group.
(n) The aspartate aminotransferase levels of the simvastatin group were 60% higher than the no-statin group.
(o) The alkaline phosphatase levels of the simvastatin group were 6% higher than the no-statin group.(p) The bilirubin levels of the simvastatin group were 45% higher than the no-statin group.
(q) The alanine transaminase levels of the high dose (20 mg a day) simvastatin group were 150% higher than the no-statin group.
(r) The aspartate aminotransferase levels of the high dose (20 mg a day) simvastatin group were 102% higher than the no-statin group.
(s) The alkaline phosphatase levels of the high dose (20 mg a day) simvastatin group were 3% higher than the no-statin group.
(t) The bilirubin levels of the high dose (20 mg a day) simvastatin group were 55% higher than the no-statin group.
(u) The alanine transaminase levels of the long term usage (over 12 months) simvastatin group were 255% higher than the no-statin group.
(v) The aspartate aminotransferase levels of the long term usage (over 12 months) simvastatin group were 240% higher than the no-statin group.
(w) The alkaline phosphatase levels of the long term usage (over 12 months) simvastatin group were 3% higher than the no-statin group.
(x) The bilirubin levels of the long term usage (over 12 months) simvastatin group were 83% higher than the no-statin group.

The results from this study revealed significant increases of alanine transaminase, aspartate aminotransferase and bilirubin levels in the lovastatin group compared with the control group and significant increases of alanine transaminase and bilirubin in the simvastatin group when compared with the control group.

The study also revealed that the higher the dose of the statin or the longer the dose of the statin generally correlated with increased levels of the liver enzymes.

Statin users have a 26% increased risk of liver function test abnormalities

This study was published in Pharmacotherapy 2004 May;24(5):584-91

 

Study title and authors:

Statins and liver toxicity: a meta-analysis.

de Denus S, Spinler SA, Miller K, Peterson AM.

Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA 19103-4495, USA.

 

This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/15162892

Liver function tests measure various chemicals in the blood made by the liver. An abnormal result indicates the presence of liver disease.

The objective of the study was to assess the risk of liver function test abnormalities with the use of statins. The study was a meta-analysis of 13 randomized, placebo-controlled trials of statins including 49,275 patients.

The study found that statin users had a 26% increased risk of liver function test abnormalities compared to non users.

After six months of taking statins, over 20% of people develop muscle pain

This study was published in Arquivos Brasileiros de Cardiologia 2014 Jul;103(1):33-40

 

Study title and authors:

Evaluation of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin therapy in a southern brazilian cohort.

Smiderle L, Lima LO, Hutz MH, Sand CR, Van der Sand LC, Ferreira ME, Pires RC, Almeida S, Fiegenbaum M.

Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.

 

This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/25120083

This study evaluated the effects of simvastatin/atorvastatin on men and women. The six month study included 495 patients, aged 25-82 years, (331 women and 164 men), who received simvastatin/atorvastatin.

When high levels of creatine phosphokinase are detected in the blood, it is considered to be an abnormal result. High levels of the enzyme may occur due to the following conditions:

• heart attack
• pericarditis after a heart attack
• polymyositis or dermamyositis
• heart muscle inflammation
• myopathy (a disease of the muscles)
• rhabdomyolysis (a breakdown of muscle tissues)
• muscular dystrophies
• convulsions
• stroke
• brain injury
• delirium tremens
• hypothyroidism (a decrease in the activity of the thyroid gland) or hyperthyroidism (an increase in activity of the thyroid gland)
• death of lung tissue

After six months the study found:
(a) 20.3% of the patients developed muscle pain.
(b) 11.1% of the patients had increased creatine phosphokinase levels and/or abnormal liver function.

Statins are a potential cause of cholestatic hepatitis

This paper was published in the American Journal of Gastroenterology 1999 May;94(5):1388-90

Study title and authors:
Acute cholestatic hepatitis associated with pravastatin.

Hartleb M, Rymarczyk G, Januszewski K.
Department of Gastroenterology, Silesian Medical School, Katowice, Poland.

This paper can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/10235223

This paper describes a 57 year old man with acute cholestatic hepatitis. (Acute cholestatic hepatitis is where the bile ducts of the liver become obstructed by inflammation and may lead to jaundice).

The report found:
The man's symptoms had appeared 7 weeks after he was started on pravastatin 20 mg/day for "high cholesterol".

Investigations revealed a diagnosis of intrahepatic nonobstructive jaundice.

The liver function abnormalities normalized 7 weeks after cessation of therapy.

This paper shows that statins should be considered as a potential cause of cholestatic hepatitis.

Acute hepatitis induced by lovastatin

This study was published in Digestive Diseases and Sciences 1994 Sep;39(9):2032-3

Study title and authors:
Acute hepatitis induced by HMG-CoA reductase inhibitor, lovastatin.

Grimbert S, Pessayre D, Degott C, Benhamou JP.
Service d'Hépatologie, Unité de Recherches de Physiopathologie Hépatique (INSERM U 24), Hôpital Beaujon, Clichy, France.

This paper can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/8082513

This paper reports the case of an adult who suffered from clinical hepatitis three months after the onset of lovastatin administration.

The patient suffered:
(i) Loss of strength and energy.
(ii) Jaundice.
(iii) Increased aminotransferase levels. (Elevated levels of aminotransferase (an enzyme) suggest the existence of medical problems such as viral hepatitis, diabetes, congestive heart failure, liver damage and bile duct problems).
(iv) Increased alkaline phosphatase levels. (Elevated levels of alkaline phosphatase (an enzyme) indicate the presence of liver disease or bone disorders).

Examination of the patients liver cells revealed:
(a) Cell death.
(b) Blocked bile ducts.
(c) Increased white blood cell levels. (Elevated white blood cells in the liver, suggest the existence of liver damage).

Withdrawal of lovastatin was followed by complete normalization of liver tests within two months.

This report shows that statins may induce hepatitis.

The unintended adverse effects of statins in men and women

This study was published in the British Medical Journal 2010 May 20;340:c2197

Study title and authors:
Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database.

Hippisley-Cox J, Coupland C.
Division of Primary Care, University Park, Nottingham NG2 7RD. julia.hippisley-cox@ntlworld.com

This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/20488911

The objective of the study was to quantify the unintended effects of statins. The study included 2,004 692 patients aged 30-84 years.

The study found after five years:
(a) Women who used statins had a 56% increased risk of acute renal (kidney) failure compared to women who did not use statins.
(b) Women who used statins had a 30% increased risk of cataracts compared to women who did not use statins.
(c) Women who used statins had a 53% increased risk of liver disease compared to women who did not use statins.
(d) Women who used statins had a 197% increased risk of myopathy (muscle disease) compared to women who did not use statins.
(e) Men who used statins had a 61% increased risk of acute renal (kidney) failure compared to men who did not use statins.
(f) Men who used statins had a 32% increased risk of cataracts compared to men who did not use statins.
(g) Men who used statins had a 53% increased risk of liver disease compared to men who did not use statins.
(h) Men who used statins had a 515% increased risk of myopathy (muscle disease) compared to men who did not use statins.

The study highlights some of the unintended adverse effects of using statins.
Statins increase the death rate by 150-300%
Statins increase the incidence of liver damage
Statin use increases muscle damage after exercise (including the heart muscle)

Statins increase the death rate by 150-300%

This post includes a synopsis of a study published in the Archives of Internal Medicine 1991; 151 (1): 43-49

Study title and authors:
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study Results: 1. Efficacy in Modifying Plasma Lipoproteins and Adverse Event Profile in 8245 Patients With Moderate Hypercholesterolemia
Reagan H. Bradford, MD, PhD; Charles L. Shear, DPH; Athanassios N. Chremos, MD; Carlos Dujovne, MD; Maria Downton, MS; Frank A. Franklin, MD, PhD; A. Lawrence Gould, PhD; Michael Hesney, MS; Jim Higgins, PhD; Dennis P. Hurley, DSc; Alexandra Langendorfer, MS; David T. Nash, MD; James L. Pool, MD; Harold Schnaper, MD

This study can be accessed at: http://archinte.ama-assn.org/cgi/reprint/151/1/43

The study investigated the relationship between statins and death rates. In the study 8,245 'patients', aged 18 to 70, with cholesterol levels between 232mg/dL (6.0 mmol/l) and 300mg/dL (7.8 mmol/l) received one of four different doses of lovastatin (Mevacor) or a placebo.

The study found after 1 year:
(a) Higher transaminase levels (which may be an indicator of liver damage) were found in the subjects taking statins.
(b) Higher incidence of clinical adverse experiences requiring patients to discontinue the 'treatment' were found in the subjects taking statins.
(i) 16% more patients taking 20 mg/day statins discontinued their treatment compared to patients taking a placebo.
(ii) 50% more patients taking 80 mg/day statins discontinued their treatment compared to patients taking a placebo.
(c) Higher levels of muscle damage were detected in the subjects taking statins.
(d) The four groups taking lovastatin lowered their low density lipoprotein (LDL) cholesterol levels by 24%-40%.
(e) The four groups taking lovastatin lowered their cholesterol levels by 17%-29%.
(f) The death rate of the four groups taking various doses of lovastatin was 150-300% higher than the placebo group.



Statins increase the incidence of liver damage

This post includes a synopsis of a study published in the New England Journal of Medicine 2006; 355:549-559 August 10, 2006

Study title and authors:
High-Dose Atorvastatin after Stroke or Transient Ischemic Attack

Karam JG et al The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
This study can be accessed at: http://www.nejm.org/doi/full/10.1056/NEJMoa061894

The study divided up 4731 patients who had had a stroke into 2 groups who had treatment of either (i) 80 mg of a statin drug per day or (ii) placebo.

Elevated liver enzymes may indicate the liver is damaged.

The study found:
(a) The statin group had a 66% higher incidence of  hemorrhagic strokes.
(b) The statin group had a 2.31% more deaths.
(c) Elevated liver enzyme values were more common in patients taking statins.



Adverse Effects of Statins

This post features a summary of a study published in the International Journal of Pharmacology 1 (3): 210-225, 2005

Study title and authors:
Adverse Effects of Statins
Anna Jamroz-Wisniewska and Jerzy Bettowski
This study can be accessed at: http://198.170.104.138/3/detail.php?id=1&jid=ijp&theme=3&issueno=157&articleno=55015

Dr Anna Jamroz-Wisniewska reviewed the evidence concerning the adverse effects of statins.

The review found:
(i) Statins inhibit the production of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, an enzyme in cholesterol biosynthesis pathway, which initially converts HMG-CoA to mevalonate. Mevalonate is the precursor to cholesterol.
(ii) Apart from cholesterol, mevalonate is also a precursor for nonsteroid isoprenoids including farnesylpyrophosphate, geranylgeranylpyrophosphate, coenzyme Q, dolichol and isopentenylpyrophosphate which play an essential role in cellular physiology. 
(iii) The authors report that myopathy (muscle disease) is the most frequent side effect of statins. Other's include peripheral neuropathy (damage to nerves of the peripheral nervous system), hepatotoxicity (liver damage), increased risk of cataract and, according to some studies, increased risk of breast cancer.
(iv) Some studies suggest that statins may sometimes even be the cause of clogged arteries and heart failure.

Liver toxicity and statins

This post contains a summary of a paper published in the World Journal of Gastroenterology 2007 February;13(8):1286-1288 and a recipe for chicken with chard, asparagus, and mushrooms.

Study title and authors:
Liver toxicity of rosuvastatin therapy
Famularo G, Miele L, Minisola G, Grieco A.

Books:

Department of Internal Medicine, San Camillo Hospital, Circonvallazione Gianicolense, Rome 00152, Italy. gfamular@scamilloforlanini.rm.it

 

This paper can be accessed at: http://www.wjgnet.com/1007-9327/abstract_en.asp?f=1286&v=13
 
The authors report a case of clinically significant liver toxicity after a brief course of rosuvastatin.

(i) A 64-year-old man was hospitalised with a seven-days history of malaise, anorexia, upper abdominal discomfort, and jaundice.
(ii) Four months earlier the patient had a heart attack. His liver function tests were normal and he was discharged on a number of drugs including atorvastatin (40 mg daily).  
(iii) One week later, rosuvastatin (10 mg daily) was prescribed instead of atorvastatin as the patient reported an itching skin rash that developed soon after he took the second tablet of atorvastatin; at that time serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 55 U/L and 45 U/L (normal range 10-36 U/L for both), respectively. (High levels of aspartate aminotransferase and alanine aminotransferase are associated with liver damage).
(iv) At the present hospital admission, he had mild jaundice and his aspartate aminotransferase and alanine aminotransferase levels had dramatically increased to 880 U/L and 775 U/L respectively.
(v) Rosuvastatin was withdrawn and aspartate aminotransferase and alanine aminotransferase levels fell to 216 U/L and 198 U/L, respectively on the 3rd day.
(vi) Over the subsequent course symptoms gradually resolved, which was paralleled by declining levels of liver enzymes and the patient was discharged on the 6th day. At that time, aspartate aminotransferase and alanine aminotransferase levels were 40 U/L and 32 U/L, respectively.
 
The researchers conclude: "According to the Naranjo probability scale our patient had a highly probable rosuvastatin-related adverse event. Furthermore, liver function tests were normal before statin treatment was started and we did not find any other plausible alternative cause to explain the onset of such a severe hepatitis in this case. As a matter of fact, we identified a clear temporal relationship between initiation of rosuvastatin therapy and the elevation of liver enzymes and the patient rapidly achieved a complete clinical and biochemical recovery after rosuvastatin was interrupted".

This report supports the view there is a clinically significant risk of liver toxicity when rosuvastatin is given at the range of doses used in common clinical practice.

More information on this subject: Books : Scientific Studies : Websites : Videos : Food Mall

Recipe of the day

Chicken with Chard, Asparagus, and Mushrooms

Food Mall: Chicken Breasts

Ingredients:

2 Chicken Breasts
2 T. Butter
Sea Salt and Pepper, to taste

1 Large Bunch of Chard, rinsed, trimmed, and chopped
1 Leek, halved lengthwise, sliced, and rinsed
3/4 C. White Wine
6 Extra Large Asparagus, sliced diagonally
1 Cluster of Mushrooms

Instructions:
Preheat oven to 350F.

Heat oil and 1 T. butter in an ovenproof saute pan over medium-high heat.

Season chicken breasts with salt and pepper, on both sides, and add to heated pan, presentation (smooth) side down. Cook until browned. Flip and brown on the second side.

Remove chicken from pan and set aside.

Add leeks to pan and toss in leftover oil and juices. After two minutes (or once leeks just begin to soften) add the chard and toss to coat. Cook for another 2-3 minutes. Add 1/2 cup of white wine and toss to coat.

Nestle chicken breasts into chard-leek mixture and place in oven. Cook for 15 minutes or until chicken breast is cooked, but still has a little give (it will continue to cook once removed from the oven). Check this post, if you are using a thermometer and want to know what temp to cook to.

Set chicken and chard aside.

Turn off the oven and, in the hot pan, add 1 T. butter (or oil, if using). Add asparagus, toss to coat, and cook for 3-5 minutes, until brown and tender.

Add mushrooms and toss to coat. Cook asparagus and mushrooms until tender and browned. Add any remaining juices from the plate you set the chicken on and add the remaining 1/4 cup of wine. Cook until liquid is almost absorbed.

Push the mixture to the outside of the pan and return the chicken, presentation-side down, to the pan to brown.

Plate chard. Top with chicken and then finally, top with mushroom-aspargus mixture.

Statins cause hepatitis in 65 year old woman

This post contains a summary of a paper published in the European Journal of Gastroenterology & Hepatology August 2003 - Volume 15 - Issue 8 - pp 921-924 and a recipe for balsamic glazed sticky lamb cutlets with thyme.

Books:

Study title and authors: 

Autoimmune hepatitis revealed by atorvastatin
Pelli, Nicoletta; Setti, Maurizio; Ceppa, Paola; Toncini, Carlo; Indiveri, Francesco

This paper can be accessed at: http://journals.lww.com/eurojgh/Abstract/2003/08000/Autoimmune_hepatitis_revealed_by_atorvastatin.14.aspx

This paper describes the case of autoimmune hepatitis induced by a statin.

(i) A 65-year-old woman was admitted to hospital because of fatigue, jaundice and altered liver function tests while on treatment with atorvastatin.
(ii) The doctor diagnosed autoimmune hepatitis and after investigations concluded that atorvastatin was the trigger of the disease.

The case shows the potential link between statins and autoimmune hepatitis.

More information on this subject: Books : Scientific Studies : Other Websites : Videos : Food Mall

Recipe of the day

Balsamic Glazed Sticky Lamb Cutlets with Thyme

Ingredients:

Food Mall: Lamb

8 lamb cutlets, French trimmed

Salt and freshly milled black pepper

30ml/2tbsp finely chopped fresh thyme leaves

100ml/3½floz. good, aged balsamic vinegar

30ml/2tbsp fermented soy sauce

25g/1oz unsalted butter

Method:

1.Preheat the oven to Gas mark 6, 200°C, 400°F.

2.Season the cutlets and sprinkle with the thyme on both sides. Transfer to a metal rack in a roasting tin and cook for 15-20 minutes (depending on how you like your lamb).

3.Meanwhile, pour the vinegar and fermented soy sauce into a small pan. Bring to the boil, reduce the heat and simmer for about 10 minutes until the mixture is reduced by half. Whisk in the butter.

4.Remove the cutlets from the roasting tin and transfer to a large bowl. Drizzle the balsamic glaze over the cutlets.

Statins And Cancer: Cause For Concern

This post featues a paper published in the British Medical Journal 17 November 2001;323:1145

Study title and authors:
Statins And Cancer: Cause For Concern
Uffe Ravnskov, Paul J. Rosch, Peter H.Langsjoen, Joel M. Kauffman, and Kilmer S. McCully
Magle Stora Kyrkogata 9, S-22350 Lund, Sweden.
This paper can be accessed at: http://www.bmj.com/cgi/eletters/323/7322/1145#26439
 
Dr Uffe Ravnskov has published over 80 scientific papers regarding the cholesterol, saturated fat, heart disease hypothesis. Here he questions the wisdom of recommending statin treatment for a large segment of the world’s population simply because they have elevated cholesterol levels or are assumed to be at increased risk for coronary events because of the presence of other risk markers.

He finds:
(i) It is already known that statins may induce fatal rhabdomyolysis, cardiac insufficiency, peripheral polyneuropathy, hepatic toxicity, and mental disturbances.
(ii) A much more momentous issue is that all statins have proven carcinogenic.
(iii) In the Heart Protection Study non-melanoma skin cancer was seen in 243 patients treated with simvastatin compared with 202 cases in the control group. 
(iv) In the Scandinavian Simvastatin Survival Study non-melanoma skin cancer was seen in 13 patients treated with simvastatin compared with six in the control group.
(v) Also disquieting was the significant increase in breast cancer rates in patients treated with pravastatin in the Cholesterol and Recurrent Events trial.