JAC Advance Access originally published online on February 7, 2008
Journal of Antimicrobial Chemotherapy 2008 61(4):774-785; doi:10.1093/jac/dkn019
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Systematic review |
Statins for infection and sepsis: a systematic review of the clinical evidence
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece 2 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
* Correspondence address. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Greece. Tel: +30-694-61-10-000; Fax: +30-210-68-39-605; E-mail: m.falagas{at}aibs.gr
Received 17 October 2007; returned 9 November 2007; revised 18 December 2007; accepted 28 December 2007
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
Introduction: Statins are currently used for hyperlipidaemia control and considered useful for protection from cardiovascular events. In addition, there is increasing evidence for the potential use of statins in preventing and treating infections.
Methods: We performed a systematic review of the literature that compared the outcome between statin and non-statin users among patients suffering from sepsis or other infections. The relevant studies were identified from searches of PubMed, Scopus and the Cochrane Library databases.
Results: Twenty studies were identified (13 of them were retrospective), out of which 9 examined the use of statins in patients with sepsis, bacteraemia or multiorgan dysfunction syndrome, 4 community-acquired pneumonia (CAP), 1 ICU infections, 2 other bacterial infections and 4 viral infections. Eleven studies had data regarding mortality as the main outcome: 8 showed decreased mortality in statin users (3 of them reported on patients with bacteraemia), 2 showed no difference in mortality and 1 reported an increased mortality in patients who received statins. Seven studies examined the risk of sepsis as the main outcome; six of these studies showed a decreased risk of sepsis in patients receiving statins, whereas one study found no difference.
Conclusions: The majority of the studies suggest that statins may have a positive role in the treatment of patients with sepsis and infection. However, the majority of the reviewed studies have the inherent methodological limitations of retrospective studies. Conclusions regarding this important clinical question should wait for the results of ongoing relevant randomized controlled trials.
Keywords: atorvastatin , simvastatin , lovastatin , pravastatin , rosuvastatin , HIV , intensive care
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
Sepsis is considered one of the leading causes of mortality in the hospital setting. Although some advances have been made in treating patients with sepsis, the mortality of patients with sepsis remains extremely high.1
Sepsis is a process consisting of numerous inflammatory cascades and it is initiated by the presence of bacterial toxins and results in systematic inflammation and multiple organ and tissue damage. Cytokines have a prominent role in the defence mechanisms of the host. Their production is mediated by numerous metabolic pathways, which are independent one from another.2 In order to treat sepsis effectively, intervention should be made at multiple levels, as controlling just one or two pathways does not impede the process overall.
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, namely statins, are a class of drugs used for their ability to lower cholesterol levels. Their primary indication is the prevention of cardiovascular disease. Recently, however, statins have been attributed anti-inflammatory and immunomodulatory pleiotropic effects. They inhibit the synthesis of products of mevalonate pathway such as isoprenoids and geranyl-geranylpyrophosphate.3 In addition, they modify the intercellular interactions and the cellular chemotaxis of the immune system. Furthermore, statins reduce the release of cytokines and acute-phase proteins. They demonstrate antioxidant properties, although they reduce ubiquinone (CoQ10) levels, which is an important endogenous antioxidant.4 They may also exert an anti-apoptotic action, contribute to the stabilization of the atheromatic plaque, modify cell activity by inhibiting the expression of certain genes and participate in various other mechanisms of the inflammatory response.
Having all these properties, statins have been suggested as an adjunct in the treatment of patients with sepsis. Although there have been reviews regarding various aspects of statin use in patients with sepsis, to our knowledge, there has been only one limited systematic review of the evidence about their use for this indication. Thus, we sought to critically examine the relevant data from studies regarding the use of statins for the treatment of patients with sepsis.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
Search strategy
We performed an electronic search through Pubmed, Scopus and the Cochrane Library databases by using the following key terms: ‘statins’, ‘infection’, ‘sepsis’, ‘bacteremia’, ‘pneumonia’, ‘ICU infections’, ‘viral infections’, ‘HIV’, ‘CMV’, ‘HBV’, ‘HCV’ and/or ‘HAV’. Two independent reviewers (G. C. M. and D. K. M.) performed the literature search, study selection and data extraction. There was no time, language or publication limit in our literature search, and all references from identified articles were also searched for relevant information. An online search through http://clinicaltrials.gov was also performed for ongoing randomized control trials. The end date of the review was 30 June 2007.
We identified studies that were relevant to statins and different kinds of infection (Figure 1). Studies included in our systematic review were observational cohort studies (prospective or retrospective) or case–control studies that compared the mortality and/or morbidity in patients with different infection profiles with and without use of statins. We identified no randomized control trials. Studies that were experimental or laboratory based were excluded.
|
Data extraction
We extracted data about the number of patients included, study design, type of infection (sepsis, bacteraemia, pneumonia, viral and others), co-morbidity (coronary artery disease, renal failure and diabetes), population settings, clinical outcomes and the protocol followed for statin administration before, during or after hospital admission. A quality score of the retrieved studies was performed with the use of the methodological index for non-randomized studies (MINORS).5
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
We identified 20 studies6–25 regarding the use of statins and their potential clinical application in patients with infectious diseases. We also identified six randomized control trials (RCTs)26–31 in the online registry of RCTs of US National Institutes of Health. Most of these trials were in recruiting state.
Fifteen out of 20 evaluable studies were cohort studies (10 retrospective and 5 prospective), 2 were retrospective case–control studies,15,16 1 study included both cohort and case–control methodology22 in an overlapping patient population and 2 were prospective with small patient numbers (1 a pilot study24 and 1 a placebo–control crossover study).25
The evaluable studies were divided into three groups according to the type of infection: studies regarding the use of statins in patients with sepsis, bacteraemia and multiorgan dysfunction syndrome (MODS) (Table 1); in patients with pneumonia, ICU infection, and other bacterial infections (Table 2); and in patients with viral infection (Table 3). In the first group, there are nine studies (four sepsis related, four bacteraemia related and one for MODS). In the second group, there are seven studies (four with pneumonia, one with ICU infections and two with other infections). In the third group, there are four studies on viral infections.
|
|
|
Studies examining the use of statins in patients with sepsis, bacteraemia or MODS (Table 1)
The maximum numbers in the study populations was 69 168 patients9 and 5353,12 whereas the minimum number was 53 patients.7 Seven studies6,7,9–11,13,14 showed statistical significance in favour of the use of statins in patients with sepsis, bacteraemia or MODS regarding the rate of sepsis,6,7,9,11 the rate of hospital-acquired bacteraemia and mortality,13,14 and overall hospital mortality.7,10,11,13,14 In the study by Yang et al.,8 no such statistical significance was observed, and in the study by Thomsen et al.,12 it was shown that long-term mortality was reduced in statin users and short-term survival was not significantly altered.
Clinical evidence for the use of statins in patients with pneumonia, ICU infection and other infections (Table 2)
The largest patient sample20 was 11 362 and the minimum 438.19 Three of the studies were based on patients with certain pathological backgrounds such as diabetes,16 atherosclerotic disease20 and patients with a high risk of ICU infection.19
Clinical evidence for patients with pneumonia. We identified four studies where the role of statins was examined in patients with pneumonia.15–18 The patients in these studies were admitted with the diagnosis of community-acquired pneumonia; in the study by van de Garde et al.,16 the patients were also suffering from diabetes mellitus type 1 or 2. Three of these studies15,16,18 reported beneficial effects from the use of statins in the reduction of mortality15,18 and the risk of developing pneumonia.16 However, in the study by Majumdar et al.17 there was no difference between the two groups regarding the outcome of pneumonia or the need for admission to an ICU. In the same study,17 documented bacteraemia was more common in patients who did not receive statins in comparison to those who did (6% versus 3%, P = 0.03). In multivariate analysis, documented bacteraemia was an independent risk factor for mortality on admission, whereas the use of statins was not.
Clinical evidence for patients with ICU-related infections. We identified one study regarding the use of statins in patients entering the ICU at high risk for ICU-acquired infections.19 This study showed a statistical significance in favour of patients not receiving statins regarding the outcome and suggested that this happened probably due to underlying clinical conditions that are insufficiently considered in mortality predictors.
Clinical evidence for patients with other bacterial infections. In the study by Almog et al.,20 the population consisted of atherosclerotic patients with various types of infections, namely lung, urinary tract, soft tissue, biliary and gastrointestinal infections. There was a statistically significant reduction in the infection-related mortality in patients who received statins before admission.
In the study by Hauer-Jensen et al.,21 the population consisted of patients having undergone inguinal or ventral hernia repair. There was no difference between patients receiving statins and those not receiving statins as regards the risk of wound infection and delayed wound healing. Furthermore, there was a statistically significant increase in the risk of post-operative haemorrhage and haematoma for patients receiving statins.
Clinical evidence for the use of statins in patients with viral infection (Table 3)
The evaluable studies comprised patients with influenza,22 coronary artery disease (CAD) and cytomegalovirus (CMV) seropositivity23 and patients with human immunodeficiency virus (HIV) seropositivity.24,25 In the study by Frost et al.,22 there was a statistically significant reduction regarding mortality due to influenza/pneumonia in favour of the patients receiving statins in moderate doses. In the study by Horne et al.,23 there was a statistically significant reduction regarding mortality in patients with CAD, CMV seropositivity and high C-reactive protein who were receiving statins. Two studies with small study populations24,25 focused on the potential benefit from the statin therapy in lowering the HIV viral load in seropositive patients. There was no difference in the viral load of the two groups.
In total, 11 studies had data regarding mortality as the main outcome: 8 showed decreased mortality in statin users10,12–14,18,20,22,23 (3 of them reported on patients with bacteraemia12–14). Two out of the 11 studies showed no difference in mortality8,17 and in one there was increased mortality in patients who received statins.19 Seven studies examined the risk of sepsis as the main outcome; six of these studies6,7,9,11,15,16 showed a decreased risk of sepsis in patients receiving statins (compared with those patients that did not receive them), whereas one study found no difference.21 The two studies24,25 that examined the effect of statin therapy on HIV viral load found no difference between statin and non-statin users. There is no relationship between the quality of MINORS scoring of the studies and the obtained results (regarding a favourable or non-favourable effect of statins). Specifically among the three studies that achieved a maximum MINORS score (24 out of 24), two studies showed a favourable outcome,11,20 whereas one showed a non-favourable outcome.17 Six studies had a MINORS score of 20 out of 24; four of them showed a favourable outcome,6,9,12,15 whereas two studies19,25 showed a non-favourable effect (in one of them19 mortality was increased in statin users). Among the studies that scored below 20 (10 studies had a score of 18/24 and 1 study 10/16), 8 studies showed a favourable outcome7,10,13,14,16,18,22,23 and 3 studies showed no effect.8,21,24 Otherwise with a MINORS cut-off score at the mean (19.1), 9 studies scored above the cut-off (7 with a favourable and 2 with a non-favourable effect) and 11 studies scored below the cut-off (8 with a favourable and 3 with a non-favourable effect); Spearman's 
correlation was –0.06 and non-significant (0.7). Hence, MINORS score was not significantly associated with either a favourable or non-favourable statin effect. Looking specifically into a favourable or non-favourable outcome of the 11 studies examining mortality, 4 studies were above and 7 below the MINORS cut-off score at the mean (19.1); the Spearman correlation was –0.38 (P = 0.24).
The healthy user effect was assessed in nine of the studies by their primary authors. In seven out of these nine studies, a statistically significant association was found in the univariate analysis; adjustment for the healthy user effect did show that the use of statins was still associated with a favourable outcome (Table 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
In our study, we sought to critically examine the data from studies regarding the use of statins for the treatment of patients with sepsis. We identified 20 studies including various population settings. The majority of the reviewed studies suggested a clinically significant superiority of statins in patients with sepsis and infection as shown by decreased mortality (8/11 studies) or decreased risk of infection (6/7 studies), while no effect was observed regarding HIV load (2/2 studies). In the reviewed studies, decreased mortality was noted in patients with bacteraemia as well as in patients with community-acquired pneumonia; the decreased risk for infection referred to decreases in the events of sepsis and risk of pneumonia.
These positive effects of statins cannot be ignored. However, no definitive conclusions could be drawn from the pooled data of the available studies for several reasons. The included studies are rather heterogeneous in certain aspects such as the population setting, the number of patients included, the dosage and duration of statin administration and the type of infection of the patients. Also, the majority of them are either retrospective studies or case series with different methodologies, which may not allow a formal meta-analysis. Ideally, an RCT would give more insight in the role of statins in infection; prospective cohort studies would probably also allow for more accurate evaluation than retrospective cohort studies.
A possible inherent bias of the selected studies which was also noted by the authors was the so-called ‘healthy user effect’. It is suggested that patients receiving statins belong to higher socioeconomic classes than patients who do not. This means that they may have a higher education, better awareness regarding their health, they may pay more visits to GPs and be more compliant with the treatments they are administered, thus increasing the possibility for a better outcome in case of infection. Additionally, in a study by Brookhart et al.,32 statin users were more likely to have been vaccinated against influenza virus [hazard ratio (HR): 1.21, 95% CI: 1.12–1.31] and Streptococcus pneumoniae (HR: 1.46, 95% CI: 1.17–1.83) and hence a decreased incidence of pneumonia. On the other hand, these patients usually demonstrate higher co-morbidity, which, in many cases, was the cause for the prescription of statins in the first place. In the majority of the reviewed studies that adjusted for the healthy user effect in the multivariate analysis, a favourable outcome was associated with the use of statins (Table 4). Thus, the beneficial effects of statin therapy cannot be explained by the healthy user effect alone. For example, in the study by Thomsen et al.,12 75% of the cost of statins was reimbursed by the respective national health service and all patients had access to the county's seven hospitals, suggesting that the benefit observed was possibly due to the medication itself.
Another potential source of bias is publication bias. Since we did not perform any quantitative synthesis of the extracted data due to considerable clinical heterogeneity between the included trials, it is not possible to assess the possibility of publication bias in mathematical terms. Although the literature search has been done in a systematic way, we cannot exclude the possibility of publication bias; this should be taken under consideration when interpreting the findings of our review.
Although statins seem to pose a useful complement in the treatment of sepsis, to draw a safe conclusion, more prospective and randomized controlled trials should be conducted. The absolute effect size of the use of statins in infections varies extensively in some of the studies; for example, the number needed to treat (NNT) to avoid one episode of sepsis is 588 in one study9 compared with six in another.11 This 100-fold difference in the NNT patients receiving statins has to be kept in mind when interpreting the results. Especially because, in the past, there have been examples of medications that seemed innovative and have been regarded for decades as useful complementary treatments for certain diseases, but evidence has shown that this is not true. A well-known example is the use of hormone therapy not only for the amelioration of menopausal symptoms but also for its cardioprotective effects in women of post-partum age. Although such drugs were administered regularly as post-menopausal supportive treatment for several years in most countries, recent data suggest that this treatment carries an excess risk of breast cancer while concurrently it does not offer cardioprotection.33,34
The key question regarding the effect of statins in patients with sepsis remains, and a recommendation based on current clinical evidence cannot be given. It has to be acknowledged that statins did not result in a decreased rate of non-vascular death in a recent meta-analysis of RCTs involving 90 056 patients, while their positive effect on reducing vascular death was indisputable.35 In the mentioned meta-analysis, no difference regarding non-vascular causes of death was detected between statin users and non-statin users; mortality was 3.8% and 4.0% [relative risk (RR): 0.95, 95% CI: 0.91–1.12] respectively, in the comparators. In contrast, mortality due to any vascular cause was 4.7% versus 5.7% in statin and non-statin users, respectively [RR: 0.83, 95% CI: 0.79–0.87). In addition, other pleiotropic effects of statins (e.g. on cancer) have not been verified in RCTs.36
Future RCTs and prospective cohort studies aiming to elucidate the issue should address whether statins influence the frequency and mortality of sepsis. Specifically, the dose and duration of administration of statins for this purpose need to be clarified. The question of whether statins have to be given continuously as prophylaxis against sepsis (as is the case in primary and secondary prevention of cardiovascular disease) or whether the initiation of statin administration should occur when the infection begins has to be examined. Of even more importance, the possible adverse effects of statins in the septic patient, if any, have to be examined as well, to detect whether the frequency of muscle involvement or liver involvement due to sepsis per se and due to a variety of factors in the ICU setting are augmented.
Currently there are six clinical trials recruiting patients in order to examine the potential clinical benefit from the use of statins in infection. Three of them examine the use of statins in patients with sepsis: two studies are in Phase II26,27 and one in Phase IV.28 Furthermore, three studies examine the potential benefit of statin use in patients with viral infections. One of them examines patients with HIV (Phase II)29 and two examine patients with hepatitis C infection (Phase II).30,31 It is obvious that there is a substantial effort from the scientific community to find evidence concerning this issue.
|
Conclusion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
There is an increasing interest about the use of statins for other purposes apart from their original one. Part of this trend is the hypothesis that statins might play a role in the prophylaxis and treatment of infections. The majority of the existing evidence seems to support this hypothesis in different kind of infections. However, these studies are mainly retrospective and have several limitations. There is a need for prospective studies and randomized controlled trials in order to draw a safe conclusion regarding the consideration of statins as useful complementary agents in the treatment of sepsis and infection.
- Statins are the treatment of choice in the majority of patients with hyperlipidaemia. Basic science studies show that there is a rationale for their clinical use in sepsis.
- In the majority of the reviewed studies, statins had a beneficial effect in sepsis (mortality or risk of infection is decreased in statin users in comparison to non-users).
- However, there are several methodological issues that limit the interpretation of the reviewed studies.
- Clinical decision-making should wait for the results of the ongoing RCTs.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
None to declare.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionTransparency declarationsReferences |
|---|
1 Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA (1995) 273:117–23.
2 Terblanche M, Almog Y, Rosenson RS, et al. Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis (2007) 7:358–68.[CrossRef][Web of Science][Medline]
3 Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature (1990) 343:425–30.[CrossRef][Medline]
4
Rundek T, Naini A, Sacco R, et al. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol (2004) 61:889–92.
5 Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg (2003) 73:712–6.[CrossRef][Medline]
6
Gupta R, Plantinga LC, Fink NE, et al. Statin use and hospitalization for sepsis in patients with chronic kidney disease. JAMA (2007) 297:1455–64.
7 Martin CP, Talbert RL, Burgess DS, et al. Effectiveness of statins in reducing the rate of severe sepsis: a retrospective evaluation. Pharmacotherapy (2007) 27:20–6.[CrossRef][Medline]
8 Yang KC, Chien JY, Tseng WK, et al. Statins do not improve short-term survival in oriental population with sepsis. Am J Emerg Med (2007) 25:494–501.[CrossRef][Web of Science][Medline]
9 Hackam DG, Mamdani M, Li P, et al. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet (2006) 367:413–8.[CrossRef][Web of Science][Medline]
10 Schmidt H, Hennen R, Keller A, et al. Association of statin therapy and increased survival in patients with multiorgan dysfunction syndrome. Intensive Care Med (2006) 32:1248–51.[CrossRef][Medline]
11
Almog Y, Shefer A, Novack V, et al. Prior statin therapy is associated with decreased rate of severe sepsis. Circulation (2004) 110:880–5.
12 Thomsen RW, Hundborg H, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med (2006) 34:1080–6.[CrossRef][Web of Science][Medline]
13 Kruger P, Fitzsimmons K, Cook D, et al. Statin therapy is associated with fewer deaths in patients with bacteremia. Intensive Care Med (2006) 32:75–9.[CrossRef][Web of Science][Medline]
14 Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis (2001) 33:1352–7.[CrossRef][Web of Science][Medline]
15 Schlienger RG, Fedson DS, Jick SS, et al. Statins and the risk of pneumonia: a population based, nested case-control study. Pharmacotherapy (2007) 27:325–32.[CrossRef][Web of Science][Medline]
16
van de Garde EMW, Hak E, Souverein PC, et al. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax (2006) 61:957–61.
17
Majumdar SR, McAlister FA, Eurich DT, et al. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ (2006) 333:999.
18 Mortensen EM, Restrepo MI, Anzueto A, et al. The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia. Respir Res (2005) 6:82.[CrossRef][Medline]
19 Fernandez R, De Pedro VJ, Artigas A. Statin therapy prior to ICU admission: protection against infection or a severity marker? Intensive Care Med (2006) 32:160–4.[CrossRef][Web of Science][Medline]
20 Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases. Crit Care Med (2007) 35:372–8.[CrossRef][Web of Science][Medline]
21 Hauer-Jensen M, Fort ZC, Mehta ZJL, et al. Influence of statins on postoperative wound complications after inguinal or ventral herniorrhaphy. Hernia (2006) 10:48–52.[CrossRef][Medline]
22 Frost FJ, Petersen H, Tollestrup K, et al. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest (2007) 131:1006–12.[CrossRef][Web of Science][Medline]
23
Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy interacts with cytomegalovirus seropositivity and high C-reactive protein in reducing mortality among patients with angiographically significant coronary disease. Circulation (2003) 107:258–63.
24 Moncunill G, Negredo E, Bosch L, et al. Evaluation of the anti-HIV activity of statins. AIDS (2005) 19:1697–1700.[Medline]
25 Sklar PA, Masur H, Crubb JR, et al. Pravastatin does not have a consistent effect in chronically HIV-infected individuals on antiretroviral therapy. AIDS (2005) 19:1109–12.[Web of Science][Medline]
26 Use of statins of modulation on inflammatory in septic patients. Clinical trials identifier. NCT 00452608.www.clinicaltrials.gov/ct/show/NCT00452608?order=1 (30 June 2007, date last accessed).
27 Use of rosuvastatin in integral management of abdominal sepsis. Clinical trials identifier. NCT 00357123.www.clinicaltrials.gov/ct/show/NCT00357123?order=1 (30 June 2007, date last accessed).
28 Simvastatin in patients with septic shock. Clinical trials identifier: NCT NCT00450840.www.clinicaltrials.gov/ct/show/NCT NCT00450840?order=1 (30 June 2007, date last accessed).
29 A randomized placebo control trial of atorvastatin in HIV positive patients not on antiretroviral medications with the specific aims of studying the effect of atorvastatin on HIV viral load and immune activation markers. Clinical trials identifier: NCT 00367458.www.clinicaltrials.gov/ct/show/NCT00367458?order=1 (30 June 2007, date last accessed).
30 Treatment with rosuvastatin in patients with Hepatitis C. Clinical trials identifier. NCT 00371579.www.clinicaltrials.gov/ct/show/NCT00371579?order=1 (30 June 2007, date last accessed).
31 Dose finding trial of rosuvastatin and atorvastatin versus Hepatitis C. Clinical trials identifier: NCT00446940.www.clinicaltrials.gov/ct/show/NCT00446940? Order=1 (30 June 2007, date last accessed).
32
Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol (2007) 166:348–54.
33
Pettiti DB. Some surprises, some answers, and more questions about hormone therapy: further findings from the Women's Health Initiative. JAMA (2005) 294:245–6.
34
Col NF, Pauker SG. The discrepancy between observational studies and randomized trials of menopausal hormone therapy. Ann Intern Med (2003) 139:923–9.
35 Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet (2005) 366:1267–78.[CrossRef][Web of Science][Medline]
36
Bonovas S, Filioussi K, Tsavaris N, et al. Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol (2006) 24:4808–17.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Parquet, S. Briolant, M. Torrentino-Madamet, M. Henry, L. Almeras, R. Amalvict, E. Baret, T. Fusai, C. Rogier, and B. Pradines Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria Antimicrob. Agents Chemother., June 1, 2009; 53(6): 2248 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. G. Athyros, A. I. Kakafika, K. Tziomalos, A. Karagiannis, and D. P. Mikhailidis CORONA, Statins, and Heart Failure: Who Lost the Crown? Angiology, October 1, 2008; 59(5): 641 - 642. [PDF]
|
|
|
|
 |
|
 I. I. Siempos, K. Z. Vardakas, P. Kopterides, and M. E. Falagas Adjunctive therapies for community-acquired pneumonia: a systematic review J. Antimicrob. Chemother., October 1, 2008; 62(4): 661 - 668. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||