515
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors Giuseppe Lippi, MD1
Emmanuel J. Favaloro, PhD, FFSc (RCPA)2
1 Dipartimento di Patologia e Medicina di Laboratorio, U.O. di
Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy 2 Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia 3 Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/ INCLIVA, Valencia, Spain
Fabian Sanchis-Gomar, MD3
Address for correspondence Fabian Sanchis-Gomar, MD, Department of Physiology, Faculty of Medicine, University of Valencia, Av. Blasco Ibañez, 15, Valencia, 46010 Spain (e-mail:
[email protected]).
Abstract
Keywords
► venous thrombosis ► statin ► HMG-CoA reductase inhibitors ► C-reactive protein ► therapy
Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as “statins”) belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn.
Hypercholesterolemia, especially when associated with an increased level of low-density lipoprotein (LDL) cholesterol, is a major risk factor for cardiovascular disease (CVD), along with age, hypertension, family history of premature coronary heart disease, cigarette smoking, and low levels of high-density lipoprotein (HDL) cholesterol.1 According to the most updated
recommendations, lifestyle modifications should be initiated whenever LDL cholesterol levels are above target and for all high-risk or moderately high-risk individuals. According to the same recommendations, when lifestyle adjustments are ineffective, pharmacologic therapy should be initiated, with the target of reducing LDL cholesterol by 30 to 40%.2
published online April 29, 2013
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Disease-Specific Thrombosis; Guest Editor, Marcel Levi, MD, PhD
DOI http://dx.doi.org/ 10.1055/s-0033-1343892. ISSN 0094-6176.
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Semin Thromb Hemost 2013;39:515–532.
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors Table 1 Principal statins (i.e., HMG-CoA reductase inhibitors) available in the market • • • • • • • •
Atorvastatin Cerivastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin
Lippi et al.
Among the various hypolipidemic drugs, 3-hydroxy-3methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (herein referred to as “statins”) belong to a chemically and pharmacologically heterogeneous class of molecules, sharing an identical hypocholesterolemic effect (from 18 to 55%) by inhibition of a rate-limiting step in the cholesterol pathway (►Table 1).3 Their mechanism of action entails a competitive inhibition of the enzyme HMG-CoA reductase, a key step in the endogenous synthesis of cholesterol. Because of the strict structural homology between these drugs and HMG-CoA, the latter compound is competitively displaced from its binding with the enzyme, thus substantially reducing the rate of mevalonate synthesis, which is the next compound in the pathway that culminates in cholesterol production (►Fig. 1). It is also noteworthy that the impaired synthesis of
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516
Fig. 1 Biochemical pathway of cholesterol synthesis. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A.
Seminars in Thrombosis & Hemostasis
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Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
Statins and Venous Thrombosis: Facts and Speculations Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of mortality and disability worldwide, representing the first cause of in-hospital death.9 Although the pathogenesis is complex and multifaceted, involving both acquired and congenital risk factors,10,11 VTE substantially remains a preventable disease by means of pharmacological and mechanical approaches, 12,13 especially when expert guidelines and recommendations are appropriately followed.14 Several lines of evidence now suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, and greater susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would also provide efficient prophylaxis.15 Accordingly, in this review, we have included the vast majority of previous studies linking HMG-CoA reductase inhibitors with VTE, DVT, and/or PE to attempt to tease out the facts from the speculations.
517
Clinical Studies Several retrospective and original prospective studies, as well as meta-analysis and reviews, have been published about the relationship between statins and VTE over the past decades, often reporting controversial results and conclusions owing to the heterogeneous methodological approach. We have included in this article all reviews and meta-analyses published so far, which incorporate the vast majority of, and most relevant, independent trials. Accordingly, original articles have only been included in our systematic literature review if published after 2011, to avoid redundancies and duplications (►Table 2). We have also excluded editorials, viewpoints, or trials that were not clinically significant to this context. In 2001, Ray and Rosendaal reviewed the association between hyperlipidemia and VTE16 assessing two cohort17,18 and six case–control studies,19–24 to investigate the relationship between dyslipidemia or serum lipoprotein(a) excess and VTE. According to their analysis of data, the authors concluded that although some studies suggested an association between hyperlipidemia and VTE, the results remained controversial. The association between VTE and both hypercholesterolemia and hyperlipoproteinemia(a) was mostly inconsistent, even if preliminary research suggested that statin therapy may decrease the VTE risk through several pathways. It was also concluded that statins should not be recommended for either prevention or treatment of VTE, whereas additional studies would be needed to precisely define the risk reduction for VTE with statin use and clarify whether a difference may exist in the antithrombotic properties of the various compounds. More recently, Evans and Green performed a MEDLINE search combining the keywords “venous thromboembolism” or “venous thrombosis” and “statins,” which finally produced 60 articles. Fifty-three articles were excluded because they were reviews, editorials, or not reporting significant clinical outcomes.25 Within the residual articles, there was only a single randomized controlled trial, based on a selected group of subjects, which may therefore limit the study finding’s generalizability to the whole subset of population at risk for VTE. In this study, 17,802 subjects free of known CVD but with high C-reactive protein (CRP) levels of 2.0 mg/L or more were randomly assigned to rosuvastatin versus placebo, with a prespecified secondary outcome of symptomatic PE or DVT.26 Over a median 1.9 years of follow-up, 34 participants in the rosuvastatin arm and 60 in the placebo arm developed VTE, for a odds ratio (OR) of 0.57 (95% confidence interval [CI], 0.37 to 0.86; p ¼ 0.007). Analogously, Ramcharan et al analyzed 4,538 cases of VTE and 5,914 controls, and reported that the administration of any statin yielded to an OR of 0.55 (95% CI, 0.46 to 0.67) for VTE.27 Similar results were reported by Sørensen et al, who studied 5,824 patients with VTE and 58,240 controls, and concluded that any statin use resulted in an OR of 0.74 (95% CI, 0.63 to 0.85) for VTE.28 Taken together, these results led Evans and Green to conclude that although there was a growing body of evidence to suggest that statins may be effective in the prevention of VTE, more evidence Seminars in Thrombosis & Hemostasis
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cholesterol is accompanied by a lower liver content and a consequent favorable effect, inasmuch as an increased synthesis of LDL receptor occurs in the hepatocytes to compensate for the reduced liver storage.4 A variety of clinical trials have definitely proven the beneficial effects of statins in lowering LDL cholesterol and preventing CVD, so that they have now become the cornerstone for the primary and secondary prevention, as well as for therapy of this condition.3 The beneficial effect of statins on the cardiovascular risk is also supported by additional, so-called pleiotropic mechanisms, which are considered independent from LDL cholesterol lowering, and include improvement of endothelial function, modulation of the inflammatory response, stabilization of atherosclerotic plaques, reduction of oxidative stress, attenuation of vascular and myocardial remodeling, as well as interference in coagulation pathways and thereby in thrombogenesis.5,6 The half-life of the different compounds is variegated, with atorvastatin and rosuvastatin displaying longer halflife (i.e., 16 to 30 and 20 hours, respectively), whereas simvastatin, pravastatin, lovastatin, and fluvastatin are characterized by a half-life of 1 to 3 hours.7 Beyond a different chemical composition, the catabolism is also heterogeneous, wherein atorvastatin, lovastatin, and simvastatin are mainly metabolized by cytochrome p-450 3A4, fluvastatin and rosuvastatin by cytochrome p-450 2C9, whereas pravastatin is degraded by sulfation.8 Cerivastatin, which was originally marketed along with atorvastatin in the late 1990s, has then been voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis. Pitavastatin has been available in Japan since the 2003, but it is now only marketed under license in South Korea and India.
Lippi et al.
Seminars in Thrombosis & Hemostasis
Vol. 39
1998
1999
2000
LIPID study 55
Nowak-Göttl et al21
von Depka et al22
1997
Kawasaki et al19
1998
1997
Goldhaber et al18
Downs et al54
Year published
Study (Reference)
No. 5/2013
Patients with any VTE (n ¼ 961)
Patients with any VTE (n ¼ 272)
NA
NA
73.2 (average)
62.4 (average)
NA
192
Follow-up duration (months)
34
5
31–75
Men aged 45 to 73. Postmenopausal women aged 55–73
Patients: 49.9 14.7 Controls: 47.7 16.0
30–55
Age in years (mean/range/SD)
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Case–control study
Case–control study
Cohort study
Cohort study
Case–control retrospective study
Case–control prospective study
Type of study
NA
NA
P
L
NA
NA
Study drugs
Risk of VTE associated with Lp(a) levels: Lp(a) > 10 mg/dL; OR, 1.6; 95% CI, 1.2–2.2 Lp(a) > 20 mg/dL; OR, 2.2; 95% CI, 1.5–3.3 Lp(a) > 30mg/dL; OR, 3.2; 95% CI, 1.9–5.3
Risk of VTE associated with Lp(a) levels: OR, 7.2; 95% CI, 2.0–13.0
Death from CHD: RRR of 24% (95% CI, 12–35; p < 0.001)
First acute major coronary events: RR, 0.63; 95% CI, 0.50–0.79; p ¼ 0.001 MI: RR, 0.60; 95% CI, 0.43–0.83; p ¼ 0.002 Unstable angina: RR, 0.68; 95% CI, 0.49–0.95; p ¼ 0.02 Coronary revascularization: RR, 0.67; 95% CI, 0.52–0.85; p ¼ 0.001 Coronary events: RR, 0.75; 95% CI, 0.61–0.92; p ¼ 0.006 Cardiovascular events: RR, 0.75; 95% CI, 0.62–0.91; p ¼ 0.003
Interrelationship between hyperlipidemia and DVT OR, 5.1; 95% CI, 2.0–13.0
Increased risk of primary PE OR, 1.1; 95% CI, 0.7–1.5
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
9,014 patients who had a history of MI or hospitalization for unstable angina
5,608 men and 997 women with average TC and LDL cholesterol and below-average HDL cholesterol
109 consecutive DVT patients (53 men, 56 women) and 109 age- and sex-matched control subjects randomly selected
112,822 women free from diagnosed cardiovascular disease or cancer at baseline. Overall, 1,619,770 personyear of follow-up
Population/no. of participants
Table 2 Most relevant published studies reporting the frequency of VTE in statin users and nonusers and included in this review
518 Lippi et al.
2003
Sever et al57
Seminars in Thrombosis & Hemostasis
Fellström et al58
2004
2004
2002
Herrington et al30
Doggen et al37
2002
Yang et al38
2004
20,536 UK adults with coronary disease, other occlusive arterial disease, or diabetes
2002
Heart Protection Study Collaborative Group56
Lacut et al45
325 patients with familial hypercholesterolemia - 160 and 165 patients were randomized to receive A (66 men, 94 women), or S (62 men, 103 women), respectively
2001
Smilde et al74
2,102 patients, who had received a renal transplant more than 6 months before randomization
Vol. 39
Prospective cohort study—RCT
Population-based case–control study
Case–control study
Prospective cohort study
Prospective cohort study
Case–control study
Prospective cohort study
Randomized, double-blind clinical trial
Retrospective cohort study
Type of study
61.2
NA
NA
60
49.2
NA
60
24
96
Follow-up duration (months)
50
30–89
18
40–79
66.7
40–79
40–80
48
65 or older
Age in years (mean/range/SD)
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465 postmenopausal women with a first venous thrombosis and 1,962 controls
377 patients consecutively hospitalized for a documented VTE event and 377 controls
19,342 hypertensive patients
2,763 postmenopausal women with heart disease
89,093 individuals
125,862 men and women in the primary cohort and 89,508 women in the secondary cohort
2001
Ray et al31
Population/no. of participants
Year published
Study (Reference)
Table 2 (Continued)
F
S
Any statin
A
Any statin
Any statin
S
A/S
Any statin
Study drugs
(Continued)
Decreased low density LDL cholesterol levels: 32% (95% CI, 33 to 30)
Risk of VTE users vs. nonusers OR, 0.84; 95% CI, 0.51–1.37
Decreased risk of VTE OR, 0.42; 95% CI, 0.23–0.76; p ¼ 0.002
Total cardiovascular events: (HR ¼ 0.79; 95% CI, 0.69– 0.90; p ¼ 0.0005) Total coronary events: (HR ¼ 0.71; 95% CI, 0.59– 0.86; p ¼ 0.0005)
Rates of VTE events among statin users HR ¼ 0.45, 95% CI, 0.23–0.88, p ¼ 0.02
IRR current/recent statin use 0.8 (0.3–2.7)
24% (SE 3; 95% CI, 19–28) reduction in the event rate (19.8 vs. 25.2% affected individuals; p < 0.0001)
The end point was the change of IMT: A: IMT decreased 0.031 mm; 95% CI, 0.007 to 0.055; p ¼ 0.0017 S: IMT increased 0.036; 95% CI, 0.014–0.058; p ¼ 0.0005
Decreased risk of DVT in primary cohort: HR, 0.78; 95% CI, 0.69–0.87 Decreased risk of DVT in secondary cohort: HR, 0.68; 95% CI, 0.59–0.79
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors Lippi et al.
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519
Seminars in Thrombosis & Hemostasis
Vol. 39
2004
2004
2004
2005
de Lemos et al75
Nissen et al76
Cannon et al77
The FIELD Study Investigators40
2004
Asselbergs et al60
2004
2004
Colhoun et al59
Koren et al61
Year published
Study (Reference)
Table 2 (Continued)
No. 5/2013
9,795 patients with type 2 diabetes
60
24
18
At least 6 and up to 24
51.5
46
48
Follow-up duration (months)
50–75
P group: 58.3 11.3 A group: 58.1 11.2
P group: 56.6 9.2 A group: 55.8 9.8
21–80
61.1 9.0
51 12
62
Age in years (mean/range/SD)
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Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Type of study
FEN
P/A
P/A
S
A
P
A
Study drugs
Significant 24% reduction in nonfatal MI HR ¼ 0.76, 95% CI, 0.62–0.94; p ¼ 0.010
Death from any cause, MI, unstable angina and stroke: 16% reduction in the HR in favor of A (p ¼ 0.005; 95% CI, 5–26)
% change in atheroma volume showed a significantly lower progression rate in the A group (P ¼ 0.02) Progression of coronary atherosclerosis occurred in the P group: 2.7%; 95% CI, 0.2–4.7; p ¼ 0.001 Progression did not occur in the A group: 0.4%; 95% CI, 2.4 to 1.5; p ¼ 0.98
Reduction of cardiovascular death, nonfatal MI, readmission for ACS, and stroke: HR, 0.75; 95% CI, 0.60–0.95; p ¼ 0.02
Reduction in morbidity: HR, 0.83; 95% CI, 0.71–0.97; p ¼ 0.02
Subjects treated with P showed a 13% lower incidence of cardiovascular mortality and hospitalization for cardiovascular morbidity 0.87 (0.49–1.57); p ¼ 0.649 log-rank
Allocation to A was associated with a 37% reduction in incidence of major cardiovascular events (p ¼ 0.001)
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
4,162 patients who had been hospitalized for an ACS within the preceding 10 days
1,156 patients
4,497 patients with ACS
2,442 CHD patients with hyperlipidemia
1,439 subjects with microalbuminuria as an indicator of increased cardiovascular and renal risk
2,838 type 2 diabetes mellitus patients in 132 centers in the UK and Ireland
Population/no. of participants
520 Lippi et al.
Year published
2005
2005
2005
2005
Study (Reference)
Wanner et al62
Cowell et al63
LaRosa et al78
Pedersen et al79
Table 2 (Continued)
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Type of study
57.6
46.8
25
48
Follow-up duration (months)
S group: 61.6 9.5 A group: 61.8 9.5
61.2 8.8
68 11
65.7 8.3
Age in years (mean/range/SD)
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8,888 patients with a history of acute MI
10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg/dL
155 patients with calcific aortic stenosis
1,255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis
Population/no. of participants
S/A
A
A
A
Study drugs
Seminars in Thrombosis & Hemostasis
Vol. 39
(Continued)
Major coronary event occurred in 463 S patients (10.4%) and in 411 A patients (9.3%) HR, 0.89; 95% CI, 0.78–1.01; p ¼ 0.07 Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the two groups: HR, 0.83; 95% CI, 0.71–0.98; p ¼ 0.02 Major cardiovascular events occurred in 608 and 533 in the two groups, respectively: HR, 0.87; 95% CI, 0.77–0.98; p ¼ 0.02 Occurrence of any coronary event was reported in 1,059 S and 898 A patients: HR, 0.84; 95% CI, 0.76–0.91; p ¼ 0.001 Death from any cause occurred in 374 (8.4%) in the S group and 366 (8.2%) in the A group
22% relative reduction in risk HR, 0.78; 95% CI, 0.69–0.89; p < 0.001)
Progression in valvular calcification (p ¼ 0.93; ratio of posttreatment aortic-valve calcium score, 0.998; 95% CI, 0.947–1.050)
A had no significant effect on the individual components of death from cardiac causes and nonfatal MI. The RR for fatal stroke was significant: 2.03 (95% CI, 1.05–3.93; p ¼ 0.04)
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors Lippi et al.
No. 5/2013
521
Seminars in Thrombosis & Hemostasis
Vol. 39
No. 5/2013
2006
2006
Sola et al68
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Type of study
12
58.8
48
63.6
Follow-up duration (months)
53.3 6.2
63.0 0.2
61.1 8.1
58.2 7.3
Age in years (mean/range/SD)
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108 patients with nonischemic HF and an LVEF 35%
4,731 patients who had had a stroke or TIA within 1–6 months before study entry had LDL cholesterol levels of 100 to 190 mg per deciliter, and had no known CHD
2,410 subjects with type 2 diabetes. A subset of 1,905 subjects without prior MI or interventional procedure
7,832 patients with hypercholesterolemia and no history of CHD or stroke
Population/no. of participants
A
A
A
P
Study drugs
LVEF increased from 0.33 0.05 to 0.37 0.04 (p ¼ 0.01) in the A group LVEDD was reduced from 57.1 5.9 mm to 53.4 5.1 mm (p ¼ 0.007)
Experienced primary end point (nonfatal or fatal stroke): HR, 0.84; 95% CI, 0.71–0.99; p ¼ 0.03; unadjusted p ¼ 0.05 The 5-year absolute reduction in the risk of major cardiovascular events was 3.5% (HR, 0.80; 95% CI, 0.69–0.92; p ¼ 0.002)
Experienced primary end point (cardiovascular death, nonfatal MI, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization) in type 2 diabetes patients treated with A or placebo: 13.7% in A group and 15.0% in placebo group HR, 0.90 (95% CI, 0.73–1.12) Composite end point reductions were not statistically significant
CHD was significantly lower in the P group 66 events vs. 101 events; HR, 0.67; 95% CI, 0.49–0.91; p ¼ 0.01
HR, 0.98; 95% CI, 0.85–1.13; p ¼ 0.81
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
Amarenco et al66
2006
2006
Nakamura et al64
Knopp et al65
Year published
Study (Reference)
Table 2 (Continued)
522 Lippi et al.
2007
2007
Kjekshus et al67
Freeman et al41
2007
2007
Huerta et al36
Crouse et al70
Year published
Study (Reference)
Table 2 (Continued)
Seminars in Thrombosis & Hemostasis
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study—RCT
Prospective cohort study with nested case–control analysis
Type of study
24
38.4
32.8
NA
Follow-up duration (months)
57 6.2
74.9 3.1
73 7.1
20–79
Age in years (mean/range/SD)
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984 individuals, as the only CHD risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2 to < 3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL)
5,699 nonwarfarin treated men and women
5,011 patients with New York Heart Association class II, III, or IV ischemic, systolic HF
6,550 patients diagnosed of VTE. These cases were compared with a random sample of 10,000 controls
Population/no. of participants
R
P
R
Any statin
Study drugs
Lippi et al.
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No. 5/2013
(Continued)
The change in maximum CIMT for the 12 carotid sites was 0.0014 (95% CI, 0.0041 to 0.0014) mm/y for the R group vs 0.0131 (95% CI, 0.0087–0.0174) mm/y for the placebo group (p < 0.001). The change in maximum CIMT for the R group was 0.0038 (95% CI, 0.0064 to 0.0013) mm/y for the common carotid artery sites (p < 0.001), 0.0040 (95% CI, 0.0090 to 0.0010) mm/y for the carotid
There were 28 definite cases (1.0%) of incident VTE in the P group recipients and 20 cases (0.70%) in placebo group. P did not reduce VTE in PROSPER compared with placebo: HR, 1.42; 95% CI, 0.80–2.52; p ¼ 0.23
Primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) occurred in 692 patients in the R group and 732 in the placebo group (HR, 0.92; 95% CI, 0.83–1.02; p ¼ 0.12)
Statins were associated with an OR of DVT of 0.70 (95% CI, 0.50–0.97)
and LVESD was reduced from 42.4 3.8 mm to 39.1 3.8 mm (p ¼ 0.02) in the cohort of patients treated with A; these dimensions increased in the placebo group
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors 523
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Vol. 39
2007
2008
2009
2009
Tavazzi et al69
Smeeth et al35
Sørensen et al28
Year published
Yang and Kao42
Study (Reference)
Table 2 (Continued)
No. 5/2013
Population-based cohort study
NA
52.8
46.8
144
Follow-up duration (months)
18–89
40–80
68 11
36–80
Age in years (mean/range/SD)
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5,824 patients with VTE and 58,240 population controls
Population-based cohort study
Prospective cohort study–RCT
Case–control study
Type of study
Any statin
Any statin
R
NA
Study drugs
Use of statins was associated with a reduced risk of VTE: OR, 0.74 (0.63–0.85)
Statin use was not associated with an effect on VTE: HR, 1.18; 99% CI, 1.06–1.31 Adjusted HR, 1.02; 99% CI, 0.88–1.18
657 (29%) patients died from any cause in the R group and 644 (28%) in the placebo group adjusted HR, 1.00; 95.5% CI, 0.898–1.122; p ¼ 0.943. 1,305 (57%) patients in the R group and 1,283 (56%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR, 1.01; 99% CI, 0.908–1.112; p ¼ 0.903
The adjusted OR of VTE was significant among patients with peripheral atherosclerotic diseases (OR, 7.1; 95% CI, 1.4–34.4), and nondebilitating cerebrovascular diseases (OR, 2.5; 95% CI, 1.4–4.7)
bulb sites (p < 0.001), and 0.0039 (95% CI, 0.0009 to 0.0088) mm/y for the internal carotid artery sites (p ¼ 0.02). The change in mean CIMT for the R group for the common carotid artery sites was 0.0004 (95% CI, 0.0011 to 0.0019) mm/y (p < 0.001). All p values are vs. placebo group
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
People who initiated treatment with a statin (n ¼ 129,288) were compared with a matched sample of 600,241 people who did not initiate treatment
4,574 patients aged 18 years or older with chronic HF of New York Heart Association classes II–IV
173 cases of VTE (needing hospitalization and anticoagulant therapy) and 546 matched controls
Population/no. of participants
524 Lippi et al.
2009
2009
2010
Glynn et al26
Squizzato et al33
Agarwal et al32
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Fassett et al73
2010
2010
2009
Ramcharan et al27
Chan et al72
Year published
Study (Reference)
Table 2 (Continued)
RCT
RCT
Meta-analysis
Meta-analysis
Prospective cohort study—RCT
Population-based case–control study
Type of study
30
42
NA
NA
22.8
NA
Follow-up duration (months)
60.2 15.1
58.0 12.9
NA
NA
Men > 50 Women > 60
18–70
Age in years (mean/range/SD)
A
R
Any statin
Any statin
R
Any statin
Study drugs
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(Continued)
The rate of MDRD eGFR decline was 29% lower; 1.04 3.84 vs. 1.47 3.74 mL/min/1.73 m2/y (p ¼ 0.53), and the C-G CrCl was 20% lower; 1.88 5.07
The annualized increase in the peak AS gradient was 6.3 6.9 mm Hg in the R group and 6.1 8.2 mm Hg in the placebo group (p ¼ 0.83)
Statin use was associated with a statistically significant reduction in the odds of developing VTE (AOR, 0.68; 95% CI, 0.54–0.86), DVT (AOR, 0.59; 95% CI, 0.43–0.82), and PE (AOR, 0.70; 95% CI, 0.53–0.94)
The use of statins was found to significantly decrease the risk of VTE at random effects model analysis: OR, 0.81; 95% CI, 0.66–0.99
The rates of VTE were 0.18 and 0.32 event per 100 person-year of follow-up in the R and placebo groups, respectively: HR, 0.57; 95% CI, 0.37–0.86; p ¼ 0.007 The rates of PE were 0.09 in the R group and 0.12 in the placebo group: HR, 0.77; 95% CI, 0.41–1.45; p ¼ 0.42 while the rates of DVT were 0.09 and 0.20, respectively: HR, 0.45; 95% CI, 0.25–0.79; p ¼ 0.004
Use of statins was associated with a reduced risk of VTE: OR, 0.45 (0.36–0.56)
Results
Lippi et al.
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132 patients with chronic kidney disease and with serum creatinine levels > 120 μmol/L, not taking lipid-lowering therapy and at
269 patients were randomized: 134 patients to R and 135 patients to placebo
971,307 patients from 10 studies, including 1 RCT and 9 observational studies were included
850,118 patients from 12 different studies, i.e., 1 RCT, 3 cohort, and 8 case–control studies
17,802 apparently healthy men and women with both LDL cholesterol levels of less than 130 mg/dL and highsensitivity C-reactive protein levels of 2.0 mg/L or higher
10,452 patients with a first episode of deep vein thrombosis in the leg or PE
Population/no. of participants
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors 525
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2011
2011
2012
2012
2012
Freeman et al53
Delluc et al50
Delluc et al49
Rahimi et al52
2010
Armitage et al80
Pai et al47
Year published
Study (Reference)
Table 2 (Continued)
No. 5/2013
Meta-analysis
NA
29.5
48
38.4
NA
80.4
Follow-up duration (months)
NA
65.5 (45.0–75.0)
73 (58–80)
74.9 3.1
NA
18–80
Age in years (mean/range/SD)
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105,759 participants from 22 trials of statin vs. control and 40,594 participants from 7 trials of an intensive vs. a standard dose statin regimen
Prospective cohort study
Hospital-based case–control study
Prospective cohort study—RCT
Meta-analysis
RCT
Type of study
Any statin
Any statin
Any statin
P
Any statin
S
Study drugs
Statin therapy did not significantly reduce the risk of VTE events (465 [0.9%] statin vs. 521 [1.0%] control, OR, 0.89; 95% CI, 0.78–1.01; p ¼ 0.08) with no evidence of heterogeneity between effects on DVT (266 vs. 311, OR, 0.85; 95% CI, 0.72–1.01)
60 patients (13.9%) had recurrent VTE. 48 patients (11.1%) received statins. In multivariate analysis, the risk of recurrent VTE associated with statin exposure was 1.02; 95% CI, 0.36–2.91
There was no association between lipid parameters and VTE in statin users and in fibrate users
P did not reduce VTE compared with placebo unadjusted HR, 1.42; 95% CI, 0.80–2.52; p ¼ 0.23
Comparing statins to control, the OR for VTE was 0.67; 95% CI, 0.53–0.84, and for DVT was 0.53; 95% CI, 0.22–1.29
Major vascular events occurred in 1,477 (24.5%) participants allocated 80 mg S vs. 1,553 (25.7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (RR, 0.94; 95% CI, 0.88–1.01; p ¼ 0.10)
vs. 2.36 4.61 mL/min/1.73 m2/y (p ¼ 0.58) in A-treated, compared with placebo-treated patients
Results
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
432 patients after discontinuation of anticoagulation
934 patients (100 treated with statin, 91 with fibrate, and 743 not receiving LLD)
Nonwarfarin–treated P (n ¼ 2,834) and placebo (n ¼ 2,865) patients
934,817 participants from four cohort studies and four case–control studies
12,064 men and women with a history of MI. 6,031 participants were allocated 80 mg S daily, and 6,033 allocated 20 mg S daily
all levels of proteinuria and serum cholesterol
Population/no. of participants
526 Lippi et al.
2012
Macchia et al51
30 patients randomly allocated to aspirin 100 mg/ day, A 40 mg/day, both or none
Population/no. of participants
Prospective cohort study—RCT
Type of study
2–2½
Follow-up duration (months)
50
Age in years (mean/range/SD)
A
Study drugs
A significantly reduced TG measured as peak TG with saline (85.09 55.34 nmol vs. 153.26 75.55 nmol for A and control groups, respectively; p ¼ 0.018)
and effects on PE (205 vs. 222, OR, 0.92; 95% CI, 0.76–1.12). Exclusion of the JUPITER trial had little impact on the findings for VTE (431 [0.9%] vs. 461 [1.0%], OR ¼ 0.93 [95% CI, 0.82–1.07]; p ¼ 0.32 among the other 21 trials. There was no evidence that higher dose statin therapy reduced the risk of VTE compared with standard dose statin therapy (198 [1.0%] vs. 202 [1.0%], OR ¼ 0.98; 95% CI, 0.80–1.20; p ¼ 0.87)
Results
Seminars in Thrombosis & Hemostasis
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Abbreviations: A, atorvastatin; ACS, acute coronary syndrome; AOR, adjusted odds ratio; AS, aortic stenosis; C þ F, clofibrate and niacin; C-G CrCl, Cockcroft–Gault creatinine clearance; CHD, coronary heart disease; CI, confidence interval; CIMT, carotid intima-media thickness; eGFR, estimate glomerular filtration rate; F, fluvastatin; FEN, fenofibrate; FRS, Framingham risk score; HF, heart failure; HR, hazard ratio; IMT, intimamedia thickness; IRR, incidence rate ratio; JUPITER, Justification for the Use of Statins in Primary Prevention trial; L, lovastatin; LDL, low-density lipoprotein; LLD, lipid-lowering drugs; Lp(a), lipoprotein a; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; MDRD, modification of diet in renal disease; MI, myocardial infarction; NA, not applicable/not available; OR, odds ratio; P, pravastatin, PE, pulmonary embolism; R, rosuvastatin; RCT, randomized controlled trial; RR, relative risk; RRR, relative reduction risk; S, simvastatin; SD, standard deviation; SE, standard error; TC, total cholesterol; TG, triglycerides; TIA, transient ischemic attack; UK, United Kingdom; VTE, venous thromboembolism.
Year published
Study (Reference)
Table 2 (Continued)
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors Lippi et al.
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Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors from randomized controlled trials should be obtained before drawing definitive conclusions. In a systematic review, the Cochrane Peripheral Vascular Diseases Group performed a comprehensive search on their specialized register (last searched April 2011), Central (2011, Issue 2), Medline (from January 1966 to March 2011), Embase (from 1974 to March 2011), ISI Web of Knowledge (2001 to March 2011), as well as the Chinese Biomedical Literature Database (from 1978 to March 2011).29 Because the authors decided to include only randomized controlled trials, only the study of Glynn et al,26 which was already included in the previous analysis of Evans and Green and which had assessed the effect of the rosuvastatin for preventing VTE as one of the secondary end points, was deemed eligible. Specifically, this study showed a decreased incidence of DVT in patients with normal LDL cholesterol levels and elevated CRP in patients treated with 20 mg/day rosuvastatin. This led Li et al to conclude that further data would be needed before statins could be considered a suitable option for prevention of VTE prevention or as a surrogate for other forms of VTE prophylaxis. Poredos and Jezovnik performed another review on dyslipidemia, statins, and VTE, including nine studies and two meta-analyses.15 Besides the previously mentioned study of Glynn et al,26 the authors included the Heart and Estrogen/ Progestin Replacement Study, a randomized clinical trial of statin use and estrogen plus progestin versus placebo in postmenopausal women with heart disease (n ¼ 2,763), which showed that the rate of VTE was lower in statin users (relative hazard, 0.45; 95% CI, 0.23 to 0.88; p ¼ 0.02).30 Additional trials included were the two case–control studies of Ramcharan et al27 and Sørensen et al,28 as well as the prospective observational study of Ray et al,31 a retrospective Canadian Cohort Study totaling 125,862 males and females which reported that statins reduced the risk of VTE by 20 to 60%. Two meta-analyses on the efficacy of statins in prevention of VTE were also assessed.32,33 The meta-analysis by Agarwal et al32,33 included the JUPITER (Justification for the Use of Statins in Primary Prevention) study by Glynn et al26 and another nine observational studies,27,28,30,31,34–38 for a final number of 971,307 subjects.32 Agarwal et al found that statin use was associated with a statistically significant reduction in rate of developing VTE (adjusted OR, 0.68; 95% CI, 0.54 to 0.86), DVT (adjusted OR, 0.59; 95% CI, 0.43 to 0.82), and PE (adjusted OR, 0.70; 95% CI, 0.53 to 0.94). It was hence concluded that statin use may be associated with a significantly reduced risk of developing VTE, DVT, or PE by 32, 41, and 30%, respectively. It is also noteworthy that, after limiting the analysis to observational studies, the results were comparable and remained statistically significant. The metaanalysis by Squizzato et al33 also assessed the effect of lipid-lowering drugs, specifically statins and fibrates, including three randomized controlled trials, three cohort, and eight case–control studies,26–28,30,31,34–36,38–42 for a total number of 836,805 patients. Statins use significantly reduced the risk of VTE by nearly 20% (adjusted OR, 0.81; 95% CI, 0.66 to 0.99). Despite most studies showing agreement in a favorable effect of statins on VTE risk, Poredos and Jezovnik concluded, however, that these drugs must not be considered Seminars in Thrombosis & Hemostasis
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a substitute for well-established prophylactic VTE therapy, and their use cannot be extended to embrace prophylaxis of venous thrombosis. More recently, an additional critical review of the literature performed by Rodriguez et al43 assessed the antithrombotic nature of statins in seven studies, including one randomized controlled trial, four case–control studies, one retrospective cohort study, and one basic science trial which assessed nearly all commercially available molecules, that is, pravastatin, simvastatin, atorvastatin, rosuvastatin, lovastatin, fluvastatin, and cerivastatin.26,27,31,37,44–46 Overall, the analysis of the data showed similar effects for limiting the burden of VTE in postmenopausal women, patients with solid organ tumors, and patients with recurrent DVT.27,31,37,44,45 In the case–control study, pravastatin was found to have a greater effect than simvastatin for reducing DVT rate, thus suggesting that a difference in efficacy according to statin type may exist.27 In another meta-analysis of observational studies recently performed by Pai et al,47 the authors finally included eight studies with a total of 934,817 participants.27,28,30,31,35,38,45,48 It was hence shown that the OR for VTE was 0.67 (95% CI, 0.53 to 0.84) by comparing statins versus control, whereas the OR for DVT was 0.53 (95% CI, 0.22 to 1.29). Recently, Delluc et al assessed the association between the risk of recurrence of VTE after anticoagulation and the use of lipid-lowering drugs (i.e., fibrates and statins) in a prospective cohort study.49 The authors followed up 432 patients (median age 65.5 years) for a median of 29.5 months after discontinuation of anticoagulation. Sixty patients (13.9%) had recurrent VTE. Forty-eight patients (11%) received statins and 36 patients (8%) received fibrates. The consequent risk of recurrent VTE associated with statin therapy was 1.02 (95% CI, 0.36 to 2.91), although it was also interestingly reported that recurrent VTE risk with fibrate administration was significantly higher than those not using these agents (OR, 2.15; 95% CI, 1.01 to 4.61). The same group of authors also studied the association between lipids and lipoproteins with the development of VTE.50 The authors measured the lipid profile (i.e., total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A-I, and apolipoprotein B) of 467 patients with a first unprovoked VTE event diagnosed between May 2000 and December 2004 and 467 age- and sex-matched controls. The association between lipid profile parameters and VTE was determined in statin users, fibrate users, as well as in the control group. In agreement with previous evidence, a reduced risk of VTE was found in statin users (OR, 0.49; 95% CI, 0.30 to 0.78), whereas an opposite trend was observed for fibrate (OR, 1.40; 95% CI, 0.87 to 2.26). No association was found between lipid parameters and VTE in both statin and fibrate users, thus suggesting that the reduced risk of VTE associated with statins, as well as the increased risk associated with fibrates, may be intrinsically related to the drugs and not mediated by their effects on blood lipid. Macchia et al assessed the effects of aspirin and statins on thrombotic risk evaluated by thrombin generation among patients with type II diabetes mellitus (i.e., 30 patients were randomly allocated to aspirin 100 mg/day, atorvastatin 40
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Fig. 2 Summary of the lipid and nonlipid effects of coenzyme A (HMG-CoA) reductase inhibitors (statins) on different human biological systems. FV, factor V; FXIII, factor XIII; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NO, nitric oxide; MMP, metalloproteinase; VTE, venous thromboembolism. Data extracted from references.87–94
mg/day, both or none).51 The thrombin generation at baseline was comparable in all groups and no interaction was observed between drugs. The results of thrombin generation (i.e., peak assay with saline and adenosine diphosphate 8 106 mol/L) were however significantly reduced after atorvastatin but not after aspirin therapy, thus suggesting that the reduced thrombotic risk attributable to therapy with statins may also be due to antithrombotic mechanisms targeting blood coagulation. A recent and original meta-analysis has also been published by Rahimi et al,52 in which the authors searched Medline, Embase, and Cochrane Central up to March 2012 for randomized controlled trials which had compared therapy and no therapy with HMG-CoA reductase inhibitors, high versus standard dose of HMG-CoA reductase inhibitors, including not less than 100 participants and not less than 6 months of follow-up. Twentytwo clinical studies of HMG-CoA reductase inhibitors versus control (105,759 participants),53–73 and seven trials of an intensive versus standard dose regimen (40,594 participants),74–80 were finally included. At variance with the previous metaanalyses and critical reviews, statin therapy was found to exert no effect on the risk of VTE events (0.9 vs. 1.0% in controls; OR, 0.89; 95% CI, 0.78 to 1.01; p ¼ 0.08). Identical results were found when restricting the analysis to DVT (OR, 0.85; 95% CI, 0.72 to 1.01) or PE (OR, 0.92; 95% CI, 0.76 to 1.12). Even the exclusion of the original trial that prompted the meta-analysis (i.e., the JUPITER study)26 had no impact on VTE risk (OR, 0.93; 95% CI, 0.82 to 1.07; p ¼ 0.32). No significant effect of higher doses of statins as compared with standard dose was found for VTE (1.0
vs. 1.0%; OR, 0.98; 95% CI, 0.80 to 1.20; p ¼ 0.87), as well as for DVT (OR, 0.83; 95% CI, 0.57 to 1.21) and PE (OR, 1.19; 95% CI, 0.84 to 1.68) risk. These results led Rosendaal to put forward the hypothesis that therapy with statins does not significantly reduce the risk of VTE, taken into account that the data included in the meta-analysis were obtained from randomized studies and large numbers of patient years.81
C-Reactive Protein, Statin, and Venous Thromboembolism There is an intriguing relationship between CRP, statin, and venous thrombosis. It is already widely acknowledged that part of the benefits of statins on CVD are through their pleiotropic effect on (systemic) inflammation, wherein patients who achieve lower levels of CRP after statin therapy display better clinical outcomes than those with higher concentration of the protein, independent from the levels of LDL cholesterol.82,83 Basically, the definitive functions of this acute-phase reactant are mostly unknown, although it has been hypothesized that an increased concentration may somehow support a kaleidoscope of immune functions, including protection against bacterial infections, efficient elimination of necrotic cells for limiting endogenous immunization against autoantigens, as well as promotion of reparative processes. Several lines of evidence, recently reviewed elsewhere,84 suggest that CRP may take part in the pathogenesis of VTE, wherein this protein displays prothrombotic activities, such as induction of platelet hyperreactivity, capability of activating Seminars in Thrombosis & Hemostasis
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Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors secondary hemostasis, and interference with the fibrinolytic system. Even more interestingly, some epidemiological trials have consistently demonstrated that CRP is positively associated with VTE risk, whereas the evidence that therapy with statins is effective to substantially decrease CRP concentration as part of their pleiotropic effects provides another reliable and plausible link between HMG-CoA reductase inhibitors and venous thrombosis.84 It is still uncertain, however, as to whether CRP would exert a causal role on VTE (i.e., as an independent risk factor) or rather the increase of its concentration in blood would represent a simple marker of other interplaying risk factors of venous thrombosis.
10
Conclusions
11
Several plausible biological links can be found between statin therapy and reduction of thrombotic risk, entailing especially effects on immune system, blood coagulation, endothelium, lipid metabolism, and inflammation (►Fig. 2). It is undeniable that the earlier JUPITER trial, where 17,802 healthy subjects were randomly allocated to receive either statin or matching placebo,26 provided the most attractive evidence that the risk of VTE may be lowered by therapy with statins (43% reduction over a median 1.9 years follow-up). The results of the following clinical trials and—especially—those of the recent meta-analysis of Rahimi et al52 have however seriously questioned this previous finding. At this point in time, it seems thus cautious to conclude that the use of statins as part of the intervention measures for preventing VTE appears unwarranted. This is attributable only in part to the existence of the controversial clinical evidence outlined previously. Also to be considered is the large number of patients that would need to be treated to prevent one case of venous thrombosis,85 as well as to the tangible risk of side effects that these drugs carry, especially rhabdomyolysis and liver abnormalities.86 More randomized studies including larger numbers of subjects are therefore needed before definitive conclusions can be drawn on this issue. Some interesting trials are already in progress (e.g., ClinicalTrials.gov identifiers NCT01021488, NCT00259662, and NCT01613794). Hopefully, when results of these trials become available, a more definitive role of statins in VTE will be defined, or otherwise effectively refuted.
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References 1 Lippi G, Franchini M, Targher G. Arterial thrombus formation in
cardiovascular disease. Nat Rev Cardiol 2011;8(9):502–512
24
2 Gotto AM Jr, Moon JE. Management of cardiovascular risk: the
importance of meeting lipid targets. Am J Cardiol 2012;110(1) (Suppl):3A–14A 3 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106 (25):3143–3421 4 Matsuyama H, Sato K, Nakamura Y, Suzuki K, Akiba Y. Modulation of regulatory factors involved in cholesterol metabolism in re-
Seminars in Thrombosis & Hemostasis
Vol. 39
No. 5/2013
25
26
27
Lippi et al.
sponse to feeding of pravastatin- or cholesterol-supplemented diet in chickens. Biochim Biophys Acta 2005;1734(2):136–142 Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(23)(Suppl 1):III39–III43 Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J 2010;74(5):818–826 Stolla D, Dariolia R, Rodondia N. Lipid-lowering therapies and liver enzymes. Kardiovaskuläre Medizin 2009;12(9):239–244 Pella D, Rybar R, Mechirova V. Pleiotropic effects of statins. Acta Cardiol Sin 2005;21:190–198 Lippi G, Favaloro EJ. Coagulopathies and thrombosis: usual and unusual causes and associations, part VI. Semin Thromb Hemost 2012;38(2):125–128 Lippi G, Franchini M, Favaloro EJ. Unsuspected triggers of venous thromboembolism—trivial or not so trivial? Semin Thromb Hemost 2009;35(7):597–604 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008;34 (8):747–761 Tufano A, Coppola A, Cerbone AM, Ruosi C, Franchini M. Preventing postsurgical venous thromboembolism: pharmacological approaches. Semin Thromb Hemost 2011;37(3):252–266 Lippi G, Favaloro EJ, Cervellin G. Prevention of venous thromboembolism: focus on mechanical prophylaxis. Semin Thromb Hemost 2011;37(3):237–251 Bikdeli B, Sharif-Kashani B. Prophylaxis for venous thromboembolism: a great global divide between expert guidelines and clinical practice? Semin Thromb Hemost 2012;38(2):144–155 Poredos P, Jezovnik MK. Dyslipidemia, statins, and venous thromboembolism. Semin Thromb Hemost 2011;37(8):897–902 Ray JG, Rosendaal FR. The role of dyslipidemia and statins in venous thromboembolism. Curr Control Trials Cardiovasc Med 2001;2(4):165–170 Goldhaber SZ, Savage DD, Garrison RJ, et al. Risk factors for pulmonary embolism. The Framingham Study. Am J Med 1983;74(6):1023–1028 Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997;277 (8):642–645 Kawasaki T, Kambayashi J, Ariyoshi H, Sakon M, Suehisa E, Monden M. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res 1997;88(1):67–73 McColl MD, Sattar N, Ellison J, et al. Lipoprotein (a), cholesterol and triglycerides in women with venous thromboembolism. Blood Coagul Fibrinolysis 2000;11(3):225–229 Nowak-Göttl U, Junker R, Hartmeier M, et al. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood. Circulation 1999;100(7):743–748 von Depka M, Nowak-Göttl U, Eisert R, et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000;96(10):3364–3368 Lippi G, Bassi A, Brocco G, Manzato F, Marini M, Guidi G. Lipoprotein (a) concentration is not associated with venous thromboembolism in a case control study. Haematologica 1999;84(8):726–729 Ignatescu M, Kostner K, Zorn G, et al. Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension. Thromb Haemost 1998;80(2):231–232 Evans NS, Green D. ASH evidence-based guidelines: statins in the prevention of venous thromboembolism. Hematology (Am Soc Hematol Educ Program) 2009:273–274 Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360(18):1851–1861 Ramcharan AS, Van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJ. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost 2009;7(4):514–520
Downloaded by: Universita di Parma. Copyrighted material.
530
Lippi et al.
28 Sørensen HT, Horvath-Puho E, Søgaard KK, et al. Arterial cardio-
48 Resh M, Mahmoodi BK, Navis GJ, Veeger NJ, Lijfering WM. Statin
vascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost 2009;7(4):521–528 Li L, Sun T, Zhang P, Tian J, Yang K. Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev 2011; (12):CD008203 Herrington DM, Vittinghoff E, Lin F, et al; HERS Study Group. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002;105(25):2962–2967 Ray JG, Mamdani M, Tsuyuki RT, Anderson DR, Yeo EL, Laupacis A. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001;161(11):1405–1410 Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a metaanalysis. Int J Clin Pract 2010;64(10):1375–1383 Squizzato A, Galli M, Romualdi E, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J 2010;31 (10):1248–1256 Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia? Thromb Res 2008;122(3):314–319 Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009;67 (1):99–109 Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007;167(9):935–943 Doggen CJ, Lemaitre RN, Smith NL, Heckbert SR, Psaty BM. HMG CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women. J Thromb Haemost 2004;2(5):700–701 Yang CC, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 2002;53(1):101–105 The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231(4):360–381 Keech A, Simes RJ, Barter P, et al; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366(9500):1849–1861 Freeman DJ, Robertson M, Ford I, et al. Risk factors for the development of incident venous thrombotic events in the prospective study of pravastatin in the elderly at risk (PROSPER). (Abstract)Platelets 2007;18(Suppl 1):S18 Yang CC, Kao CC. Cardiovascular diseases and the risk of venous thromboembolism: a hospital-based case-control study. J Chin Med Assoc 2007;70(3):103–109 Rodriguez AL, Wojcik BM, Wrobleski SK, Myers DD Jr, Wakefield TW, Diaz JA. Statins, inflammation and deep vein thrombosis: a systematic review. J Thromb Thrombolysis 2012;33(4): 371–382 Khemasuwan D, Divietro ML, Tangdhanakanond K, Pomerantz SC, Eiger G. Statins decrease the occurrence of venous thromboembolism in patients with cancer. Am J Med 2010;123(1):60–65 Lacut K, Oger E, Le Gal G, et al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam Clin Pharmacol 2004;18(4):477–482 Momi S, Impagnatiello F, Guzzetta M, et al. NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. Eur J Pharmacol 2007;570(1-3):115–124 Pai M, Evans NS, Shah SJ, Green D, Cook D, Crowther MA. Statins in the prevention of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 2011;128(5):422–430
use in patients with nephrotic syndrome is associated with a lower risk of venous thromboembolism. Thromb Res 2011;127(5): 395–399 Delluc A, Tromeur C, Le Moigne E, et al. Lipid lowering drugs and the risk of recurrent venous thromboembolism. Thromb Res 2012;130(6):859–863 Delluc A, Malécot JM, Kerspern H, et al. Lipid parameters, lipid lowering drugs and the risk of venous thromboembolism. Atherosclerosis 2012;220(1):184–188 Macchia A, Laffaye N, Comignani PD, et al. Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial. PLoS ONE 2012;7(3):e32894 Rahimi K, Bhala N, Kamphuisen P, et al. Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials. PLoS Med 2012;9(9):e1001310 Freeman DJ, Robertson M, Brown EA, et al. Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). BMC Geriatr 2011;11:8 Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279 (20):1615–1622 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339(19):1349–1357 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7–22 Sever PS, Dahlöf B, Poulter NR, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial —Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361(9364):1149–1158 Fellström B, Holdaas H, Jardine AG, et al; Assessment of Lescol in Renal Transplantation Study Investigators. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Kidney Int 2004;66(4):1549–1555 Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364(9435):685–696 Asselbergs FW, Diercks GF, Hillege HL, et al; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004;110(18):2809–2816 Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol 2004;44(9):1772– 1779 Wanner C, Krane V, März W, et al; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353 (3):238–248 Cowell SJ, Newby DE, Prescott RJ, et al; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352(23):2389–2397
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Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors
Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors 64 Nakamura H, Arakawa K, Itakura H, et al; MEGA Study Group.
65
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67
68
69
70
71
72
73
74
75
76
77
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368(9542):1155–1163 Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006;29(7):1478–1485 Amarenco P, Bogousslavsky J, Callahan A III, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355(6):549–559 Kjekshus J, Apetrei E, Barrios V, et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357 (22):2248–2261 Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;47(2):332–337 Tavazzi L, Maggioni AP, Marchioli R, et al; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231–1239 Crouse JR III, Raichlen JS, Riley WA, et al; METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297(12):1344–1353 Feldman HH, Doody RS, Kivipelto M, et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74(12):956–964 Chan KL, Teo K, Dumesnil JG, Ni A, Tam J; ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121(2):306–314 Fassett RG, Robertson IK, Ball MJ, Geraghty DP, Coombes JS. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trial. Atherosclerosis 2010;213(1):218–224 Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357(9256):577–581 de Lemos JA, Blazing MA, Wiviott SD, et al; Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292(11):1307–1316 Nissen SE, Tuzcu EM, Schoenhagen P, et al; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291(9):1071–1080 Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myo-
Seminars in Thrombosis & Hemostasis
Vol. 39
No. 5/2013
78
79
80
81 82
83
84
85
86
87 88 89 90 91 92 93
94
Lippi et al.
cardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350(15):1495–1504 LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352 (14):1425–1435 Pedersen TR, Faergeman O, Kastelein JJ, et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294(19):2437–2445 Armitage J, Bowman L, Wallendszus K, et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376(9753):1658–1669 Rosendaal FR. Statins and venous thrombosis: a story too good to be true? PLoS Med 2012;9(9):e1001311 Ridker PM, Cannon CP, Morrow D, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20–28 Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21): 2195–2207 Lippi G, Favaloro EJ, Montagnana M, Franchini M. C-reactive protein and venous thromboembolism: causal or casual association? Clin Chem Lab Med 2010;48(12):1693–1701 Perez A, Bartholomew JR. Interpreting the JUPITER trial: statins can prevent VTE, but more study is needed. Cleve Clin J Med 2010;77(3):191–194 Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 2010;48(6):749–756 Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005;25(2):287–294 Kinlay S. Potential vascular benefits of statins. Am J Med 2005;118 (Suppl 12A):62–67 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89–118 Yoshida M. Potential role of statins in inflammation and atherosclerosis. J Atheroscler Thromb 2003;10(3):140–144 Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther 2003;99(1):95–112 Davignon J. Pleiotropic effects of pitavastatin. Br J Clin Pharmacol 2012;73(4):518–535 Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev 2010;18 (6):298–304 Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011;4:261–271
Downloaded by: Universita di Parma. Copyrighted material.
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