Venous Thrombosis Associated with HMG-CoA

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.

Downloaded by: Universita di Parma. Copyrighted material.

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


516

Fig. 1 Biochemical pathway of cholesterol synthesis. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A.

Seminars in Thrombosis & Hemostasis

Vol. 39

No. 5/2013

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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No. 5/2013


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.


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)


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


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


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


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


50

30–89

18

40–79

66.7

40–79

40–80

48

65 or older



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


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.

No. 5/2013

519


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


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










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


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


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)





Type of study

57.6

46.8

25

48


S group: 61.6 9.5 A group: 61.8 9.5

61.2 8.8

68 11

65.7 8.3



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


S/A

A

A

A

Study drugs


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


No. 5/2013

521


Vol. 39

No. 5/2013

2006

2006

Sola et al68





Type of study

12

58.8

48

63.6


53.3 6.2

63.0 0.2

61.1 8.1

58.2 7.3



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


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


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)





Prospective cohort study with nested case–control analysis

Type of study

24

38.4

32.8

NA


57 6.2

74.9 3.1

73 7.1

20–79



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


R

P

R

Any statin

Study drugs

Lippi et al.

Vol. 39

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


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


18–89

40–80

68 11

36–80



5,824 patients with VTE and 58,240 population controls

Population-based cohort study

Prospective cohort study–RCT


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


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


524 Lippi et al.

2009

2009

2010

Glynn et al26

Squizzato et al33

Agarwal et al32


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


Population-based case–control study

Type of study

30

42

NA

NA

22.8

NA


60.2 15.1

58.0 12.9

NA

NA

Men > 50 Women > 60

18–70


A

R

Any statin

Any statin

R

Any statin

Study drugs

Vol. 39

No. 5/2013

(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.


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


Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors 525


Vol. 39

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


NA

65.5 (45.0–75.0)

73 (58–80)

74.9 3.1

NA

18–80



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


Hospital-based case–control study


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


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


526 Lippi et al.

2012

Macchia et al51

30 patients randomly allocated to aspirin 100 mg/ day, A 40 mg/day, both or none



Type of study

2–2½


50


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



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)


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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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Lippi et al.

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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Lippi et al.

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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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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