The basic assumption beneath the use of a common therapy for preventing both arterial
and venous thrombosis is that the biology of blood clot formation expresses some overlap,
so that thrombus structure and composition would not be markedly different when developing
in arterial or venous blood vessels.[1 ] Briefly, both arterial and venous thrombi are largely composed of platelets and
fibrin, although the main components of the so-called Virchow's triad (i.e., hypercoagulability,
venous stasis, and endothelial injury) may have some differential impact on thrombus
formation in arteries versus veins. Thrombosis in arterial vessels mostly results
from fissuration, ulceration, or complete rupture of pre-existing atherosclerotic
plaques, thus leading to local release of several prothrombotic substances, which
may finally promote both platelet aggregation and blood clotting. Unlike this process
in the arteries, the pathogenesis of vein thrombosis is more profoundly influenced
by a pre-existent prothrombotic milieu in the circulation, which interplays with the
lower blood pressure present in these vessels (up to venous stasis) to trigger blood
coagulation and platelet activation. Atherosclerotic plaques are typically absent
in normal veins,[2 ] and can only develop once these vessels are implanted, as bypass conduits, to replace
important arteries (typically coronaries) irreversibly occluded or injured.[3 ] Based on this premise, it seems at first glance counterintuitive to conclude that
lowering atherogenic lipoproteins (i.e., mostly low-density lipoproteins) would not
have the same favorable effect against thrombosis in both arteries and veins. This
conceptual dichotomy has been firmly endorsed by epidemiological studies, showing
that serum levels of atherogenic lipoproteins are not associated with the risk of
developing either incident[4 ] or recurrent[5 ] venous thrombosis.
Statins, which mainly act as competitive inhibitors of the enzyme 5-hydroxy-3-methylglutaryl-coenzyme
A reductase, have become a mainstay for treatment of patients with cardiovascular
disease, although their use in primary prevention of cardiovascular disorders remains
largely debated.[6 ] Several lines of evidence, as reviewed in this issue of the journal by Orsi et al,[7 ] seemingly demonstrate that these drugs are also effective to dampen platelet function
and may also interfere with blood coagulation, thus representing potentially suitable
agents for also lowering the risk of venous thrombosis. However, some clinical studies,
also reviewed by Orsi et al,[7 ] have provided controversial evidence on the role of statins for reducing the risk
of venous thromboembolism (VTE). For example, the recent systematic review and meta-analysis
published by Kunutsor et al concluded that the risk of VTE was 15% lower (relative
risk [RR], 0.85; 95% confidence interval [95% CI], 0.73–0.99) with statin therapy
compared with no treatment, but no clear risk reduction was seen for pulmonary embolism
(RR, 1.02; 95% CI, 0.74–1.40).[8 ] Interestingly, a similar lack of significant effect was noted in a recent study
in a high-risk population (i.e., cancer patients), in which these drugs were shown
not to prevent either deep vein thrombosis (hazard ratio [HR], 0.96; 95% CI, 0.88–1.05)
or pulmonary embolism (HR, 0.91; 95% CI, 0.79–1.05).[9 ]
Thus, statins still have an uncertain role in primary prevention of VTE; however,
what cannot be discounted is the fact that all drug use carries some risks for adverse
effects. With the anticoagulant agents, the main adverse risk factor is bleeding ([Fig. 1 ]).[10 ]
[11 ]
[12 ]
Fig. 1 Possible harms and benefits of statins in primary prevention of venous thromboembolism,
as compared with anticoagulant use.
Statin use does not seem to confer an increased risk of bleeding, and thus may be
seen as an attractive alternative to anticoagulant use. Nevertheless, statin use still
carries significant potential for side effects, especially in the general population.
These adverse effects include muscle injury (up to rhabdomyolysis), pancreatic and
liver impairment, neuropathy, cognitive loss, and sexual dysfunction.[13 ]
[14 ] Importantly, a recent cross sectional study of the National Health and Nutrition
Examination Survey concluded that statin intake was associated with significantly
enhanced prevalence of musculoskeletal pain in all body areas (prevalence ratios comprised
between 1.3 and 1.6).[15 ] As regards statin-induced rhabdomyolysis, safety data identifies the prevalence
of this severe and often life-threatening condition to be as high as 1.35 cases per
100,000 prescriptions,[16 ] and this is consistently magnified by concomitant use of statins with fibrate.[17 ] In another retrospective study, including 32,225 subjects (10,247 with diabetes
and 21,978 without), Nichols and Koro reported a prevalence of severe myositis and
rhabdomyolysis of 0.4 to 0.8 and 0.1 to 0.2 per 1000 person-years, respectively.[18 ]
Thus, the use of statins for primary prevention would notably not only be associated
with a significant clinical risk of side effects for patients but also raise issues
of healthcare sustainability, since such treatment would entail larger healthcare
expenditures for both administering the drug to the general population and for managing
potential complications.[19 ] More epidemiological evidence is therefore advisable to prove both cost-effectiveness
and safety of statins in primary and secondary prevention of VTE.[20 ] For the interim, our conviction remains that the balance between possible harms
and benefits of using statins in the general population would currently make their
widespread usage unwarranted ([Fig. 1 ]), while their impact on risk reduction of recurrent VTE, ranging between 26 and
38%, was found to be limited to long-term statin users.[7 ] It is understandable that clinicians and patients alike desire a magic bullet to
treat and prevent thrombosis. It is unclear if statin use will find a place in treatment
of select patient groups. However, for most patients, lifestyle changes based on appropriate
nutrient intake and preventing a sedentary lifestyle[21 ] may still be the best options to reducing primary thrombosis risk. Although, like
statins, focusing on individual foods or nutrients may not provide the answer either.[22 ]
[23 ]
[24 ] We eagerly await further advances in the field.
