Keywords
blood coagulation - clinical trials - hydroxymethylglutaryl-CoA reductase inhibitors
- prevention - venous thrombosis
Venous thromboembolism (VTE) is a condition that comprises deep vein thrombosis (DVT),
pulmonary embolism (PE) or both. The reported annual incidence of VTE ranges from
7.5 to 26.9 per 10,000 individuals in the population, with the highest rates being
reported in the elderly.[1] In addition, VTE mortality rates range from 0.94 to 3.23 per 10,000 individuals
per year, varying across countries.[2] Due to the high incidence rates, associated disabilities and mortality, VTE causes
a major disease burden worldwide,[1] which underscores the necessity of effective preventive measures and adequate treatment.
Approximately 50 to 60% of VTE episodes are provoked by major risk factors, such as
cancer, surgery, immobilization, estrogen therapy, and pregnancy. Cases in which a
transient or a persistent risk factor cannot be identified are categorized as unprovoked
VTE.[3]
[4] Because the risk of recurrent VTE is higher after an unprovoked event compared with
a provoked one, categorizing VTE episodes is important to determine the duration of
anticoagulation treatment.[5] After anticoagulation therapy is discontinued, the risk of VTE recurrence is up
to 10% per year in patients with unprovoked VTE,[6] and extended use of oral anticoagulants is associated with a sevenfold decrease
in the risk of recurrent VTE.[7]
[8] However, prolonged oral anticoagulant therapy increases by two- to threefold the
risk of having a clinically significant bleeding episode compared with placebo,[7]
[8] which may result in treatment avoidance. Therefore, the search for new medications
capable of decreasing VTE risk without increasing the risk of bleeding is warranted.
In this context, statins could be an alternative medication for VTE prophylaxis because
they may have antithrombotic effect without causing bleeding complications.[9] Available evidence from clinical trials consistently indicates that statins do not
increase the risk of bleeding. Although results from the Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL) trial[10] indicated that atorvastatin at 80 mg per day was associated with a 66% increase
in the risk of hemorrhagic stroke compared with placebo (hazard ratio, 1.66; 95% confidence
interval [CI]: 1.08–2.55), these observations were not confirmed in other trials.[11]
[12]
[13]
[14] This suggests that results from the SPARCL trial were due to a type I error. In
the Heart Protection Study,[11] no difference in hemorrhagic stroke was observed between simvastatin at 40 mg per
day and placebo (incidence rate ratio, 0.95; 95% CI: 0.65–1.40). The Justification
for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial found no difference between rosuvastatin
at 20 mg per day and placebo in the rates of intracranial hemorrhage[12] or other bleeding episodes.[13] A meta-analysis of randomized trials and observational studies[14] demonstrated that statins were not associated with an increased risk of intracerebral
hemorrhage. The pooled risk ratio for bleeding on statin in randomized trials was
1.10 (95% CI: 0.86–1.41) and was 0.94 (95% CI: 0.81–1.10) in cohort studies. Finally,
the American Heart Association/American Stroke Association guidelines[15] state that there is insufficient data to recommend restrictions on use of statin
agents for the management of intracerebral hemorrhage. In addition, long-term use
of statins, which is required for prophylactic treatments, is well tolerated and side
effects are manageable.[16]
Statins are widely used in patients with cardiovascular risk factors for prophylaxis
of cardiovascular disease (CVD).[17] Since CVD and VTE have some common risk factors, such as older age, male sex, smoking
history, sedentary lifestyle, obesity, and hypercoagulability,[18]
[19]
[20]
[21] statins are frequently recommended anyway to patients requiring VTE prophylaxis.
Thus, the possibility of using one single drug to prevent arterial CVDs and VTE would
diminish the pill burden associated with the use of several classes of drugs. Therefore,
statin therapy could become an alternative treatment for VTE prophylaxis if statins
are proven to downregulate hemostasis and prevent VTE episodes.
In this article, evidence of association between statins, hemostasis, and VTE risk
will be reviewed. For this purpose, we searched MEDLINE electronic databases to select
the manuscripts. The searches combined the MESH terms related to the intervention
(i.e., hydroxymethylglutaryl-CoA reductase inhibitors) and outcomes (i.e., hemostasis,
blood coagulation, VTE, embolism, and thrombosis). Basic science studies and clinical
studies, particularly meta-analysis and systemic reviews, were selected for this review.
The Effect of Statins on Hemostasis
The Effect of Statins on Hemostasis
Statins are a class of drugs that decrease the serum levels of cholesterol through
the inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. By inhibiting
this enzyme, statins reduce the hepatocyte cholesterol content, thus promoting enhanced
expression of low-density lipoprotein (LDL) receptors on the cell membrane. The increased
expression of this receptor leads to increased receptor-mediated endocytosis of LDL
and, in turn, to decreased serum levels of LDL.[22]
Statin use decreases the risk of CVD not only because of the lipid-lowering effect
but also because of an anti-inflammatory effect.[23] Results from the JUPITER trial demonstrated that the risk of CV events decreased
by 79% in participants who achieved the targets of high-sensitivity C-reactive protein
less than 1 mg/L and LDL cholesterol less than 1.8 mmol/L (hazard ratio 0.21, 95%
CI: 0.09–0.51). On the other hand, the effect of rosuvastatin on decreasing the risk
of CV events was less prominent in patients who achieved only the target of LDL cholesterol
(hazard ratio 0.49, 95% CI: 0.37–0.66). These results suggest that both lipid lowering
and anti-inflammatory effects are important for the prevention of CV events.[23]
Besides the lipid lowering and the anti-inflammatory effects, statins are alleged
to have pleiotropic effect on the process of hemostasis. Basic research and clinical
studies have investigated whether statins can interfere with platelet activity, coagulation,
thrombin generation, and fibrinolysis. These studies will be reviewed in this topic.
Effects of Statins on Platelet Activity
Studies in vitro and in animal models have demonstrated that statins can decrease
platelet activation by several mechanisms. Rosuvastatin was shown to inhibit platelet
degranulation in rat models of myocardial infarction[24] and atorvastatin to decrease platelet activation and upregulate the synthesis of
nitric oxide (NO) by platelets and endothelial cells in mice models of cerebral ischemia.[25]
[26]
[27] Pravastatin was shown to suppress platelet-dependent procoagulant activity in vitro
by decreasing the expression of P-selectin and the deposition of tissue factor (TF),
thrombin, and fibrin on adherent platelets.[28]
[29]
The first clinical study that evaluated the effects of statins on platelet activity
enrolled patients with hypercholesterolemia, and showed that pravastatin could affect
platelet aggregation and platelet-dependent thrombin generation in association with
reduced serum cholesterol levels.[30] Atorvastatin, simvastatin, fluvastatin, and cerivastatin were also shown to reduce
P-selectin levels[31] and platelet aggregation with different agonists, such as arachidonic acid,[32]
[33] adenosine diphosphate, collagen, and epinephrine.[34]
[35] Conversely, the discontinuation of statins led to increased platelet activity.[33] In patients with hypercholesterolemia, the effect of statins on platelet aggregation
seemed to occur in association with increased platelet-derived NO release, in a dose-dependent
manner and independently of cholesterol-lowering effect.[34] In healthy individuals, use of simvastatin for 7 days led to a reduction in platelet
aggregation triggered by arachidonic acid.[36] Although these studies point to an effect of statins on platelet activity, most
of the data came from nonrandomized studies, and therefore these results may be biased
by confounding or due to regression to the mean.
In the STAtins Reduce Thrombophilia (START) trial, in which individuals with prior
VTE were randomized to receive either rosuvastatin at 20 mg daily for 28 days or no
intervention, rosuvastatin use had no effect on platelet activation mediated by thromboxane
A2 (TxA2).[37] Although the observations from this randomized controlled trial (RCT) do not confirm
that rosuvastatin decreases platelet activation mediated by TxA2, it is not possible to exclude potential other antiplatelet effects of rosuvastatin
since other platelet function assays were not performed.
Effect of Statins on Coagulation
Evidence with regard to the effect of statins on coagulation was first demonstrated
in the late 1990s and early 2000s. The first studies, performed in vitro, demonstrated
that both simvastatin and fluvastatin were capable of reducing TF gene expression
in human monocytes, endothelial cells, and smooth muscle cells in a dose-dependent
manner.[38]
[39] Not only TF was suppressed but also thrombin formation could be inhibited by simvastatin
in vitro.[40] Lovastatin, simvastatin, and mevastatin were shown, in vitro, to enhance the activated
protein C-mediated suppression of thrombin generation, in part via increased levels
of thrombomodulin, in a concentration-dependent manner, that is dependent on inhibition
of the Rho/Rho-kinase pathway.[41] Later on, the inhibitory effect of statins on TF expression was replicated in vivo.
Studies in hyperlipidemic mice models showed that statins diminished the expression
of TF in atherosclerotic lesions and monocytes,[42] independently of the reduction in plasma lipids.[43]
[44] The mechanisms of statin-induced TF inhibition involved a direct inhibitory effect
on Rho/Rho-kinase pathway and, in turn, TF expression.[39]
[45] This lipid-independent mechanism was further confirmed in a study with a atherosclerotic
rabbit model showing that fluvastatin directly interfered with the transcriptional
activation of TF gene, by downregulating the nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-kB) pathway in endothelial cells.[46] Therefore, basic research studies consistently demonstrated that statins can downregulate
TF expression[38]
[39]
[42] through a direct pathway, independent of the lipid-lowering mechanism.[45]
[46]
Clinical trials have also demonstrated that statin therapy, either with simvastatin,[47] atorvastatin[48]
[49]
[50] or cerivastatin,[35]
[51] affects coagulation factors and thrombin generation, although the mechanisms behind
these effects are less clear. The first study, published in 1997,[52] showed that simvastatin treatment decreased plasma levels of prothrombin fragment
F1 + 2 (F1 + 2) by 35% and monocyte TF antigen and activity by 68 and 61%, respectively,
in hypercholesterolemic patients. The effect of simvastatin and cerivastatin in reducing
tissue factor pathway inhibitor (TFPI) and factor (F) VII was also demonstrated in
crossover studies[35]
[51] and in a small randomized trial.[53] In an RCT aimed to compare atorvastatin with placebo in patients eligible for two-step
carotid endarterectomy (CEA), atorvastatin reduced TF and TFPI antigen levels in blood
(29 and 18% reduction, respectively), and TF activity (56% reduction) in plaques removed
at the second CEA, as compared with placebo.[48] Further clinical studies demonstrated that 12 weeks of atorvastatin therapy could
lead to decreased FVII levels and activity,[49]
[50] coinciding with a decrease in the serum levels of LDL-cholesterol (LDL-C), very
low-density lipoprotein cholesterol (VLDL-C), and triglycerides.[32] The effect of statin on TF was also evaluated in individuals without dyslipidemia
or CVD. In a study of experimental endotoxemia, 20 healthy men were randomized to
receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration
of lipopolysaccharides (LPS). Simvastatin premedication attenuated the increase in
monocyte TF expression and reduced the formation of F1 + 2 in response to LPS without
affecting platelet aggregation.[54]
The effect of statin therapies on FV,[55]
[56]
[57] von Willebrand factor (VWF),[55]
[58]
[59] and natural anticoagulants[59] has also been reported in several studies.[55]
[56]
[57]
[58]
[59] Two small clinical studies performed in patients with CVD[56]
[57] showed that early simvastatin therapy decreased FVa generation and increased FVa
inactivation by protein C in blood samples collected from sites of microvascular injury
(bleeding-time wounds). Simvastatin and pravastatin reduced VWF levels in patients
with hypercholesterolemia after 3 months of therapy. In a clinical trial, 45 patients
with unstable angina were randomized to receive either atorvastatin or placebo for
6 weeks. Levels of coagulation markers, such as tissue plasminogen activator (tPA)
levels, protein C, protein S, FV, FVII, and VWF, were measured after 1 and 6 weeks
with treatment and compared with baseline.[55] In the placebo arm, all coagulation markers, except for protein S, increased from
baseline to the end of the first week with treatment. At 6 weeks, protein C and antithrombin
remained elevated in patients receiving placebo, when compared with baseline. These
parameters did not change substantially in patients who received atorvastatin, suggesting
that atorvastatin could regulate the levels of liver-derived coagulation markers.[55] Furthermore, in a randomized trial conducted with 60 patients with acute coronary
syndrome, both atorvastatin low (10 mg) and high (80 mg) dose prevented elevation
of VWF from baseline to the end of the first week with treatment, when compared with
placebo.[59] After 2 weeks with treatment, levels of VWF were similar between both treatment
arms and placebo.[59] Besides the reduction in some coagulation factors, simvastatin,[47]
[51]
[56]
[60] pravastatin,[58] and atorvastatin[61]
[62] therapies were also shown to reduce the thrombin generation potential and the level
of D-dimer,[63] both markers of hypercoagulability. In the Long-Term Intervention with Pravastatin
in Ischaemic Disease (LIPID) study, 9,014 patients were randomized to pravastatin
40 mg or placebo for 3 to 36 months after an acute coronary syndrome. After 1 year
of treatment, D-dimer levels in placebo group did not change from baseline (mean change
of 1 ng/mL), while D-dimer levels in patients receiving pravastatin decreased significantly
(mean change −12 ng/mL). The difference between groups in absolute change of D-dimer
levels from baseline to the end of the first year of the study was statistically different
(mean levels at year 1 were 172 ng/mL in placebo arm and 166 ng/mL in patients receiving
pravastatin).[64]
It is noteworthy that most of these data came from nonrandomized studies in which
confounding and regression to the mean cannot be ruled out. Stronger evidence that
statins can affect coagulation came from two meta-analyses of randomized trials.[65]
[66] These meta-analyses demonstrated a significant decrease in the plasma levels of
VWF (standardized mean difference [SMD] −0.54, 95 % CI: −0.87 to −0.21)[65] and D-dimer (SMD −0.988 µg/mL, 95% CI: −1.590 to −0.385)[66] following statin therapy. In both studies, the effects on VWF and D-dimer levels
were more evident after atorvastatin or simvastatin therapy was commenced, when compared
with no statin use. Limitations of the two meta-analyses are the inclusion of heterogeneous
patient populations and treatment assignments and, according to funnel plot analyses,
the possibility of publication bias.
Evidence of the effect of statin therapy on coagulation factors recently came from
the START trial, in which patients with a prior VTE were randomized to rosuvastatin
treatment or nonstatin.[67] The mean FVIII:C levels decreased 7.2 IU/dL (95% CI: 2.9–11.5) in rosuvastatin users
from baseline to the end of treatment, while among nonusers, no change in FVIII:C
was observed (mean difference −0.1; 95% CI: −3.0 to 2.9). Rosuvastatin therapy also
decreased the levels of FVII:C (mean change −3.6 IU/dL; 95% CI: −0.2 to −7.1) and
FXI:C (mean change −5.9 IU/dL; 95% CI: −2.7 to −9.0) from baseline to the end of the
study. Subgroup analyses revealed that the effect of rosuvastatin on decreasing the
levels of coagulation factors was more pronounced in participants with unprovoked
VTE or with cardiovascular risk factors.[67] The results are illustrated in [Fig. 1].
Fig. 1 Effects of rosuvastatin on coagulation factors VIII, XI, VII, VWF, and D-dimer according
to (A) VTE classification (unprovoked and provoked) and (B) the presence/absence of cardiovascular risk factors. Results from the START (STAtins
Reduce Thrombophilia) trial.[63] CI, confidence interval; CV, cardiovascular; VTE, venous thromboembolism; VWF, von
Willebrand factor.
Effect of Statins on Fibrinolysis
Clinical studies that evaluated the effect of statins on fibrinolysis have presented
controversial results. In a study with 46 patients with coronary artery disease randomized
to receive either placebo or fluvastatin, patients receiving fluvastatin had a decrease
in tPA and an increase in plasminogen activator inhibitor-1 (PAI-1) activity.[68] Pravastatin decreased tPA[69] and PAI-1[69]
[70] levels by 10 to 20% among hyperlipidemic patients, accompanied by a decrease in
LDL-C levels. Atorvastatin also increased the levels of PAP by 50%, decreased PAI-1
activity by 34%, and decreased platelet-dependent thrombin generation by 48% in hyperlipidemic
patients.[71] A shift to a profibrinolytic profile related to statin therapy was also observed
in sets of patients with coronary disease undergoing coronary artery bypass grafting,[72] in hyperlipidemic women,[73] in patients with essential hypertension,[74] and in patients with chronic obstructive pulmonary disease.[75] In healthy individuals, a large cohort study showed that participants using statins
had lower levels of D-dimer and FVIII and higher levels of fibrinogen and PAI-1, in
comparison with nonstatin users.[76] These results, however, seem contradictory since lower D-dimer and FVIII suggest
a decrease in hemostatic activity, while higher fibrinogen and PAI-1 levels suggest
hypercoagulability.
The strongest evidence for the effect of statin therapy on fibrinolysis came from
a recent meta-analysis of RCTs, where the pooled analysis revealed that statin therapy
reduced plasma levels of PAI-1compared with no statin therapy.[77] Although these findings suggest that statins stimulate fibrinolysis, result could
also be plagued by publication bias. No additional evidence from RCTs of the effect
of statin therapy on fibrinolysis has been published recently.
The Importance of the Lipid-Lowering Effect on Hemostasis
Basic research studies have consistently shown that the effect of statins on hemostasis
is independent of the drug-related lipid-lowering effect. Studies in vitro have confirmed
that statins can directly inhibit the Rho/Rho-kinase pathway and consequently NF-kB
activity and TF expression in monocytes and endothelial cells.[39]
[40]
[45]
[46] Such mechanisms of action are different from that involved in the lipid-lowering
process.[22]
Additionally, studies in hyperlipidemic mice and rabbits have shown that statins can
decrease the expression of TF in atherosclerotic lesions and monocytes independently
of the decrease in plasma lipids.[43]
[44] The effect of statins on increasing platelet-derived NO release and, in turn, decreasing
platelet activity was also shown to be independent of the lipid-lowering effect.[26]
[34]
In the clinical data, the distinction between a potential direct effect of statin
and the lipid-lowering effect on hemostasis is less clear. Most of the studies were
conducted in patients with dyslipidemia, and although studies in individuals without
dyslipidemia have also demonstrated an effect of statin therapy on hemostasis,[54]
[67]
[76] it is not possible to rule out that the observed effect was due to decreased serum
levels of lipids, since many lipoproteins are related to coagulation activity.[29]
The Effect of Statins on the Risk of Venous Thromboembolism
The Effect of Statins on the Risk of Venous Thromboembolism
Evidences from Basic Research Studies
Data on the effect of statins on in vivo venous thrombosis are limited to few studies.
In a mouse model of venous thrombosis, mice treated with high-dose atorvastatin or
rosuvastatin displayed 25% reduction in venous thrombus mass and accelerated thrombus
resolution, compared with control animals treated with saline.[78] The reduction in thrombus formation observed in statin treated mice was accompanied
by several changes in platelet activity, fibrinolysis, and coagulation factors.[78] More recently, a study in a murine model of hyperlipidemic APOE knockout mice showed that mice treated with high doses of rosuvastatin had a 12%
decrease in venous thrombus formation compared with controls.[79] The effect of statin on reducing thrombus formation occurred independently of the
effect on lipid levels.[79] Results from these animal studies confirm a biological effect of statins on venous
thrombus formation. However, supratherapeutic doses of statins were used in the studies,
and doses currently used in the clinical scenario were not tested.
Statins to Prevent First Venous Thromboembolism
The first study to suggest that statin therapy was associated with a reduced risk
of VTE was conducted in a selected population of postmenopausal women.[80] Since then, several population-based studies have aimed to evaluate the effectiveness
of statin therapy on VTE prevention. Most of them are observational studies and were
performed in selected populations of patients with CVD.[81]
The only RCT supporting the effect of statins on decreasing VTE risk was published
in 2009. In the JUPITER trial,[13] 17,802 apparently healthy individuals, with normal cholesterol levels, were randomized
to receive rosuvastatin at 20 mg per day or placebo and were followed for a median
period of 1.9 years. Rosuvastatin reduced the incidence of VTE by 40% (hazard ratio:
0.57; 95% CI: 0.37–0.86) compared with placebo.
Since the results of the JUPITER trial were published, additional evidence of the
association between statin therapy and reduced VTE risk came from at least four meta-analyses
of observational studies and clinical trials. A meta-analysis of RCTs, published in
2012, compared statin use with no statin (20 trials), and also high dose versus standard
dose statin (7 trials).[82] Results from the pooled analysis did not confirm a risk reduction in VTE by statin
treatment. Albeit the CIs were wide, the hazard ratios suggest that rosuvastatin,
which is the statin that is most related with halting/regression of atherosclerosis,
dyslipidemia, and inflammation,[23]
[83]
[84] also provides the largest risk reductions for the occurrence of VTE. The results
are illustrated in [Fig. 2].
Fig. 2 Effect of rosuvastatin, pravastatin, atorvastatin, and simvastatin on venous thromboembolism.[77]
[78] aExcluding results from the JUPITER (The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial. CI, confidence interval; HR, hazard ratio.
A meta-analysis of 36 studies (13 cohort studies and 23 RCTs) of statin treatment
versus no-statin (placebo or control) was published in 2017.[85] When evaluating RCTs, the meta-analysis demonstrated a pooled relative risk for
VTE of 0.85 (95% CI: 0.73–0.99) when statin was compared with a nonstatin treatment.
The lowest relative risk for VTE was observed in individuals who were randomized to
rosuvastatin (relative risk, 0.57; 95% CI: 0.42–0.75). Among observational studies,
the pooled relative risk for VTE was 0.75 (95% CI: 0.65–0.87). A stronger effect,
that is, a 54% risk reduction, was observed in populations with pre-existing disease
or at high VTE risk, in contrast with a 14% VTE risk reduction in studies that recruited
participants from the general population. These results are in line with those from
a previous meta-analysis of seven observational studies that demonstrated that statin
therapy was associated with a 40% decrease in VTE risk, as compared with no statin
use.[86]
Although the results from the JUPITER trial and the meta-analyses of observational
studies and RCTs might encourage the use of statins for VTE prevention, these data
must be interpreted with caution for several reasons. First, meta-analyses of observational
studies have limitations that are related to potential biases in the studies. Some
examples are as follows: (1) the underlying disease severity in patients selected
for statin therapy may be different, even milder than that in patients for whom statin
was not indicated (healthy user effect)[87] (2) the inclusion of prevalent statin users results in missing the events that occurred
in statin users before the inclusion, early after starting treatment (survivor bias);
and 3) observational studies are not able to control for those patients who adhere
or not to statin treatment (adherence bias).[88] Second, the meta-analyses of RCTs included nonpublished data and were influenced
by the results of the JUPITER trial. Finally, the results on VTE from the JUPITER
trial came from the analysis of a secondary end-point in the trial, in which the primary
outcome was the occurrence of a first major cardiovascular event. These results may
have run into the statistical problem of small numbers, since in the statin treatment
arm only 34 participants developed a venous thrombotic event, and randomness, or a
type I error, may have influenced this result. Replication of the results from the
JUPITER trial is important, therefore, to confirm that statin therapy reduces the
risk of VTE.
Statins to Prevent Recurrent Venous Thromboembolism
Over the last years, clinical studies have aimed to determine the role of statins
in preventing VTE recurrence, with heterogeneous results. Cohort studies that observed
a protective effect of statin therapy on the risk of recurrent VTE have reported a
risk reduction that varies from 26 to 38%.[89]
[90]
[91] A recently published meta-analysis of observational cohort studies demonstrated
that the pooled relative risk for VTE recurrence was 0.73 (95% CI: 0.68–0.79) in statin
users in comparison with no use.[92] Statin therapy reduced the risk for recurrent PE by 25% and the risk of recurrent
DVT by 34%, in comparison with no statin.[92]
A more detailed analysis of the cohort studies, however, reveals that the results
may have been affected by the inclusion of long-term (or prevalent) statin users.
Long-term statin users may be healthier than nonusers and less susceptible to VTE
recurrence, which results in survivor bias and healthy user effect.[93] As an example, in a large cohort study, Schmidt et al[90] reported a 29% decrease (hazard ratio, 95% CI: 0.58–0.87) in the risk of recurrent
VTE in long-term statin users as compared with nonusers, while among new users the
relative risk reduction dropped to a nonsignificant 17% (0.45–1.52). Therefore, a
biased association between statin use and prevention of VTE recurrence cannot be ruled
out.
Conclusion
Several studies have consistently demonstrated that statins affect hemostasis, particularly
by downregulating TF expression on endothelium cells and monocytes through a direct,
lipid-lowering independent effect on transcriptional activation of TF gene. This drug effect is, thus far, the best described mechanism by which statins
may reduce thrombus formation. Additionally, statins were also shown to impair platelet
activation, decrease multiple coagulation factors, and increase fibrinolysis. A summary
with documented biological influence of statins on the different phases of hemostasis
is provided in [Fig. 3].
Fig. 3 Biologically documented effects of statins on distinct phases of the process of hemostasis.
PAI-1, plasminogen activator inhibitor-1; TFPI, tissue factor pathway inhibitor; tPA,
tissue plasminogen activator; VWF, von Willebrand factor.
Recent data from randomized trials pointed to a potential effect of statins on decreasing
the levels of coagulation factors. Although these studies have provided stronger evidence
that statins may affect coagulation in humans, the exact mechanisms by which this
happens are not elucidated. Furthermore, the question whether the observed effect
of statin therapy on coagulation is sufficient to prevent VTE is still open.
From the clinical perspective, recent meta-analyses of randomized trials have demonstrated
that rosuvastatin therapy may reduce the risk of incident VTE, reinforcing the results
reported by the JUPITER trial. However, a direct relationship between statin therapy
and recurrent VTE risk cannot be assumed from the current clinical data, since the
results still need to be replicated. The lack of randomized data also provides uncertainty
about the effect of statin therapy on reducing the risk of recurrent VTE.
Clinical trials are currently underway for assessing whether rosuvastatin (NCT01524653)
or simvastatin (NCT02285738) therapy would reduce the risk of incident VTE in patients
with cancer. The two studies have surrogate biomarkers of hypercoagulability as a
primary endpoints, D-dimer levels, and soluble P-selectin levels, respectively. A
third study aims to evaluate whether rosuvastatin can reduce post-thrombotic syndrome
in VTE patients (NCT02679664). A fourth trial (NCT02331095) aims to determine whether
atorvastatin plus anticoagulation can reduce the thrombin generation potential in
patients with acute VTE compared with anticoagulation alone. The results of these
trials will contribute to the body of evidence on the association between statin therapy
and hemostasis. However, the question whether statin therapy is effective to prevent
incident or recurrent VTE will probably remain unanswered for the following years,
since no studies on this issue have been started yet.
In conclusion, findings from clinical studies point to a potential effect of statins
on decreasing the levels of coagulation factors and reducing the risk for VTE. These
effects were mainly attributed to rosuvastatin, which is the most potent LDL-C and
atherosclerosis reducing statin. However, stronger evidence on efficacy of statins
in preventing VTE, in particular the recurrent events, is still lacking. Recent data
showing the effect of rosuvastatin on levels of coagulation factors in patients with
prior VTE provides a solid basis for interventional studies necessary to establish
the efficacy of statins on reducing the risk of incident of recurrent VTE.
