Key messages
- Statin use for the primary prevention of venous thromboembolism (VTE; a condition in which a blood clot, or embolism, forms in the vein) may slightly decrease the incidence of VTE and death from any cause, but the reduction may be too small to be important.
- Statins may make no difference to the likelihood of experiencing deep vein thrombosis (DVT; a blood clot in the lower legs), pulmonary embolism (PE; a blood clot in the lungs), or myopathy (a condition affecting the skeletal muscles).
- Available evidence was limited, and we are not certain about its reliability. Future prospective studies should be well-planned and conducted. They should involve a large number of people and should be conducted over a reasonable duration of at least a year.
What is venous thromboembolism (VTE)?
VTE is a condition in which a blood clot (embolism) forms in the veins. Blood flow through the affected vein is reduced by the clot, causing swelling and pain. VTE most commonly occurs in the 'deep veins' in the lower legs, thighs, or pelvis, and is referred to as DVT. If the blood clot breaks loose and travels to the lungs, it is known as PE. Annually, from 100,000 individuals, 57 are diagnosed with VTE, 35 with DVT, and 21 with PE, worldwide.
Statins, which include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, are the most frequently used cholesterol-lowering drugs. These statins potentially lower cholesterol levels and consequently may have the potential to decrease the incidence of VTE.
What did we want to find out?
We aimed to discover the benefits and risks of statins for the primary prevention of VTE (first diagnosis) in individuals with no prior history of VTE.
What did we do?
We searched for randomized controlled trials (RCTs) comparing statins use with placebo (i.e. fake or 'dummy' pill) or usual care (routine care such as changing diet), to assess if the statins made a difference in the number of individuals who developed a first-time VTE or experienced any side effects.
RCTs are experimental studies where participants are randomly assigned to two or more treatment groups. This random method of allocating people to groups helps reduce the risk of bias by ensuring that the groups are similar, and that neither the investigators nor the participants know who is in which group.
What did we find?
Our review encompasses 27 RCTs comprising 122,601 adults (over 18 years of age); two studies focused on participants older than 60 years. While one study involved a healthy population, the participants in the remaining 26 studies had various diseases. All studies involved both male and female participants. Two studies engaged participants from primary care centers, while the remaining 25 incorporated participants from hospitals.
The statins included were atorvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and simvastatin. Most of the studies (23 of the 27) continued their follow-up with participants for more than a year. Similarly, most of the studies (24 of the 27) received funding from commercial companies.
We pooled the results of individual studies and found that statins may slightly reduce the number of VTE cases. The number of VTE cases prevented by statins was small. However, statins may not reduce the number of blood clots in the leg or lung, identified as DVT and PE, respectively. We did not find any evidence of a difference in the quantity of less severe side effects, such as myopathy. There is a possibility that statins might reduce the incidence of death from any cause or reduce the number of severe side effects.
What are the limitations of the evidence?
We are not very confident in the results due to concerns about the methods used in some of the studies. The low number of blood clots makes it difficult to detect effects. Differences in the general health of participants, as well as the dosage and types of statins used across studies, introduce further complexity. The exclusion of studies that did not publish the incidence of VTE could mean that relevant studies have been missed, which might affect the conclusions of this review.
How up-to-date is this evidence?
The evidence is current up to 13 March 2023.
Using statins for the primary prevention of VTE may slightly reduce the incidence of VTE and all-cause mortality. However, this effect is likely too weak to be considered significant. Statin use may not decrease the occurrence of DVT and PE. The current evidence is insufficient to draw strong conclusions because of the risk of bias in the studies, imprecision in the effect estimates, and potential publication bias. More evidence from well conducted and fully reported RCTs is needed to assess the preventive effects of different types of statins, as well as the effects of different dosages and treatment durations in various populations.
Venous thromboembolism (VTE) involves the formation of a blood clot in a vein, and includes deep venous thrombosis (DVT) or pulmonary embolism (PE). The annual incidence for VTE varies from 0.75 to 2.69 per 1000 individuals, with about 40 million people worldwide impacted by VTE. Statins, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, inhibit cholesterol biosynthesis and display several vascular-protective effects, including antithrombotic properties. However, the potential role of statins in the primary prevention of VTE is still not clear.
To evaluate the benefits and risks of statins in preventing venous thromboembolism (VTE) in individuals with no prior history of VTE.
We used standard Cochrane search methods. The search was last updated on 13 March 2023.
We included randomized controlled trials (RCTs) comparing statins with any control intervention (including placebo and usual care) in healthy individuals or participants with conditions other than VTE. There were no restrictions on the dose, duration, route, or timing of statins.
We used standard Cochrane methods. Our primary outcomes were VTE, DVT, and PE. Our secondary outcomes were serious adverse events, adverse events, and mortality. We used the trial sequential analysis (TSA) method to judge whether the evidence was sufficient, and we used the GRADE approach to assess the certainty of the evidence for each outcome.
We included 27 RCTs involving 122,601 adults (aged 18 years and above) who were healthy, had various medical conditions (e.g. hypercholesterolemia), or were at risk for cardiovascular disease. Both males and females were included in all studies. Two studies focused solely on participants over 60 years of age. We deemed four studies to have a low risk of bias overall, while 19 were at high risk of bias, and four were unclear.
The 27 studies compared use of statins versus placebo or usual care in individuals who had never experienced VTE. The statins used in the studies were atorvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and simvastatin. Twenty-three studies followed up participants for over a year, with six of those extending follow-ups for over five years. Twenty-five studies were based in hospitals, and 24 studies were funded by industry. Only one study used VTE as a primary endpoint.
The median incidence of VTE in the statins group was 0.72% (ranging from 0% to 10.53%), and in the control group it was 0.89% (ranging from 0% to 6.83%). Our pooled analysis of the 27 studies showed that, relative to control groups, statins may slightly reduce the overall incidence of VTE (odds ratio (OR) 0.86, 95% confidence intervals (CI) 0.76 to 0.98; 27 studies, 122,601 participants; low-certainty evidence). Of the statins we evaluated, only rosuvastatin seemed to be associated with a reduced incidence of VTE, albeit the reduction in incidence was very small. The evidence did not clearly indicate a difference between groups in the incidence of DVT (OR 0.70, 95% CI 0.41 to 1.18; six studies, 40,305 participants; low-certainty evidence), PE (OR 0.83, 95% CI 0.46 to 1.52; five studies, 28,427 participants; low-certainty evidence), or myopathy (OR 1.10, 95% CI 0.83 to 1.45; 10 studies, 75,551 participants; low-certainty evidence). Nonetheless, statin use might slightly decrease the incidence of any serious adverse event (OR 0.95, 95% CI 0.91 to 0.99; 13 studies, 67,020 participants; low-certainty evidence) and any death (OR 0.90, 95% CI 0.86 to 0.95; 24 studies, 116,761 participants; low-certainty evidence), compared to control.