VTE Increases Risk of Arterial CV Events
They explain that they undertook the research because previous studies examining associations between VTE and arterial cardiovascular (CV) events have yielded conflicting results. Sorensen told heartwire that "we have shown there is an association between two very common diseases. Now we need to find out whether there is a direct link between them or whether they share risk factors. Future studies are needed to clarify the association and to evaluate its implications for clinical practice."
In an accompanying commentary[2], Dr Gordon DO Lowe (University of Glasgow, Scotland) says: "This large study substantially extends the evidence for an association between VTE and risk of subsequent arterial thromboembolism that precipitates MI or ischemic stroke."
Risk highest in the first year after VTE
The Danish researchers and Lowe explain that VTE and arterial thrombosis have traditionally been viewed as separate diseases with different risk factors, pathogenesis, and treatments. VTE disorders are generally considered to be distinct from thrombotic atherosclerotic disorders because arterial thrombi consist mainly of platelets, in contrast to venous thrombi, which consist mainly of red blood cells and fibrin.
But in 2003, two case-control studies suggested an association between the two. However, further research failed to find a link, and these inconsistent findings mean that it is not clear whether VTE is associated with arterial CV morbidity.
Sorensen et al thus undertook a large 20-year population-based assessment of the risk of hospitalization for acute MI or stroke after a diagnosis of VTE, using data from Danish medical databases. After excluding those with known CV disease, they assessed the risk of MI and stroke in 25 199 patients with deep vein thrombosis (DVT), 16 925 patients with pulmonary embolism (PE), and 163 566 population controls.
For patients with DVT, the relative risk of MI was 1.60 and risk of stroke was 2.19 in the first year after the thrombotic event. For patients with PE, relative risks were 2.60 for MI and 2.93 for stroke in the first year.
The relative risks were also raised, although less markedly, during the subsequent 20 years of follow-up, with 20% to 40% increases in risk for arterial CV events, say Sorensen et al. The relative risks were similar for those with unprovoked and provoked (eg, due to pregnancy, surgery, or other factors) DVT and PE.
Lowe says that the fact that the increased risk of MI and stroke was highest in the first year after diagnosis of VTE "is perhaps surprising because the standard treatment (oral anticoagulant drugs for three to six months) should lower the risk of MI and ischemic stroke."
Link explained by shared risk factors?
Sorensen et al say the mechanism underlying the association between VTE and atherosclerotic disease is not known and that it might even be different for MI and for stroke. However, it is likely that the link is due to shared risk factors, etiologic pathways, or both, they suggest.
In his comment, Lowe says, "The association is probably because of shared risk factors." He cites others studies that have shown that smoking, hypertension, and diabetes (but not cholesterol) are significantly associated with VTE.
Hypertension was an exclusion criterion in the study by Sorensen et al, but "the shared risk-factor profile of obesity, smoking, and diabetes might account for much of the increased risk of arterial thrombotic events in patients with VTE," Lowe notes. He adds that shared thrombotic tendency might also play a part.
Sorensen agrees that shared risk factors are a likely culprit. "I think Lowe is right. I believe obesity is at least a part of the explanation," he told heartwire. He added that in their study, they did not adjust for obesity or smoking, and they did not have data on cholesterol. "However, diabetes did not explain the association we found," he said, noting that although this analysis with regard to diabetes was performed, it is not included in the final Lancet paper.
"Further epidemiologic studies (especially prospective studies) and systematic reviews are needed to establish the magnitude, duration, and possible causes of increased risk of MI and stroke after a diagnosis of VTE," says Lowe.
What are the implications? Will aspirin or statins reduce risk?
In the meantime, it is necessary to know what the implications for management are, says Lowe. Sorensen et al agree: "Our findings could have clinical implications," they observe. "However, the value of preventive measures against MI and stroke in patients with VTE is uncertain."
Two ongoing studies are evaluating the effect of aspirin on the long-term treatment of VTE, and a few observational studies have shown that statins might reduce the risk of VTE, "but the role of these drugs specifically for prevention of MI and stroke in patients with VTE has not yet been explored," the Danish researchers say.
In fact, Sorensen told heartwire that his team is doing work on statins and aspirin to see whether they can prevent an increased risk of atherosclerosis in patients with VTE and vice versa (ie, whether they can prevent VTE in patients with atherosclerosis). They are using a low dose of aspirin (75 mg/day) or a prescribed daily dose of a statin. Patients will likely stay on the medications for life, Sorensen noted. He says there is preliminary evidence that statins might prevent VTE in patients with atherosclerotic disease, but the full findings will be reported at a later date.
Sources
Sorensen HT, Horvath-Puho E, Pedersen L, et al. Venous thromboembolism and subsequent hospitalization due to acute cardiovascular events: a 20-year cohort study. Lancet. 2007;370:1773-1779.
Lowe GDO. Is venous thromboembolism a risk factor for arterial thrombosis? Lancet. 2007;370:1742-1744.
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