154
Incidence of Arterial Embolism in Patients on Treatment with Old and New Anticoagulants for Venous Thromboembolism Paolo Prandoni, MD, PhD1 Marta Milan, MD1 Sofia Barbar, MD1 Lucia Sarolo, MD1 Chiara Piovella, MD1 Raffaele Pesavento, MD1 Franca Bilora, MD1
University of Padua, Padua, Italy
Address for correspondence Paolo Prandoni, MD, PhD, Department of Cardiovascular Sciences, Vascular Medicine Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:154–159.
Abstract
Keywords
► venous thromboembolism ► arterial embolism ► atherosclerosis ► aspirin ► vitamin K antagonists ► direct anticoagulants
The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.
Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities, partly because of the obvious anatomical differences, as well as their distinct clinical presentations. In particular, arterial thrombosis has long been held to be largely a phenomenon of platelet activation, whereas venous thrombosis is largely a matter of activation of the clotting system. However, there is evidence that this dichotomy is likely to be an oversimplification. Fibrin-rich thrombi may form in the left atrial appendage of patients with atrial fibrillation and in the coronary artery system of patients with myocardial infarction. Accordingly, anticoagulant
drugs are highly effective for prevention of arterial embolism related to atrial fibrillation,1 and for prevention and treatment of coronary artery disease.2 Likewise, platelets play an inevitable role in the formation of thrombi in the venous system, and antiplatelet agents have been shown to be effective for prevention of venous thromboembolic (VTE) disorders, although to a smaller extent than anticoagulant drugs.3–5 To assess whether an association exists between VTE and atherosclerosis, we performed a prospective case–control study.6 Ultrasonography of the carotid arteries was performed in 299 unselected patients with deep venous thrombosis (DVT)
published online February 17, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
DOI http://dx.doi.org/ 10.1055/s-0035-1544162. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
1 Department of Cardiovascular Sciences, Vascular Medicine Unit,
without symptomatic atherosclerosis and in 150 control subjects. In a multivariate analysis taking into account risk factors for atherosclerosis, the odds ratio (OR) for carotid plaques in patients with unprovoked as compared with secondary DVT (i.e., DVT associated with active cancer, recent puerperium, trauma or fracture, prolonged immobilization, or current estrogens use) and controls was found to be 2.4 (95% confidence interval [CI], 1.4–4.0). Subsequently, two studies have provided further evidence in support of the association between VTE and atherosclerosis. In a case–control study, Hong et al found a higher prevalence of coronary artery calcium, as assessed by chest CT scan, in patients with unprovoked VTE than in matched control individuals.7 In a series of almost 24,000 consecutive autopsies, Eliasson et al found an increased prevalence of VTE in patients with arterial thrombosis, except for those with coronary artery thrombosis.8 Recently, Ageno et al reviewed the evidence favoring the association of the most important risk factors for atherosclerosis and VTE.9 After reviewing 21 case–control and cohort studies dealing with a total of 63,552 patients meeting the inclusion criteria, factors that were found to be significantly associated with an increased risk of VTE were obesity, blood hypertension, diabetes mellitus, and hypertriglyceridemia. The association is not surprising. In nature, there are many examples of conditions accounting for both arterial and venous thromboembolic disorders, such as hyperhomocysteinemia, antiphospholipid antibodies, malignancies, paroxysmal nocturnal hemoglobinuria, infectious states, inflammatory bowel disease, and the use of hormonal therapy.10 Arterial and venous thrombosis may share common mechanisms or risk factors, and may have a common origin in abnormalities of various blood constituents. For example, a few markers of endothelial dysfunction have been found to be significantly higher in patients with unprovoked DVT than in matched control individuals.11 Microalbuminuria, a well-known marker of endothelial dysfunction and arterial cardiovascular events, was found to be independently associated with an increased risk for VTE as well.12 According to results of an impressive series of prospective cohort, case–control, and population-based studies, patients with VTE have a definitely increased risk of subsequent symptomatic arterial cardiovascular events.13–20 Whether this applies to all VTE patients or the only patients with unprovoked disease is uncertain. According to the results of a recent meta-analysis, the risk of arterial cardiovascular events appears higher in patients with unprovoked VTE compared with those with provoked VTE.21 Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of not only venous but also of arterial cardiovascular events in patients in whom the antithrombotic treatment is instituted for the initial and long-term treatment of VTE. This potential will be reviewed in the article.
Aspirin As aspirin shows a substantial effect in VTE prevention in high-risk surgical patients,5 it has recently been suggested as
Prandoni et al.
an alternative to prolonged vitamin K antagonists in patients with unprovoked VTE. A potential benefit from antiplatelet therapy in the secondary prevention of VTE first became evident with the results of a randomized study involving only 39 patients, in which the combination of low-dose aspirin with dipyridamole was tested and found to be highly beneficial.22 The encouraging results of this small study in combination with increasing evidence in support of the link between arterial and venous cardiovascular disorders prompted the execution of the WARFASA and the ASPIRE multicenter randomized clinical trials.23,24 In a multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked VTE who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment.23 The primary efficacy outcome of the WARFASA trial was recurrence of VTE, and major bleeding was the primary safety outcome. VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6 vs. 11.2% per year; HR, 0.58; 95% CI, 0.36–0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 patients taking placebo had a recurrence (5.9 vs. 11.0% per year; HR, 0.55; 95% CI, 0.33–0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. In conclusion, aspirin reduced the risk of recurrence when given to patients with unprovoked VTE who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. The ASPIRE trial, which involved 822 patients, showed a nonsignificant decrease in the rate of recurrent VTE with aspirin (100 mg/day) as compared with placebo (rate of recurrence, 4.8 vs. 6.5% per year; hazard ratio, 0.74; 95% CI, 0.52–1.05; p ¼ 0.09).24 However, since arterial thrombotic events occurred only about half as often in the aspirintreated group as in the placebo group (10 vs. 19 events), aspirin was associated with a significant reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.48–0.92; p ¼ 0.01). Both studies used identical low-dose aspirin regimens and had similar enrollment criteria and outcome measures, making them amenable to meta-analysis. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio, 0.68; 95% CI, 0.51–0.90; p ¼ 0.008) and a 34% reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.47–0.92; p ¼ 0.002). Moreover, these benefits were achieved with a low risk of bleeding.25 Based on available evidence, aspirin in low doses offers an appealing, safe, and highly cost-effective option for the long-term prevention of recurrent VTE in patients with unprovoked VTE and in those with minor risk factors for thrombosis. While reducing by approximately 30 to 40% the risk of recurrent VTE, this simple, quite inexpensive, and safe approach is associated with a considerable protection against the development of arterial cardiovascular events. Seminars in Thrombosis & Hemostasis
Vol. 41
No. 2/2015
155
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Incidence of Arterial Embolism
Seminars in Thrombosis & Hemostasis
Vol. 41
No. 2/2015
6 (0.1)
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
–
Abbreviations: ACS, acute coronary syndrome; AMI, acute myocardial infarction; CVD, cardiovascular disease. Note: Number in parenthesis indicates percentages.
5 (0.1) 2 (
Incidence of Arterial Embolism in Patients on Treatment with Old and New Anticoagulants for Venous Thromboembolism Paolo Prandoni, MD, PhD1 Marta Milan, MD1 Sofia Barbar, MD1 Lucia Sarolo, MD1 Chiara Piovella, MD1 Raffaele Pesavento, MD1 Franca Bilora, MD1
University of Padua, Padua, Italy
Address for correspondence Paolo Prandoni, MD, PhD, Department of Cardiovascular Sciences, Vascular Medicine Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:154–159.
Abstract
Keywords
► venous thromboembolism ► arterial embolism ► atherosclerosis ► aspirin ► vitamin K antagonists ► direct anticoagulants
The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.
Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities, partly because of the obvious anatomical differences, as well as their distinct clinical presentations. In particular, arterial thrombosis has long been held to be largely a phenomenon of platelet activation, whereas venous thrombosis is largely a matter of activation of the clotting system. However, there is evidence that this dichotomy is likely to be an oversimplification. Fibrin-rich thrombi may form in the left atrial appendage of patients with atrial fibrillation and in the coronary artery system of patients with myocardial infarction. Accordingly, anticoagulant
drugs are highly effective for prevention of arterial embolism related to atrial fibrillation,1 and for prevention and treatment of coronary artery disease.2 Likewise, platelets play an inevitable role in the formation of thrombi in the venous system, and antiplatelet agents have been shown to be effective for prevention of venous thromboembolic (VTE) disorders, although to a smaller extent than anticoagulant drugs.3–5 To assess whether an association exists between VTE and atherosclerosis, we performed a prospective case–control study.6 Ultrasonography of the carotid arteries was performed in 299 unselected patients with deep venous thrombosis (DVT)
published online February 17, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
DOI http://dx.doi.org/ 10.1055/s-0035-1544162. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
1 Department of Cardiovascular Sciences, Vascular Medicine Unit,
without symptomatic atherosclerosis and in 150 control subjects. In a multivariate analysis taking into account risk factors for atherosclerosis, the odds ratio (OR) for carotid plaques in patients with unprovoked as compared with secondary DVT (i.e., DVT associated with active cancer, recent puerperium, trauma or fracture, prolonged immobilization, or current estrogens use) and controls was found to be 2.4 (95% confidence interval [CI], 1.4–4.0). Subsequently, two studies have provided further evidence in support of the association between VTE and atherosclerosis. In a case–control study, Hong et al found a higher prevalence of coronary artery calcium, as assessed by chest CT scan, in patients with unprovoked VTE than in matched control individuals.7 In a series of almost 24,000 consecutive autopsies, Eliasson et al found an increased prevalence of VTE in patients with arterial thrombosis, except for those with coronary artery thrombosis.8 Recently, Ageno et al reviewed the evidence favoring the association of the most important risk factors for atherosclerosis and VTE.9 After reviewing 21 case–control and cohort studies dealing with a total of 63,552 patients meeting the inclusion criteria, factors that were found to be significantly associated with an increased risk of VTE were obesity, blood hypertension, diabetes mellitus, and hypertriglyceridemia. The association is not surprising. In nature, there are many examples of conditions accounting for both arterial and venous thromboembolic disorders, such as hyperhomocysteinemia, antiphospholipid antibodies, malignancies, paroxysmal nocturnal hemoglobinuria, infectious states, inflammatory bowel disease, and the use of hormonal therapy.10 Arterial and venous thrombosis may share common mechanisms or risk factors, and may have a common origin in abnormalities of various blood constituents. For example, a few markers of endothelial dysfunction have been found to be significantly higher in patients with unprovoked DVT than in matched control individuals.11 Microalbuminuria, a well-known marker of endothelial dysfunction and arterial cardiovascular events, was found to be independently associated with an increased risk for VTE as well.12 According to results of an impressive series of prospective cohort, case–control, and population-based studies, patients with VTE have a definitely increased risk of subsequent symptomatic arterial cardiovascular events.13–20 Whether this applies to all VTE patients or the only patients with unprovoked disease is uncertain. According to the results of a recent meta-analysis, the risk of arterial cardiovascular events appears higher in patients with unprovoked VTE compared with those with provoked VTE.21 Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of not only venous but also of arterial cardiovascular events in patients in whom the antithrombotic treatment is instituted for the initial and long-term treatment of VTE. This potential will be reviewed in the article.
Aspirin As aspirin shows a substantial effect in VTE prevention in high-risk surgical patients,5 it has recently been suggested as
Prandoni et al.
an alternative to prolonged vitamin K antagonists in patients with unprovoked VTE. A potential benefit from antiplatelet therapy in the secondary prevention of VTE first became evident with the results of a randomized study involving only 39 patients, in which the combination of low-dose aspirin with dipyridamole was tested and found to be highly beneficial.22 The encouraging results of this small study in combination with increasing evidence in support of the link between arterial and venous cardiovascular disorders prompted the execution of the WARFASA and the ASPIRE multicenter randomized clinical trials.23,24 In a multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked VTE who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment.23 The primary efficacy outcome of the WARFASA trial was recurrence of VTE, and major bleeding was the primary safety outcome. VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6 vs. 11.2% per year; HR, 0.58; 95% CI, 0.36–0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 patients taking placebo had a recurrence (5.9 vs. 11.0% per year; HR, 0.55; 95% CI, 0.33–0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. In conclusion, aspirin reduced the risk of recurrence when given to patients with unprovoked VTE who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. The ASPIRE trial, which involved 822 patients, showed a nonsignificant decrease in the rate of recurrent VTE with aspirin (100 mg/day) as compared with placebo (rate of recurrence, 4.8 vs. 6.5% per year; hazard ratio, 0.74; 95% CI, 0.52–1.05; p ¼ 0.09).24 However, since arterial thrombotic events occurred only about half as often in the aspirintreated group as in the placebo group (10 vs. 19 events), aspirin was associated with a significant reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.48–0.92; p ¼ 0.01). Both studies used identical low-dose aspirin regimens and had similar enrollment criteria and outcome measures, making them amenable to meta-analysis. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio, 0.68; 95% CI, 0.51–0.90; p ¼ 0.008) and a 34% reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.47–0.92; p ¼ 0.002). Moreover, these benefits were achieved with a low risk of bleeding.25 Based on available evidence, aspirin in low doses offers an appealing, safe, and highly cost-effective option for the long-term prevention of recurrent VTE in patients with unprovoked VTE and in those with minor risk factors for thrombosis. While reducing by approximately 30 to 40% the risk of recurrent VTE, this simple, quite inexpensive, and safe approach is associated with a considerable protection against the development of arterial cardiovascular events. Seminars in Thrombosis & Hemostasis
Vol. 41
No. 2/2015
155
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Incidence of Arterial Embolism
Seminars in Thrombosis & Hemostasis
Vol. 41
No. 2/2015
6 (0.1)
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
–
Abbreviations: ACS, acute coronary syndrome; AMI, acute myocardial infarction; CVD, cardiovascular disease. Note: Number in parenthesis indicates percentages.
5 (0.1) 2 (
