Dual versus triple antithrombotic therapy: is there a role for direct oral anticoagulants in arterial thrombosis?

The number of patients receiving dual antiplatelet therapy with an additional indication for long-term oral anticoagulation has substantially increased over time. This population is facing an unacceptable risk of bleeding events, particularly among elderly individuals, who are especially vulnerable to complications. Further strategies to minimize this bleeding risk, including various drug combinations, different dosage regimens and even numerous attempts to find the appropriate duration of the treatment, have been evaluated in a multitude of randomized control trials. Moreover, the recent incorporation of the direct oral anticoagulants (DOACs) to the therapeutic armamentarium may represent an alternative to treat such patients, since they have demonstrated to be noninferior to the classic vitamin K antagonists and with lower bleeding rates. The aim of this review is to summarize the most recent literature on the use of DOACs in patients with an indication for dual antiplatelet therapy (mostly subjects with coronary artery disease) and also an established indication for chronic anticoagulation (chiefly individuals with nonvalvular atrial fibrillation). The role of DOACs in ischemic heart disease alone is also discussed.

Platelet function normalization after a prasugrel loading-dose: time-dependent effect of platelet supplementation.

BACKGROUND: Hemostatic benefits of platelet transfusions in thienopyridine-treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation. OBJECTIVES: To estimate the earliest time after a prasugrel loading-dose when added platelets are no longer inhibited by prasugrel's active metabolite. METHODS: Baseline platelet reactivity of healthy subjects (n=25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 µm) and VerifyNow(®) P2Y12 and was followed by a 60 mg prasugrel loading-dose. At 2, 6, 12 and 24 h post-dose, fresh concentrated platelets from untreated donors were added ex-vivo to subjects' blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrel's active metabolite's inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time-points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time-point). RESULTS: Supplemented samples showed concentration-dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow(®) at all assessment time-points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P=NS) between 6 and 12 h. CONCLUSIONS: The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading-dose. These findings may have important implications for prasugrel-treated ACS patients requiring platelet transfusions during surgery.

Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.

BACKGROUND: Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. MATERIALS AND METHODS: Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue. RESULTS: Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. CONCLUSIONS: In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.

A novel anti-ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects.

BACKGROUND: Platelet and endothelial production of nitric oxide (NO) is known to be impaired in coronary artery disease patients. Compounds that release NO (e.g. nitrates) have antiplatelet effects, but at supratherapeutic doses with hypotensive side effects. OBJECTIVES: To investigate the antithrombotic effect on human blood of a novel NO donor (LA419) with known anti-ischemic properties but without hypotensive side effects and to compare with abciximab. PATIENTS/METHODS: Healthy subjects (n = 8; 32 +/- 3 years) received daily aspirin starting three days prior to the study day. Treatments (LA419 10 and 20 microm, and abciximab 4 microm) were added ex vivo to non-anticoagulated blood, and the antithrombotic properties were assessed by measuring changes in thrombus size from pretreatment baseline in the Badimon perfusion chamber at low and high shear rates. Platelet surface adhesion using a Cone and Platelet Analyzer (CPA) and platelet fibrinogen-receptor activation with flow cytometry were also evaluated. RESULTS: At low shear rates, LA419 displayed a reduction in thrombus area of 43% +/- 8% (10 microm) and 56% +/- 6% (20 microm), whereas at high shear rates the reductions were 44% +/- 3% (10 microm) and 62% +/- 6% (20 microm). Platelet surface adhesion with the CPA was also reduced. Abciximab exhibited a strong inhibitory effect on thrombus formation, platelet surface adhesion and fibrinogen receptor activation. CONCLUSIONS: The novel NO donor, LA419, shows a strong antithrombotic effect in human blood, which is comparable to abciximab, especially under high shear rate conditions. Our observations suggest that the availability of an NO donor could prove beneficial in the prevention of thrombotic complications of cardiovascular disease. Further clinical studies are warranted.

Normalization of platelet reactivity in clopidogrel-treated subjects.

BACKGROUND: Aspirin (ASA) + clopidogrel are commonly used in acute coronary syndrome (ACS), but persistent antiplatelet effects may complicate surgery. METHODS AND RESULTS: To study the possibility of normalizing platelet reactivity after ASA + clopidogrel treatment, 11 healthy subjects received a 325-mg ASA + clopidogrel loading dose (300 or 600 mg dependent on study arm), followed by 81 mg of ASA + 75 mg of clopidogrel daily for 2 days. Platelet reactivity was assessed by light transmittance aggregometry (LTA) [challenged by adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thrombin receptor activating peptide (TRAP)] and flow cytometry for platelet activation by GPIIb/IIIa receptor exposure pretreatment, 4 and 72 h postload. To normalize platelet reactivity, increasing amounts of pooled platelets from five untreated volunteers [volunteers (V)-platelet-rich plasma (PRP)] were added ex vivo to the subject's PRP (S-PRP). At both 4 and 72 h, 40% and 50% V-PRP were needed to overcome platelet disaggregation in the 300 or 600 mg arms, respectively, after ADP challenge; an additional 10% V-PRP fully normalized aggregation. Recovery of function was linear with each incremental increase of V-PRP. ADP-induced GPIIb/IIIa activation showed the same pattern as LTA (r = 0.74). Forty percent V-PRP was required to normalize platelet function to AA, collagen, and TRAP. CONCLUSION: Our results suggest that the pre-operative transfusion of 10 platelet concentrate units (the equivalent of 40% V-PRP) after a 300-mg clopidogrel loading or 12.5 units (50% V-PRP) after a 600 mg loading may adequately reverse clopidogrel-induced platelet disaggregation to facilitate postoperative hemostasis. An additional 2.5 units fully normalized platelet function. The potential clinical implications of our observations could include shorter hospitalizations and reduced bleeding complications. But these observations should be fully explored in an in vivo clinical setting with clopidogrel-treated patients before and after surgery.