The conventional management of thrombotic and cardiovascular disorders is based on the use of
heparin, oral
anticoagulants and
aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of
heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of
heparin.
Aspirin still remains the leading
drug in the management of thrombotic and cardiovascular disorders. The newer
antiplatelet drugs such as
adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with
aspirin.
Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new
anticoagulant targets, such as
tissue factor, individual
clotting factors, recombinant forms of
serpins (
antithrombin,
heparin co-factor II and
tissue factor pathway inhibitors), recombinant activated
protein C,
thrombomodulin and site specific
serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral
anticoagulants. Both the anti-
factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver
enzyme elevations and
thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active
antithrombin agent
Ximelagatran for several indications. The synthetic pentasaccharide (
Fondaparinux) has undergone clinical development. Unexpectedly,
Fondaparinux also produced major
bleeding problems at minimal dosages.
Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer
antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with
aspirin and
clopidogrel have validated COX-1 and P2Y12 receptors as targets for new
drug development.
Prasugrel, a novel
thienopyridine,
Cangrelor and
AZD 6140 represent newer P2Y12 antagonists.
Cangrelor and
AZD 6140 are direct inhibitors, whereas
Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with
Prasugrel due to
bleeding. The newer
anticoagulant and
antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins,
warfarin and
aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come.