In this special report, we review the latest trials of novel anticoagulants and antiplatelet agents. We consider how the latest knowledge may influence management of patients undergoing surgery, percutaneous procedures, and those at high risk for embolism.
Read on to find out more.
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Antiplatelet agents – a complex array
Platelet aggregation and activation are crucial in the causation of occlusive vascular events. Given the high burden of cardiovascular disease worldwide, antithrombotic agents are some of the most widely used drugs today. They play important roles in primary and secondary prevention of cardiovascular events and in minimizing peri-operative risk, when patients’ immuno-inflammatory responses to surgery make them vulnerable to embolic events.
Aspirin has been around since the 19th century, but more recent years have seen a slew of alternative antiplatelet agents. The thienopyridines – ticlopidine, clopidogrel, and prasugrel – are prodrugs that require metabolizing into their active forms. Despite being from the same drug class, these three agents are metabolized differently, leading to disparities in patient response to the drugs, and, ultimately, clinical outcomes.
For example, the active metabolite of clopidogrel is markedly more potent than that of ticlopidine, so that a 75-mg daily dose of the former is equivalent to a 250-mg twice-daily dose of the latter. However, between 15% and 40% of patients are reportedly poor responders to clopidogrel.
Prasugrel is the most recent addition to the thienopyridine family, and unlike other members, its metabolism does not require cytochrome P450 (CYP) enzymes. Along with other differences in its metabolism, this results in increased and more rapid production of the active metabolite, relative to that for clopidogrel.
“Clinically, this translates into having a faster onset of action, greater extent of inhibition of platelet aggregation, and a more consistent response to treatment for participants on prasugrel relative to those on clopidogrel,” say Nagy Farid (Eli Lilly and Company, Indianapolis, Indiana, USA) and colleagues in a recent review.
Also, the independence from CYP enzymes reduces the likelihood of drug–drug interactions.
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 involved nearly 7000 patients with acute coronary syndromes (ACS) and planned percutaneous intervention (PCI). It found that use of prasugrel reduced rates of cardiovascular death, myocardial infarction, or stroke, relative to clopidogrel treatment, but increased patients’ risk for major bleeding.
A later cost-effectiveness analysis, using data from TRITON-TIMI, calculated that prasugrel, although more expensive than clopidogrel, yielded healthcare cost reductions through reduced rehospitalization rates and was also associated with life expectancy gains.
Relative to generic clopidogrel, at an assumed cost of US $1/day, prasugrel cost US $9727 per life-year gained for the first 30 days of treatment, and US $20,714 per life-year gained thereafter.
Even the latter figure “compares favorably with many other accepted medical interventions,” said the researchers, led by Elizabeth Mahoney (Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA).
A major disadvantage of both clopidogrel and prasugrel is that their effects are irreversible. To avoid the risk for intra-operative bleeding, patients must stop taking them at least 5 days before planned surgery, to allow time for the production of new platelets with normal function.
A recent study compared ticagrelor – a reversible antiplatelet agent with rapid onset and offset of action ¬– with clopidogrel in ACS patients with planned PCI. About three-quarters of patients actually underwent PCI, generally within a few hours of being randomly assigned to ticagrelor or clopidogrel.
A 180-mg loading dose of ticagrelor achieves in 30 minutes an equivalent level of platelet inhibition seen 8 hours after a 300-mg loading dose of clopidogrel, according to the study authors. So patients given ticagrelor theoretically achieved protection against platelet inhibition much sooner than those given clopidogrel.
This was borne out by the results, with the composite endpoint of cardiovascular death, myocardial infarction, or stroke occurring in 9.0% of ticagrelor-treated patients, compared with 10.7% of those given clopidogrel – a statistically significant difference.
So both prasugrel and ticagrelor have performed well in patients undergoing PCI. However, unlike prasurgrel, ticagrelor was not associated with an increased bleeding risk.
“The reversibility of the effect of ticagrelor could help avoid major bleeding associated with surgical procedures,” suggest Christopher Cannon (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and colleagues.
Thus, the recent expansion of antiplatelet agents will increase physicians’ treatment options. It seems that some agents may be more effective than others, and some more suited than others to certain patients and/or in certain circumstances. Further research will help physicians to decide which antiplatelet agent to use and when.
Managing the complications of heparin
Lobato RL, Despotis GJ, Levy JH, et al. Anticoagulation management during cardiopulmonary bypass: A survey of 54 North American institutions. J Thorac Cardiovasc Surg 2010; 139: 1665–1666. No abstract available.
Refaai MA, Chuang C, Menegus M, et al. Outcomes after Platelet Transfusion in Patients with Heparin-Induced Thrombocytopenia. J Thromb Haemost 2010; 8: 1419–1421. No abstract available.
However, antiplatelet agents are not enough for patients undergoing surgery, during which the surgical stress response increases inflammation and provokes clotting. Added to that, patients are immobile during, and often for several days after, the procedure, which further increases embolic risk.
Such patients require anticoagulants, with heparin frequently used during surgery. However, Elliott Bennett-Guerrero (Duke University Medical Center, Durham, North Carolina, USA) and team report wide variability in heparin use among patients undergoing cardiopulmonary bypass (CPB) in US and Canadian institutions.
The activated clotting time used to guide initiation of CPB ranged from less than 350 seconds to 500 seconds. There were also large variations in how institutes dealt with heparin resistance, with Canadian sites using predominantly fresh frozen plasma, whereas many US sites also used antithrombin concentrate.
“Previous studies have shown that heparin resistance occurs in a small percentage of patients,” say the researchers. “This low incidence might explain the paucity of literature aimed at assessing the optimal therapy for this problem.”
Another problem with heparin use is that of heparin-induced thrombocytopenia (HIT), in which an auto-immune response triggered by heparin leads to platelet activation and aggregation – precisely the opposite effect to that intended.
The condition is fortunately rare, with one study reporting the occurrence of HIT in just 0.4% of 528 critically ill patients. In another study, low platelet counts prompted testing for HIT in 153 of more than 10,000 patients undergoing cardiac surgery. Of these, just 21 patients tested positive for heparin-dependent platelet-activating antibodies.
However, Parwis Massoudy (Chefartz Klinik für Herzchirurgie, Passau, Germany) and colleagues note that patients with low platelet counts were at high risk of dying, irrespective of whether they had HIT.
Blood transfusion is potentially indicated for patients with critically low platelet counts, but this is believed to be contraindicated in HIT patients because of the risk for thrombotic complications, as outlined in some case reports.
Majed Refaai (University of Rochester Medical Center, New York, USA) and co-workers studied this issue further, by identifying 37 patients with HIT who had received at least one transfusion at their institute.
Six patients failed to respond to transfusion, three of whom died several days later. The causes of death were hemorrhage in two patients and withdrawal of life support in one. Thrombotic complications were not suspected in any patient. Three patients who initially responded died within 30 days of transfusion but, again, thrombosis was not suspected.
The team believes the findings “support the safety” of transfusion in HIT patients where indicated.
New options for oral anticoagulation
Outside of the operating theatre, anticoagulation is mostly achieved with the vitamin K antagonist warfarin. The drug is extremely effective for combating embolic events – stroke in patients with atrial fibrillation (AF), for example – but only if patients maintain a therapeutic international normalized ratio (INR).
Patients are at increased risk for embolism if their INR falls below 2.0 and are at increased risk for bleeding if it rises much above 3.0. Moreover, certain genetic mutations affect the metabolism of warfarin. Together, these create the need for regular blood testing and dose adjustment before patients achieve a stable INR. Besides the inconvenience to patients, there can be a long period before stable dosage is achieved, during which they are at increased risk for complications.
The first anticoagulant developed to avoid these problems was ximelagatran, but it was withdrawn because of hepatotoxicity concerns. Since then, several others have been developed, namely dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, which inhibit factor Xa. These were recently the subjects of a review by Mike Ufer (University Hospital Schleswig-Holstein, Kiel, Germany).
He noted that, at a Phase III level, these drugs have mostly been tested in patients undergoing knee or hip replacement and have been compared against enoxaparin (a heparin). All three drugs performed well in noninferiority, and even superiority, trials and did not increase bleeding rates.
These promising drugs are now being investigated in patients at thromboembolic risk, and also in patients with AF.
One such study has so far been published. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study included 18,113 AF patients who were at risk for stroke. They were randomly assigned to receive twice-daily dabigatran at doses of 110 or 150 mg, or warfarin, dose-adjusted to achieve a therapeutic INR.
Stroke or systemic embolism rates were similar with warfarin and dabigatran 110 mg, but were significantly lower with dabigatran 150 mg. Conversely, major bleeding rates were similar with warfarin and dabigatran 150 mg, but significantly lower with dabigatran 110 mg.
“These findings suggest that the dose of dabigatran could potentially be tailored to take into consideration the risk characteristics of a specific patient,” say Stuart Connolly (McMaster University, Hamilton, Ontario, Canada) and team.
In his review, Ufer concluded that the new anticoagulants will “hopefully contribute to a substantial improvement of the efficacy and safety of oral anticoagulation in the best interest of any given patient.”
