NEW ANTIPLATELET AGENTS: An ideal platelet agent would have the following characteristics: 1. quick onset 2. reversible 3. benefit to patients 4.

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1 NEW ANTIPLATELET AGENTS: An ideal platelet agent would have the following characteristics: 1. quick onset 2. reversible 3. benefit to patients 4. universal response 5. excellent safety profile 6. able to measure the amount of inhibition of platelet aggregation Up to 40% of patients are resistant to the standard antiplatelet agents aspirin and clopidogrel not to mention the inability to easily measure their effect and side effect profile. There are five main categories of antiplatelet therapies currently undergoing clinical study: 1. thienopyridines (P2Y12 receptor antagonists)[ticlopidine;clopidogrel;prasugrel] 2. cyclopentyltriazolopyrimidines (P2Y12 receptor antagonists) [Ticagrelor] 3. anti-von Willebrand factor aptamers 4. thrombin receptor (protease-activated receptor-1) antagonists 5. thromboxane receptor antagonists 6. COX-1 inhibitors [Aspirin] 7. Phosphodiesterase inhibitors [dipyridamole] 8. GP IIb/IIIa antagonists [tirofiban; abciximab] PRASUGREL: Prasugrel was approved for use by the FDA in July Like the other thienpyridines, prasugrel inhibits the ADP dependent pathway of platelet activation. Prasugrel has the following properties compared with clopidogrel:

2 PROPERTY PRASUGREL CLOPIDOGREL Antiplatelet Action Reversible ADP receptor antagonist Irreversible ADP receptor antagonist Prodrug Yes Yes; cyto P450 Bioavailability >79% 50% Onset of antiplatelet action 70% inhib in less than 1 hour 40-60% after 3-7 days Duration of 5-9 days 5-7 days antiplatelet action Elimination half life (antiplatelet activity) 8 hrs 6hrs after single dose Predictable pharmacokinetics Yes Interactions with No No diet or alcohol Drug interactions PPIs PPIs Dosing and dose adjustments 60mg loading dose then 10mg Monitoring daily Bleeding time; platelet aggregation No (reduced CYP219 function means nonresponder) 300mg load then 75mg daily Bleeding time, platelet aggregation Contraindicated or Use in liver failure Contraindicated or caution advised caution advised Use in severe No dose No dose renal impairment adjustment adjustment Use in pregnancy Category B Category B1 Reversibility after No No cessation Antidote No No

3 The following trials have supported the use of prasugrel: 1. TIR-TON-TIMI 38 phase III trial. This trial was a randomized double blind parallel group multinational trial of patients with percutaneous coronary interventions (PCI) for acute coronary syndrome (ACS). The Prasugrel group had less MI (9.7% v 7.4%; less urgent target revascularisation (3.7% v 2.5%) and less stent thrombosis (2.4% v 1.1%) but more risk of major bleeding (2.4% v 1.8%) compared with clopidogrel. Also those with history of stroke or TIA, age>75, and weight<60kg had less benefit or suffered actual real harm from prasugrel compared with clopidogrel. Of some concern is the finding that for every 1000 patients treated 6 will have a major bleed, 5 will have a life threatening bleed, and 3 will have a fatal bleed from prasugrel therapy. If possible prasugrel should be discontinued at least 7 days prior to CABG. TICAGRELOR: Is the first reversible oral ADP receptor antagonist. Ticagrelor is a P2Y12 inhibitor. It is a non-competitive antagonist. PROPERTY TICAGRELOR Antiplatelet Action Reversible ADP receptor antagonist Prodrug No Bioavailability 36% Onset of 95% platelet inhibition within 4 hrs antiplatelet action Duration of 5 days antiplatelet action Elimination half life Short half life- twice daily dosing (antiplatelet activity)

4 Predictable pharmacokinetics Interactions with diet or alcohol Drug interactions Dosing and dose adjustments Monitoring Use in liver failure Use in severe renal impairment Use in pregnancy Reversibility after cessation Antidote Yes No Drug met by CYP3A4 eg ketoconazole,diltiazem,dexamethasone 180mg load then 90mg bd Contraindicated No dose adjustment Category B1 Yes No The following trials support the use of Ticagrelor: 1. DISPERSE 2 that compared ticagrelor with clopidogrel. Ticagrelor showed a trend towards lower rates of recurrent myocardial infarction (MI) with no increase in bleeding. 2. PLATO trial (Phase III) of patients showed ticagrelor patients had a lower number of cardiovascular events, MI, and death compared with clopidogrel. There was no difference in overall bleeding between the 2 groups although per 100 patients 1 ticagrelor patient will have a fatal intracranial bleed. CANGRELOR: Cangrelor is a non-thienopyridine ATP analogue. It is a potent direct paltelet P2Y12 antagonist which is metabolized thru dephosphorylation pathways and has a plasma half life of 3-6 minutes. It has rapid onset and reversibility with complete reversal in minutes. It

5 involves intravenous administration. Phase II trials showed dose dependent platelet inhibition similar to abciximab but less increase in bleeding time and a more rapid return of platelet function. Phase III trials showed a good safety profile and superior platelet inhibition to clopidogrel. The PCI Bridge trial of 8877 patients (cangrelor group was started 30 minutes before PCI and continued for 2 hrs after compared with a 600mg loading dose of clopidogrel) showed no superiority over clopidogrel at 48 hrs and 30 days for PCI but an increase risk of major bleeding in cangrelor patients compared with clopidogrel. The major attraction with cangrelor would lie in those patients who may possibly need a CABG instead of a PCI. NF449: NF449 acts on the P2X1 receptor. This receptor may have a greater therapeutic potential than the myriad of other agents that act on the P2Y12 receptors as the P2X1 receptor only becomes activated in areas of high shear stress. This would seem to be ideal for use in coronary stent placement with the potential to achieve the holy grail of decreased adverse events post PCI without an increase in bleeding. Preliminary trials have showed an inhibitory effect on platelet aggregation without an increase in bleeding times. It is theoretically possible that we can therefore obtain a therapeutic agent that will work only at the site of stenosis (or shear stress) without causing any increase in systemic bleeding complications. VORAPAXAR: Is an oral PAR-1 receptor blocker that prevents thrombin induced activation of platelets by inhibition of the protease activated receptor but generation of fibrin remains intact. This may decrease bleeding risks. It is rapidly absorbed with max effect of >90% platelet function inhibition with 1

6 hour but slowly eliminated with a terminal half life of >72 hrs. Phase II trials showed a trend to lower cardiovascular events when used in combination with aspirin and clopidogrel in those having PCI but no increased risk of bleeding. Currently the results of the TRACER and TIMI- 50 trials are awaited. ELINOGREL: Elinogrel has both IV and oral preparations. It is a reversible direct P2Y12 ADP receptor antagonist. The results of the ERASEMI and Innovate PCI trials are awaited. PICOTAMIDE: Picotamide is a thromboxane inhibitor with dual inhibition of TXA2 synthase and the thromboxane receptors. PGE2 and prostacyclin production are however preserved. There is also no effect on the ADP receptors. In the DAVID study of 1209 patients comparing picotamide with aspirin there was a reduction in all cause mortality from 5.5% to 3% and less bleeding events in the picotamide group. Picotamide may be useful in patients with increased TXA2 production such as the obese, those with metabolic syndrome, high grade hypercholesterolaemia, and inflammatory states. In summary overall the new antiplatelet agents available would currently appear to offer an improvement in cardiovascular event rates when compared with traditional aspirin and clopidogrel therapy. There is also less risk of drug interactions and interpatient variability. However these agents seem to have an increased risk of bleeding and more importantly an increased risk of serious life

7 threatening bleeding. Presently they should be avoided in those at high risk of bleeding and used only in those having high risk PCI interventions. Agents such as prasugrel will obviously cause major bleeding issues in cardiac surgery. Other agents such as cangrelor are quickly reversible and would therefore been much easier to deal with at the time of cardiac surgery. Careful selection by cardiologists will be required to prevent major bleeding agents in those requiring cardiac surgery. Some agents in the pipeline hold out the promise of high efficacy without increased bleeding but until this dream is realized the newer antiplatelet agents should be used judiciously and in a targeted fashion. NEW ANTICOAGULANT AGENTS An ideal anticoagulant agent would have the following characteristics: 1. oral administration 2. effective in reducing venous thromboembolism 3. inhibits both free and clot bound coagulation factors 4. predictable dose response and kinetics 5. low non-specific plasma protein binding 6. low rate of bleeding events 7. no routine coagulation monitoring and dose adjustment required 8. wide therapeutic window 9. little interaction with food or other drugs There are four main categories of anticoagulant therapies currently undergoing clinical study: 1. direct thrombin inhibitors (ximelagatran, dabigatran, lepirudin, bivalirudin, argatroban, melagatran) 2. factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban) 3. vitamin K antagonists (warfarin)

8 4. indirect thrombin inhibitors (heparin, warfarin) Direct thrombin inhibitors have the following advantages over other agents: 1. inhibit fibrin bound thrombin 2. bind thrombus at it s active site 3. inhibit platelet factor 4 activation 4. provide more predictable anticoagulant responses because not bound to plasma proteins and have minimal drug interactions. XIMELAGATRAN: First oral direct thrombin inhibitor but 6% of patients developed liver toxicity so this drug was discontinued in DABIGATRAN ETEXILATE (Pradaxa in Australia & Europe; Pradax in Canada): Is a potent, competitive, reversible, direct thrombin inhibitor that is administered orally. It reaches peak concentration within 2 hours, has linear pharmacokinetics, has a predictable anticoagulation response, and has a limited number of direct drug interactions. It is eliminated largely unchanged in the urine at 100mls/min in a manner corresponding to the glomerular filtration rate. It has low (35%) concentration independent binding to plasma proteins. Ethnic origin doesn t appear to affect the pharmacokinetics but some groups such as African- Americans data is still lacking. There are no interactions with antacids, H2 blockers or proton pump inhibitors (PPIs). Dabigatran prevents the development of thrombin, inhibits free thrombin, inhibits fibrin bound thrombin, and inhibits thrombin induced platelet aggregation. When given once daily at doses of 150mg or 220mg in the Re-Model and Re-Novate trials of 4546 patients

9 undergoing elective hip and knee operations it was equal to enoxaprin for the prevention of DVT after major orthopedic surgery.however the Re-Mobilize trial which used enoxaparin 30mg bd as per the US recommendations failed to establish non-inferiority for dabigatran so currently the FDA has not yet approved dabigatran. The RELY trial of patients assigned patients with atrial fibrillation to receive either warfarin, 110mg of daibigatran, or 150mg of dabigatran. It was designed to assess the primary outcome of stroke or systemic embolism. The results were as follows in the table below: Stroke/Embolism per yr Major bleed Hemorrhagic Stroke Mortality /yr Warfarin 1.69% 3.6% 0.38% 4.13% Dabigatra 1.53% 2.71% 0.12% 3.75% n 110mg Dabigatra n 150mg 1.11% 3.11% 0.1% 3.64% The 110mg group therefore had similar rates of stroke and systemic embolism to warfarin but with lower bleeding complications while the 150mg group has lower rates of stroke and embolism compared with warfarin but similar rates of bleeding complications. Dyspepsia occurred in 11% of dabigatran patients compared with 5.8% of warfarin patients which could limit compliance in affected patients. The RECOVER trial showed dabigatran to be as safe and effective as warfarin in patients suffering from acute venous thromboembolism. The Remedy and Resonate trials are still progressing looking at dabigatran in prevention of secondary VTE. Digoxin and dabigatran can be coadministered without any dose adjustment of either drug.

10 Because it has both antithrombotic and antiplatelet properties dabigatran is potentially an ideal agent for ACS or PCI. Phase II trials in PCI are currently underway. There is no available antidote and there is no established monitoring for the detection of potential non-compliance in clinical practice. Dabigatran is however dialyzable. In patients with mechanical heart valves warfarin therapy is associated with thromboembolic events of 2-5% per year. While dabigatran is not yet a replacement for warfarin in those with mechanical heart valves we will now see patients presenting for cardiac surgery on dabigatran. The implications are that CPB should be delayed for 4 to 5 days to minimize bleeding risk. In those requiring more urgent surgery there is no antidote. PROPERTY DABIGATRAN WARFARIN ETEXILATE Anticoagulation Action Reversible Direct thrombin inhibitor Vitamin K antagonist Prodrug Yes No Bioavailability 6.5% high Onset of anticoagulation action Max concentration at hrs hrs Duration of anticoagulation action Elimination half life (anticoagulation activity) 12 hrs; delay major surgery 2-4 days hrs in healthy volunteers; hrs in elderly 3-5 days 7 days

11 Predictable pharmacokinetics Interactions with diet or alcohol yes Food delays peak plasma con by 2 hrs but no effect on bioavailability Drug interactions Minimal except for P- glycoprotein inhibitors including verapamil, amiodarone,clarithromycin, cyclosporine and esp quinidine which raise dabigatran conc 60% Dosing and dose adjustments Monitoring Use in liver failure 220mg daily (150mg in renal impairment) but contraindicated in those with severe renal failure GFR<30mls/min. Ecarin clotting time and thrombin time most sensitive but APTT and INR will be increased in less sensitive way No change in those with moderate hepatic insufficiency; no inhibition or induction of cyto P450 no Yes; multiple Multiple esp cyto P450 Variable INR With caution Use in severe renal impairment Eliminated unchanged in urine No dose adjustment Use in pregnancy no Catgory D Reversibility after <25% after 12 hrs. Yes cessation Antidote No but dialysable Yes HIRUDIN: Is a coagulation inhibitor obtained from the salivary glands of medicinal leeches. It is a potent inhibitor of thrombin

12 that unlike heparin works independently of antithrombin 3. Hirudin inhibits both clot bound thrombin and fluid phase thrombin. It requires no cofactor and is not neutralized by PF4. Unlike unfractionated heparin, hirudin also does not activate platelets. When hirudin is used in cardiopulmonary bypass (CPB) the loading dose is 0.25 mg/kg and then an infusion of 2.5mcg/ml is used to maintain hirudin concentrations. The ecarin clotting time (ECT) is used to monitor the hirudin effectiveness. Unfortunately ECT is not a freely available test. When compared to heparin hirudin CPB patients maintain platelet counts and hematocrits with fewer bleeding complications assuming renal function is normal. Hirudin is a small molecule easily eliminated by the kidney and easily filtered if necessary at the end of CPB. BIVALIRUDIN: Bivalirudin is a small 20 amino acid molecule with a plasma half life of 24 minutes. It is a direct thrombin inhibitor and a synthetic derivative of hirudin. It s elimination is independent of organ metabolism. It is also monitored by use of the ecarin clotting time. FONDAPARINUX: Fondaparinux is a synthetic indirect inhibitor of factor Xa. Unlike heparin it does not inactivate thrombin or inhibit factor Xa bound in the prothrombinase complex and so does not completely inhibit FXa. Its long term use is limited by the requirement for subcutaneous injections. It has a rapid onset, prolonged half life of hours but its function is critically dependant on endogenous antithrombin levels. It requires normal renal function and it is difficult to monitor because APTT is not useful and there is no antidote. Bleeding is the most common adverse event with the rate of bleeding complications being similar to that of LMWHs. Fondaparinux related bleeding may be

13 successfully treated with Novoseven (recombinant coag factor VIIa). RIVAROXABAN (Xarelto) & APIXABAN: Are both oral direct FXa inhibitors that are being investigated in large phase II and III trials. Rivaroxaban is already approved for the primary prevention of VTE after orthopedic surgery in adults in Canada,the European Union, and Australia. CONCLUSION: After a generation of warfarin therapy being the best option for long term oral anticoagulation we are now on the cusp of anew era of anticoagulation therapy. The direct thrombin inhibitors such as dabigatran hold out real promise as a safer and easier to use alternative. Warfarin is readily reversed if a patients needs urgent cardiac surgery however dabigatran has no antidote. Dabigatran needs to be ceased 2-4 days before cardiac surgery. It highly likely over the next decade we will see an increasing number of patients presenting for cardiac surgery who are taking a direct thrombin inhibitor. REFERENCES: 1. Sellers MB Tricoci P Harrington RA A new generation of antiplatelet agents. Curr Opin Cardiol (4): Cattaneo M Advances in antiplatelet therapy: overview of new P2Y12 receptor antagonists in development. Eur Heart J Suppl (suppl I): Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361:

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