By Marie McCullough Tuesday, January 5, 2010; HE05
Warfarin, one of the most inconvenient, dangerous and disliked drugs in the world, has remained vitally important for more than 50 years.
That tells you how much difficulty scientists have had coming up with safer, easier pills to do what warfarin does: fight life-threatening blood clots.
Now, at long last, better oral blood thinners are on the horizon. In July, the Food and Drug Administration approved Effient to prevent clots in patients undergoing angioplasty to unblock a coronary artery. The maker of Brilinta plans to seek FDA approval for use in such patients by year's end.
Next in the race for the FDA's imprimatur may be Xarelto and Rendix; both were recently approved in Europe for clot prevention in orthopedic-surgery patients. At least five other clot-fighters are in late stages of development, all eager to tap the estimated $20 billion global market for such drugs.
The hope is that, with more choices and less hassle, doctors can tailor therapy to patients' needs. Surgery, heart disease, faulty heart valves, cancer treatment: any of these can make short-term or long-term clot-fighting crucial. So can the abnormal heartbeat called atrial fibrillation, which puts an estimated 2.2 million Americans at elevated risk of stroke. In a study published in August, Rendix became the first drug to show benefits over warfarin in atrial fibrillation patients.
And unlike warfarin, Rendix does not need constant monitoring and dosage adjustment. "The characteristics of [Rendix] are so much more user-friendly than warfarin," said cardiologist Michael D. Ezekowitz, vice president of clinical research at Main Line Health System in suburban Philadelphia and a leader of international Rendix studies.
Still, the new blood thinners have minuses as well as pluses, and they won't come cheap. Physicians may also be reluctant to change long-established practices involving warfarin, which began its long history as a rat poison.
Geno J. Merli, who has tested many of the new entrants as director of the vascular disease center at Philadelphia's Thomas Jefferson University Hospitals, called them promising but said their value in real-life practice remained to be seen. ''We're all looking for a replacement for warfarin," Merli said. "But these new drugs are not the panacea." Until now, the only oral blood thinners besides warfarin have been Plavix (clopidogrel), the world's second-best-selling drug, and aspirin, the over-the-counter pain reliever.
Tinkering with the clotting system is dicey because it maintains an exquisitely complex balance. It keeps the circulating blood fluid yet instantly congeals a bit of blood at just the right spot to plug an injured vessel. Injury or irritation signals disk-shaped blood cells called platelets to morph into star shapes and interlock at the site of damage. Then a cascade of clotting factors, culminating with the enzyme thrombin, overlays a sticky mesh that catches passing red blood cells and knits the whole plug together.
Platelets dominate the clotting process in the arteries, while the thrombin pathway dominates in the veins. This also complicates the therapeutic challenge because, depending on where the drug disrupts this system, it may help one patient but not another.
Plavix, for example, inhibits platelet action, so it is good at retarding clots in arteries. These clots often form on top of fatty plaque, the hallmark of heart disease, and block the artery. That can trigger painful angina or a full-blown heart attack.
But Plavix, made by Sanofi-aventis, is not as good as warfarin against clots in veins deep in the legs or pelvis, the kind that typically develop after surgery. These tiny clumps can travel to the lungs or the brain, with devastating consequences. Brilinta, made by AstraZeneca, also inhibits platelets, but it's faster and stronger than Plavix. In a recently published study, Brilinta was slightly better than Plavix at preventing heart attack, stroke and cardiovascular death in patients hospitalized with chest pain.
Even so, the FDA is sure to scrutinize a risk inherent in blood thinners: bleeding. Both Brilinta and Plavix caused life-threatening or disabling bleeding in about 11 percent of patients; Brilinta had higher rates of less serious bleeding than Plavix.
Daniel Hoffman, president of Pharmaceutical Business Research Associates, a consulting firm in Glenmoore, Pa., said, "The FDA has pretty much signaled to [drugmakers] that where there are available therapies, unless you can show a substantial clinical benefit that advances the standard of care, the FDA is going to have a very low risk tolerance." Bleeding risk may chill interest in Effient (prasugrel), a platelet inhibitor made by Eli Lilly and Daiichi Sankyo. Although Effient was more effective than Plavix at preventing heart attacks and strokes in angioplasty patients, it increased fatal bleeding.
The FDA required Effient's label to carry a "black box" warning about the bleeding risks.
Although warfarin, also sold as Coumadin, costs only about $160 a year, it is not cheap therapy. Patients require frequent blood tests to check clotting time and dosage, because warfarin's potency can be affected by certain drugs, dietary supplements, genetic variations and Vitamin K-laden vegetables. Problems with warfarin are the most common reason for emergency-room visits by older adults, according to the Centers for Disease Control and Prevention.
[New entry questioning FDA status of apixaban in VTE prevention. (See MNTA ‘ReadMeFirst’ for info on M118.)]
General #msg-37480173 Market overview from May 2009 Nature #msg-25160571 Anticoagulant market has large potential (WSJ 2007) #msg-26899903 Anticoagulant market has large potential (graphic) #msg-26451612 VTE is a big, big problem (Lancet 2008) #msg-26701803 Technical information on traditional anticoagulants
Xarelto (rivaroxaban) from JNJ/Bayer #msg-44245112 JNJ revokes guidance for timing of response to FDA #msg-38200098 FDA requests more data on NDA in VTE prevention #msg-44245112 Troublesome bleeding in VTE extension study #msg-30972846 EMEA approves Xarelto for VTE prevention #msg-34103973 Phase-3 data in VTE prevention (JNJ PR) #msg-29661234 Phase-3 data in VTE prevention (Reuters) #msg-31857009 Bayer accelerates Xarelto development in ACS, but… #msg-39151366 ...Xarelto still has a long way to go in ACS! #msg-33517140 Phase-2 data in ACS #msg-29662519 Checklist rationale for Xarelto program
Pradaxa (dabigatran) from Boehringer Ingelheim #msg-41018490 Pradaxa bests warfarin in AF/stroke prevention (PR) #msg-41014644 Pradaxa bests warfarin in AF/stroke prevention (WSJ) #msg-41024424 Pradaxa bests warfarin in AF/stroke prevention (Forbes) #msg-44244839 Phase-3 Pradaxa data in acute VTE (ASH 2009) #msg-27956748 EU approves Pradaxa for VTE prevention #msg-32382343 NICE approves reimbursement for VTE prevention #msg-21155926 Phase-3 data in VTE prevention non-inferior to Lovenox #msg-25152872 BI starts phase-2 trial in ACS
Apixaban from PFE/BMY #msg-46029245 FDA apparently finds data wanting in VTE prevention #msg-31742223 ADVANCE-1 phase-3 in VTE prevention fails #msg-32024540 Tepid phase-2 results in ACS #msg-19134406 PFE, BMY ink $1B collaboration #msg-29928836 Seventh and eighth phase-3 trials begin #msg-21044973 Apixaban non-inferior to Warfarin in phase-2
DU-176b from Daiichi Sankyo #msg-34100821 Phase-3 begins in AF #msg-34100787 Comparable Safety to Warfarin in AF (phase-2) #msg-31950663 Phase-2 data in hip surgery
Betrixaban from MRK/Portola #msg-39418241 MRK licenses betrixaban (WSJ) #msg-39388813 MRK licenses betrixaban (MRK/Portola PR) #msg-21106352 Phase-2 data in VTE prevention
Lovenox from SNY #msg-43119870 Lovenox sells $4.4B/yr, 60% in US #msg-26739674 US market shares of heparin-based drugs (2007 data) #msg-28936334 Proportion of Lovenox sales in various indications #msg-33630772 Lovenox not more costly than Arixtra (CHEST 2008) #msg-11669012 Lovenox more economical than unfractionated heparin
Miscellaneous (in alphabetical order) #msg-41143344 Ablynx starts phase-2 of ALX-0081 in PCI #msg-40720487 Ablynx phase-1 ALX-0681 results in healthy volunteers #msg-10569101 Arixtra bests Lovenox in ACS #msg-27043616 ART-123 from Artisan Pharma #msg-39348082 ARYX’s Tecarfarin whiffs in phase-3 #msg-36811828 AZN reports phase-2 data for AZD0837 #msg-30965016 LLY terminates FXa program #msg-30353872 MYRX MPC-0920 begins phase-1 #msg-31461171 NUVO reports phase-1b data for NU172 #msg-41012818 Otamixaban unimpressive in phase-2 ACS trial #msg-27187973 Paion’s Solulin completes phase-1 #msg-28742653 Paion acquires flovagatran rights #msg-32171800 Regado reports phase-1 data for aptamer #msg-41018456 Sanofi’s shrinking stable of anticoagulant aspirants #msg-43004355 TB-402 (FVIII inhibitor) advances in phase-2 #msg-37562465 Warfarin genetic test rejected by Medicare
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