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New Antiplatelet That May Not Up Bleeding: Phase 2 Results Published
from Heartwire — a professional news service of WebMD
Sue Hughes
Information from Industry
The Institute for Advances in Point-of-Care Testing
Keep up with emerging trends in glycemic control, anticoagulation management, and other areas of point-of-care testing, to help reduce costs, enhance the efficacy of healthcare management, and improve patient outcomes.
March 13, 2009 (Durham, North Carolina) — A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough), suggesting it may be able to reduce ischemic events without increasing bleeding in patients undergoing elective PCI, has now been published in the March 14, 2009, issue of the Lancet [1].
The study was first presented, and reported by heartwire at the time, at the American College of Cardiology (ACC) meeting in 2007, where it was greeted with much excitement over the possibility of a drug that might be able to separate the benefits of platelet inhibition (reduced ischemic events) from the risks (increased bleeding).
Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that the Lancet paper contains the same data that were presented at ACC 2007, along with "quite a lot of additional information."
"For example, at the ACC presentation, we focused on the group of patients who actually underwent PCI, which is the set of primary interest, but in the paper we also report on the whole population of patients, including those who received the bolus dose of the drug but who then did not end up undergoing PCI but were managed medically (381 patients) or underwent CABG (76 patients) and so would not have received maintenance doses." He described this as a real-world population that would receive the drug. He added that in the patients managed medically, the bolus dose of SCH 530348 was associated with a very low rate of bleeding and no TIMI major bleeding.
SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to which thrombin binds, so the drug inhibits thrombin-induced platelet activation. Becker explained why this is thought to be able to separate the reduction in ischemia from the increased bleeding risk seen with other antiplatelet agents. "The theory is that hemostasis is predominantly platelet mediated, whereas thrombosis in the coronary artery is mediated by both platelets and thrombin generation. This drug appears to prevent the ischemic effect of thrombin generation by preventing thrombin from binding to platelets, whereas it still allows thrombin to cleave fibrinogen and form fibrin--the final step in coagulation--and it still allows platelets to aggregate for normal hemostasis. So we are attempting to uncouple the benefit/risk relationship seen with all previous antithrombotic drugs."
Note of Caution--Too Early to Know for Sure
While there clearly is much enthusiasm over this new drug, some experts are being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta (McMaster University, Hamilton, ON) summed such feeling up: "There is no question that the mechanism of action of the drug is novel and the initial results are promising. But remember, this is just a phase 2 study, and we need to wait for phase 3 trials before making definitive statements with regard to efficacy or safety. Often, drugs may initially appear to be favorable but fail to live up to expectations when studied in larger numbers of patients," he commented to heartwire.
A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto, ON). He commented to heartwire: "This agent does indeed look promising, and, compared with several other 'antithrombin' therapies we have available at present, its mechanism of action is novel. However, as with all drugs at this stage (phase 2, dose finding), it is too early to tell whether its potential will be realized, and the ongoing phase 3 studies will need to inform us further about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not powered to definitively address either of these, but it is encouraging that the absolute number of major and minor bleeding events (albeit quite low in this population that included patients undergoing non-urgent PCI) was not different from that seen in the placebo group (including in the subset of patients went on to bypass surgery). Since the non-TIMI bleeding rates were consistently numerically higher (although not statistically significant) in the SCH 530348 groups compared with placebo, I suspect there will ultimately be some increased risk of bleeding when you add another antithrombin therapy to standard therapy (eg, aspirin with or without clopidogrel) in this patient population."
Neither Mehta nor Goodman is involved with trials of SCH 530348.
Platelet-Function Tests
Becker noted that the Lancet paper also reported detailed results on platelet-function testing showing that SCH 530348 achieved 90% inhibition of PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the two higher maintenance doses. "We decided to go with the highest (2.5-mg) maintenance dose for the phase 3 studies, because the safety results suggested this was still not associated with an increase in bleeding, and we wanted to make sure that the drug was not underdosed in high-risk patients. Our feeling was that if we can induce 100% inhibition of the receptor, we should do it, so this hypothesis can be tested properly."
Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS patients, which is being coordinated at Duke and in which SCH 530348 is being given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in secondary prevention in patients with prior MI, stroke, or peripheral vascular disease. These two studies are still recruiting, and results are not expected for several years.
Becker explained that he envisages that SCH 530348 would need to be given in addition to aspirin and clopidogrel in patients undergoing PCI and receiving a new stent, especially for the first few weeks, but in secondary-prevention patients aspirin plus SCH 530348 may be all that is needed, because there is less propensity for thrombosis in these patients.
Possible Other Indications
He also pointed out that PAR-1 also occurs on smooth-muscle cells and inflammatory cells, and it is possible that drugs that inhibit this receptor may have other benefits, such as stabilizing plaques and reducing in-stent restenosis. The phase 3 studies under way will include substudies to investigate these effects--by looking at what the drug is doing to other cell types as well as platelets. There are several other PAR-1 blockers in development, and they are being investigated in other areas as well as cardiology. One of these is oncology, because there is some evidence that PAR-1 may be involved in tumor growth and metastases.
The current phase 2 study randomized 1030 patients undergoing coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group who subsequently underwent PCI were randomly assigned again to one of three maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients assigned to a placebo loading dose remained on placebo during the maintenance phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel, and heparin or bivalirudin). The primary end point was the incidence of clinically significant major or minor bleeding according to the TIMI scale.
Patients who underwent PCI were the primary evaluable cohort. In this group, there was no significant difference in bleeding rates between any of the SCH 530348 doses and placebo. The authors say: "Although the bleeding rates were low overall, we cannot exclude a small to moderate increase in bleeding with SCH 530348."
TIMI Major/Minor Bleeding in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10 mg load (n=129), n (%) SCH 20 mg load (n=120), n (%) SCH 40 mg load (n=173), n (%) SCH 0.5 mg maintenance (n=136), n (%) SCH 1 mg maintenance (n=139), n (%) SCH 2.5 mg maintenance (n=138), n (%) p*
5 (3) 12 (3) 2 (2) 3 (3) 7 (4) 3 (2) 5 (4) 4 (3) 0.7713
*For difference between all placebo groups combined and all SCH 530348 groups combined
The trial was not powered to specifically test clinical efficacy, but results showed a trend toward fewer ischemic events in SCH-530348–treated patients. The authors add: "The biology around inhibition of thrombin-induced platelet activation provides a mechanistic basis for differences that might be of clinical relevance."
Death/Major Adverse Cardiac Events in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10-mg load (n=129), n (%) SCH 20-mg load (n=120), n (%) SCH 40-mg load (n=173), n (%)
13 (9) 24 (6) 10 (8) 6 (5) 8 (5)
They conclude: "Our study provides preliminary evidence for the feasibility and safety of thrombin-receptor inhibition among patients with coronary artery disease undergoing PCI."
In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini (Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current study suggests that SCH 530348 is safe, a conclusion strengthened by its being used with two other antiplatelet agents. They add: "This clinical report of a new antithrombotic drug developed on the basis of new knowledge about the coagulation cascade suggests that the drug works. Is the dream of an effective antithrombotic drug with a low bleeding risk becoming reality? Will this approach be effective in the acute setting (eg, primary percutaneous coronary intervention) and even in secondary prevention? Phase 3 trials will determine whether we are entering a new antithrombotic era."
Becker receives research funding from Schering-Plough. Other coauthors have received honoraria, research funding, and consulting fees from Schering-Plough or are employees of Schering-Plough. One author owns stock and stock options in Schering-Plough.
1. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009; 373:919–928.
2. Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009; 373:872-873.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
* Email ThisEmail This
Publication Logo
New Antiplatelet That May Not Up Bleeding: Phase 2 Results Published
from Heartwire — a professional news service of WebMD
Sue Hughes
Information from Industry
The Institute for Advances in Point-of-Care Testing
Keep up with emerging trends in glycemic control, anticoagulation management, and other areas of point-of-care testing, to help reduce costs, enhance the efficacy of healthcare management, and improve patient outcomes.
March 13, 2009 (Durham, North Carolina) — A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough), suggesting it may be able to reduce ischemic events without increasing bleeding in patients undergoing elective PCI, has now been published in the March 14, 2009, issue of the Lancet [1].
The study was first presented, and reported by heartwire at the time, at the American College of Cardiology (ACC) meeting in 2007, where it was greeted with much excitement over the possibility of a drug that might be able to separate the benefits of platelet inhibition (reduced ischemic events) from the risks (increased bleeding).
Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that the Lancet paper contains the same data that were presented at ACC 2007, along with "quite a lot of additional information."
"For example, at the ACC presentation, we focused on the group of patients who actually underwent PCI, which is the set of primary interest, but in the paper we also report on the whole population of patients, including those who received the bolus dose of the drug but who then did not end up undergoing PCI but were managed medically (381 patients) or underwent CABG (76 patients) and so would not have received maintenance doses." He described this as a real-world population that would receive the drug. He added that in the patients managed medically, the bolus dose of SCH 530348 was associated with a very low rate of bleeding and no TIMI major bleeding.
SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to which thrombin binds, so the drug inhibits thrombin-induced platelet activation. Becker explained why this is thought to be able to separate the reduction in ischemia from the increased bleeding risk seen with other antiplatelet agents. "The theory is that hemostasis is predominantly platelet mediated, whereas thrombosis in the coronary artery is mediated by both platelets and thrombin generation. This drug appears to prevent the ischemic effect of thrombin generation by preventing thrombin from binding to platelets, whereas it still allows thrombin to cleave fibrinogen and form fibrin--the final step in coagulation--and it still allows platelets to aggregate for normal hemostasis. So we are attempting to uncouple the benefit/risk relationship seen with all previous antithrombotic drugs."
Note of Caution--Too Early to Know for Sure
While there clearly is much enthusiasm over this new drug, some experts are being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta (McMaster University, Hamilton, ON) summed such feeling up: "There is no question that the mechanism of action of the drug is novel and the initial results are promising. But remember, this is just a phase 2 study, and we need to wait for phase 3 trials before making definitive statements with regard to efficacy or safety. Often, drugs may initially appear to be favorable but fail to live up to expectations when studied in larger numbers of patients," he commented to heartwire.
A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto, ON). He commented to heartwire: "This agent does indeed look promising, and, compared with several other 'antithrombin' therapies we have available at present, its mechanism of action is novel. However, as with all drugs at this stage (phase 2, dose finding), it is too early to tell whether its potential will be realized, and the ongoing phase 3 studies will need to inform us further about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not powered to definitively address either of these, but it is encouraging that the absolute number of major and minor bleeding events (albeit quite low in this population that included patients undergoing non-urgent PCI) was not different from that seen in the placebo group (including in the subset of patients went on to bypass surgery). Since the non-TIMI bleeding rates were consistently numerically higher (although not statistically significant) in the SCH 530348 groups compared with placebo, I suspect there will ultimately be some increased risk of bleeding when you add another antithrombin therapy to standard therapy (eg, aspirin with or without clopidogrel) in this patient population."
Neither Mehta nor Goodman is involved with trials of SCH 530348.
Platelet-Function Tests
Becker noted that the Lancet paper also reported detailed results on platelet-function testing showing that SCH 530348 achieved 90% inhibition of PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the two higher maintenance doses. "We decided to go with the highest (2.5-mg) maintenance dose for the phase 3 studies, because the safety results suggested this was still not associated with an increase in bleeding, and we wanted to make sure that the drug was not underdosed in high-risk patients. Our feeling was that if we can induce 100% inhibition of the receptor, we should do it, so this hypothesis can be tested properly."
Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS patients, which is being coordinated at Duke and in which SCH 530348 is being given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in secondary prevention in patients with prior MI, stroke, or peripheral vascular disease. These two studies are still recruiting, and results are not expected for several years.
Becker explained that he envisages that SCH 530348 would need to be given in addition to aspirin and clopidogrel in patients undergoing PCI and receiving a new stent, especially for the first few weeks, but in secondary-prevention patients aspirin plus SCH 530348 may be all that is needed, because there is less propensity for thrombosis in these patients.
Possible Other Indications
He also pointed out that PAR-1 also occurs on smooth-muscle cells and inflammatory cells, and it is possible that drugs that inhibit this receptor may have other benefits, such as stabilizing plaques and reducing in-stent restenosis. The phase 3 studies under way will include substudies to investigate these effects--by looking at what the drug is doing to other cell types as well as platelets. There are several other PAR-1 blockers in development, and they are being investigated in other areas as well as cardiology. One of these is oncology, because there is some evidence that PAR-1 may be involved in tumor growth and metastases.
The current phase 2 study randomized 1030 patients undergoing coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group who subsequently underwent PCI were randomly assigned again to one of three maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients assigned to a placebo loading dose remained on placebo during the maintenance phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel, and heparin or bivalirudin). The primary end point was the incidence of clinically significant major or minor bleeding according to the TIMI scale.
Patients who underwent PCI were the primary evaluable cohort. In this group, there was no significant difference in bleeding rates between any of the SCH 530348 doses and placebo. The authors say: "Although the bleeding rates were low overall, we cannot exclude a small to moderate increase in bleeding with SCH 530348."
TIMI Major/Minor Bleeding in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10 mg load (n=129), n (%) SCH 20 mg load (n=120), n (%) SCH 40 mg load (n=173), n (%) SCH 0.5 mg maintenance (n=136), n (%) SCH 1 mg maintenance (n=139), n (%) SCH 2.5 mg maintenance (n=138), n (%) p*
5 (3) 12 (3) 2 (2) 3 (3) 7 (4) 3 (2) 5 (4) 4 (3) 0.7713
*For difference between all placebo groups combined and all SCH 530348 groups combined
The trial was not powered to specifically test clinical efficacy, but results showed a trend toward fewer ischemic events in SCH-530348–treated patients. The authors add: "The biology around inhibition of thrombin-induced platelet activation provides a mechanistic basis for differences that might be of clinical relevance."
Death/Major Adverse Cardiac Events in PCI Cohort
Placebo (n=151), n (%) SCH all (n=422), n (%) SCH 10-mg load (n=129), n (%) SCH 20-mg load (n=120), n (%) SCH 40-mg load (n=173), n (%)
13 (9) 24 (6) 10 (8) 6 (5) 8 (5)
They conclude: "Our study provides preliminary evidence for the feasibility and safety of thrombin-receptor inhibition among patients with coronary artery disease undergoing PCI."
In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini (Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current study suggests that SCH 530348 is safe, a conclusion strengthened by its being used with two other antiplatelet agents. They add: "This clinical report of a new antithrombotic drug developed on the basis of new knowledge about the coagulation cascade suggests that the drug works. Is the dream of an effective antithrombotic drug with a low bleeding risk becoming reality? Will this approach be effective in the acute setting (eg, primary percutaneous coronary intervention) and even in secondary prevention? Phase 3 trials will determine whether we are entering a new antithrombotic era."
Becker receives research funding from Schering-Plough. Other coauthors have received honoraria, research funding, and consulting fees from Schering-Plough or are employees of Schering-Plough. One author owns stock and stock options in Schering-Plough.
1. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009; 373:919–928.
2. Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009; 373:872-873.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
# posted by roodbont @ 6:35 AM 
