ESTEEM: Efficacy and Safety of Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Recent M
ESTEEM: Efficacy and Safety of Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Recent Myocardial Damage
Presenter: Lars C. Wallentin, MD, PhD; University Hospital of Uppsala (Uppsala, Sweden)
Platelets play a central role in the formation of a platelet-rich thrombus after plaque disruption. There are 3 essential steps to this process: platelet adhesion, platelet activation, and platelet aggregation. Adhesion of platelets occurs shortly after atherosclerotic plaque has eroded or ruptured, and is mediated mainly via the platelet IIb/IIIa receptors through its interaction with von Willebrand factor. Therefore, antithrombotic therapy plays an important role in the treatment of acute coronary syndromes (ACS). The current pharmacologic treatment for ACS includes thienopyridines, aspirin, fractionated or unfractionated heparin, and glycoprotein IIb/IIIa inhibitors.
Ximelagatran (Exanta; AstraZeneca) is a new oral direct thrombin inhibitor under investigation for the prevention of thromboembolic events in the long-term treatment of ACS patients. The drug is rapidly metabolized after oral administration into its active form, melagatran; it is not bound to plasma proteins, there is no need to monitor coagulation parameters while on a fixed dose, and 80% is excreted by the kidneys. Clinical data have demonstrated the efficacy of ximelagatran with twice-daily dosing.
Aim
The Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage (ESTEEM) trial was a multicenter, placebo-controlled, double-blind study that compared the safety and efficacy of 4 doses of the direct oral thrombin inhibitor ximelagatran in combination with aspirin against placebo in the long-term treatment of patients who had recently been admitted for ST-segment elevation or non-ST-segment myocardial infarction (MI).
Trial Design
Patients within 14 days of an acute MI were randomized to 4 different doses of ximelagatran (twice-daily doses of 60 mg, 48 mg, 36 mg, or 24 mg) or placebo twice daily in a 1:1:1:1:2 fashion for a period of 6 months. Both groups of patients received 160 mg aspirin once daily.
The composite primary endpoint was death, MI, and severe recurrent ischemia at 6 months. The composite endpoint of death/MI was also evaluated. Secondary endpoints included the individual components of the composite endpoint, as well as stroke, major bleeding, revascularization, and rehospitalization. Analysis was by intention to treat.
Results
Between January 2001 and September 2002, a total of 1900 patients were randomized to either 1 of the 4 doses of the drug or placebo. The trial included 191 centers in 18 countries. Baseline clinical characteristics after exclusion for protocol violations were similar in all groups and showed that patients had at least 1 high-risk factor such as diabetes or hypertension (Table).
PCI, percutaneous coronary intervention
All 4 doses of the drug were associated with significantly lower rates of the primary composite endpoint - death, MI, and severe recurrent ischemia - compared with the placebo arm (P = .0357), accounting for a 3.6% absolute risk reduction. Similar reductions in the incidence of the primary endpoint were also noted when comparing the 4 combined doses of ximelagatran with placebo (16.3% [102 of 638] vs 12.7% [154 of 1245], respectively), with a 24% relative risk reduction (hazard ratio = 0.76 [95% CI = 0.59-0.98]; P = .036) in the primary composite endpoint over the course of the 6-month study period. There was no dose-response relationship associated with the use of ximelagatran (Figure 1).
Figure 1. ESTEEM: primary composite endpoint (death/MI/severe recurrent ischemia) at 6 months by intention to treat.
The endpoint of death/nonfatal MI was also higher in the placebo arm when compared with the combined ximelagatran arm (Figure 2). Mortality was low, averaging 3% in all groups. Investigators reported that they found no serious clinically adverse outcomes associated with the use of the drug.
Figure 2. ESTEEM: death/MI at 6 months by intention to treat.
There was no significant difference in major bleeding events between the ximelagatran and placebo treatment groups (1.8% [23 of 1245] vs 0.9% [6 of 638], respectively). Total bleeding events (major and minor) were higher in the ximelagatran group (Figure 3). There was a significant elevation in liver function tests, especially at higher doses of the drug (7% to 9% of patients had > 5x the upper normal limits in patients treated with ≥ 36 mg of ximelagatran).
Figure 3. ESTEEM: bleeding events at 6 months by intention to treat.
Conclusions
On the basis of their findings, investigators concluded that long-term (6-month) ximelagatran treatment in combination with aspirin is better than aspirin alone in reducing the composite endpoint of death/MI/severe recurrent ischemia. They found that there was no dose response within the ximelagatran group. Therefore, the lower dose of 24 mg twice daily achieved optimal efficacy.
There was no significant difference between the groups with regard to major bleeding events; however, there was a dose-related increase in total bleeding events. In addition, investigators noted that an increase in liver enzymes > 3x the upper normal limit occurred in 6.5% of patients receiving 24 mg and were 12.2% to 13% in the higher dose levels compared with 1.3% of those receiving placebo. The increases in liver function tests were transient, typically asymptomatic, and without sequelae.
Discussant: Freek W.A. Verheugt, MD (Nijmegen, The Netherlands)
Commenting on the ESTEEM trial, Prof. Verheugt believes the ESTEEM trial proves the concept that long-term treatment with a novel oral antithrombotic therapy is feasible and effective. He specified that this concept had already been proven in previous trials with vitamin K antagonists showing mortality and reinfarction could be reduced by 25% in postinfarction patients (ATACS, APRICOT, ASPECT, OASIS-2, and WARIS-2 trials -- see glossary for expansion of trial names). However, vitamin K antagonists (warfarin) require frequent INR monitoring.
Regarding the ESTEEM trial and ximelagatran, Dr. Verheugt identified 3 important concerns:
Therefore, there are still many questions regarding this new drug and its use in cardiovascular disease.
Trial Glossary
APRICOT: Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis
ASPECT: ASian Paclitaxel-Eluting stent Clinical Trial
ATACS: Antithrombotic Therapy in Acute Coronary Syndromes
OASIS-2: Organization to Assess Strategies for Ischemic Syndromes
WARIS-2: WArfarin ReInfarction Study
References
Presenter: Lars C. Wallentin, MD, PhD; University Hospital of Uppsala (Uppsala, Sweden)
Platelets play a central role in the formation of a platelet-rich thrombus after plaque disruption. There are 3 essential steps to this process: platelet adhesion, platelet activation, and platelet aggregation. Adhesion of platelets occurs shortly after atherosclerotic plaque has eroded or ruptured, and is mediated mainly via the platelet IIb/IIIa receptors through its interaction with von Willebrand factor. Therefore, antithrombotic therapy plays an important role in the treatment of acute coronary syndromes (ACS). The current pharmacologic treatment for ACS includes thienopyridines, aspirin, fractionated or unfractionated heparin, and glycoprotein IIb/IIIa inhibitors.
Ximelagatran (Exanta; AstraZeneca) is a new oral direct thrombin inhibitor under investigation for the prevention of thromboembolic events in the long-term treatment of ACS patients. The drug is rapidly metabolized after oral administration into its active form, melagatran; it is not bound to plasma proteins, there is no need to monitor coagulation parameters while on a fixed dose, and 80% is excreted by the kidneys. Clinical data have demonstrated the efficacy of ximelagatran with twice-daily dosing.
Aim
The Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage (ESTEEM) trial was a multicenter, placebo-controlled, double-blind study that compared the safety and efficacy of 4 doses of the direct oral thrombin inhibitor ximelagatran in combination with aspirin against placebo in the long-term treatment of patients who had recently been admitted for ST-segment elevation or non-ST-segment myocardial infarction (MI).
Trial Design
Patients within 14 days of an acute MI were randomized to 4 different doses of ximelagatran (twice-daily doses of 60 mg, 48 mg, 36 mg, or 24 mg) or placebo twice daily in a 1:1:1:1:2 fashion for a period of 6 months. Both groups of patients received 160 mg aspirin once daily.
The composite primary endpoint was death, MI, and severe recurrent ischemia at 6 months. The composite endpoint of death/MI was also evaluated. Secondary endpoints included the individual components of the composite endpoint, as well as stroke, major bleeding, revascularization, and rehospitalization. Analysis was by intention to treat.
Results
Between January 2001 and September 2002, a total of 1900 patients were randomized to either 1 of the 4 doses of the drug or placebo. The trial included 191 centers in 18 countries. Baseline clinical characteristics after exclusion for protocol violations were similar in all groups and showed that patients had at least 1 high-risk factor such as diabetes or hypertension (Table).
| Placebo (n = 638) |
24 mg (n = 307) |
36 mg (n = 303) |
48 mg (n = 311) |
60 mg (n = 324) |
Combined (n = 1245) |
|
|---|---|---|---|---|---|---|
| Age (yrs) | 69 | 69 | 69 | 68 | 68 | 68 |
| Male gender (%) | 69 | 68 | 68 | 68 | 69 | 68 |
| Diabetes (%) | 21 | 22 | 23 | 23 | 22 | 23 |
| Hypertension (%) | 53 | 52 | 56 | 48 | 54 | 53 |
| Hyperlipidemia (%) | 52 | 51 | 56 | 49 | 55 | 53 |
| Smoking (%) | 25 | 26 | 26 | 26 | 27 | 26 |
| ST elevation (%) | 65 | 69 | 65 | 66 | 64 | 66 |
| ST depression (%) | 21 | 18 | 22 | 21 | 20 | 20 |
| PCI (%) | 9 | 7 | 10 | 12 | 10 | 8 |
All 4 doses of the drug were associated with significantly lower rates of the primary composite endpoint - death, MI, and severe recurrent ischemia - compared with the placebo arm (P = .0357), accounting for a 3.6% absolute risk reduction. Similar reductions in the incidence of the primary endpoint were also noted when comparing the 4 combined doses of ximelagatran with placebo (16.3% [102 of 638] vs 12.7% [154 of 1245], respectively), with a 24% relative risk reduction (hazard ratio = 0.76 [95% CI = 0.59-0.98]; P = .036) in the primary composite endpoint over the course of the 6-month study period. There was no dose-response relationship associated with the use of ximelagatran (Figure 1).
The endpoint of death/nonfatal MI was also higher in the placebo arm when compared with the combined ximelagatran arm (Figure 2). Mortality was low, averaging 3% in all groups. Investigators reported that they found no serious clinically adverse outcomes associated with the use of the drug.
There was no significant difference in major bleeding events between the ximelagatran and placebo treatment groups (1.8% [23 of 1245] vs 0.9% [6 of 638], respectively). Total bleeding events (major and minor) were higher in the ximelagatran group (Figure 3). There was a significant elevation in liver function tests, especially at higher doses of the drug (7% to 9% of patients had > 5x the upper normal limits in patients treated with ≥ 36 mg of ximelagatran).
On the basis of their findings, investigators concluded that long-term (6-month) ximelagatran treatment in combination with aspirin is better than aspirin alone in reducing the composite endpoint of death/MI/severe recurrent ischemia. They found that there was no dose response within the ximelagatran group. Therefore, the lower dose of 24 mg twice daily achieved optimal efficacy.
There was no significant difference between the groups with regard to major bleeding events; however, there was a dose-related increase in total bleeding events. In addition, investigators noted that an increase in liver enzymes > 3x the upper normal limit occurred in 6.5% of patients receiving 24 mg and were 12.2% to 13% in the higher dose levels compared with 1.3% of those receiving placebo. The increases in liver function tests were transient, typically asymptomatic, and without sequelae.
Discussant: Freek W.A. Verheugt, MD (Nijmegen, The Netherlands)
Commenting on the ESTEEM trial, Prof. Verheugt believes the ESTEEM trial proves the concept that long-term treatment with a novel oral antithrombotic therapy is feasible and effective. He specified that this concept had already been proven in previous trials with vitamin K antagonists showing mortality and reinfarction could be reduced by 25% in postinfarction patients (ATACS, APRICOT, ASPECT, OASIS-2, and WARIS-2 trials -- see glossary for expansion of trial names). However, vitamin K antagonists (warfarin) require frequent INR monitoring.
Regarding the ESTEEM trial and ximelagatran, Dr. Verheugt identified 3 important concerns:
There was no dose response in terms of efficacy, but there was with regard to bleeding and liver function test abnormalities.
The trial made no comparison to other drugs such as clopidogrel or warfarin.
What would have been the outcome if a larger percentage of patients had undergone coronary intervention?
Therefore, there are still many questions regarding this new drug and its use in cardiovascular disease.
Trial Glossary
APRICOT: Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis
ASPECT: ASian Paclitaxel-Eluting stent Clinical Trial
ATACS: Antithrombotic Therapy in Acute Coronary Syndromes
OASIS-2: Organization to Assess Strategies for Ischemic Syndromes
WARIS-2: WArfarin ReInfarction Study
References
Wallentin L, Wilcox RL, Weaver WD, et al for the ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial. Lancet. 2003;362:789-797. Published online September 1, 2003.
Meijer A, Verheught FW, Werter CJ, Lie KI, van der Pol JM, van Eenige MJ. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation. 1993;87:1524-1530.
Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003;348:1537-1545.
Cohen M, Adams PC, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994;89:81-88.
The Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of long-term, moderate-intensity oral anticoagulation in addition to aspirin in unstable angina. J Am Coll Cardiol. 2001;37:475-484.
Arnesen H. WArfarin ReInfarction Study (WARIS)-2. Presented at the 23rd European Congress of Cardiology; September 1-5, 2001; Stockholm, Sweden.