Pentasaccharide in Unstable Angina - PENTUA

Description:

Pentasaccharide in Unstable Angina.

Hypothesis:

Fondaparinux to treat arterial thrombotic conditions, such as ACS, would require a dose 2 to 3 times higher than that found effective to prevent deep vein thrombosis.

Study Design

Study Design:

Patients Enrolled: 1,147
Female: 23

Patient Populations:

Men and women aged 18 years and older; admitted to the hospital with ACS defined as chest pain (<24 hours), dynamic ST +/- or ST- >0.1 mV, or elevated troponin T >0.1ng/ml.

Primary Endpoints:

Death, MI, or recurrent ischemia at day 9.

Secondary Endpoints:

Incidence of major or minor bleeding; major bleeding was defined as overt bleeding and associated with death or life-threatening conditions, re-operations, retro-peritoneal or intracranial bleeding, or a hemoglobin drop (>2 g/dL or 2 transfused units); minor bleeding was defined as any other bleeding excluding hematoma <5x5 at puncture site within 2 hours.

Drug/Procedures Used:

Fondaparinux vs enoxaparin to reduce short-term death, myocardial infarction (MI), and recurrent ischemia in patients with acute coronary syndromes (ACS).

Concomitant Medications:

Aspirin (all patients), nitrates, beta blockers, calcium blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, clopidrogel, ticlopidine, glycoprotein IIb/IIIa blockers

Principal Findings:

In this phase II dose-finding study, major bleeding events occurred in <1% of patients (0% fondaparainux 2.5 mg and enoxaparin); combined major and minor bleeding rates ranged from 2.6% to 4.0%, demonstrating no dose response for fondaparinux at day 9.

There was no dose response for fondaparinux for the primary endpoint (death, MI, and recurrent ischemia) measured at day 9.

Overall, there was a 37% event rate, particularly recurrent ischemia, in patients receiving fondaparinux. This was slightly lower but not significantly different from the 40% in patients receiving enoxaparin.

However, the event rate of 30% at the lowest dose of fondaparinux (2.5 mg) was significantly lower than the 40.2% rate for enoxaparin (p<0.05) as well as the rate seen with either of the 2 intermediate dosages of fondaparinux (p<0.05).

The main clinical event noted in this trial was recurrent ischemia; incidence of death or MI was low at all dose levels of fondaparinux as well as enoxaparin.

At 30-day follow-up, there remained a significant reduction in events with fondaparinux 2.5 mg versus the 4 mg dose or enoxaparin (p<0,05), but no clear dose response.

The pattern remained consistent when combining all patients randomized and treated.

The data were analyzed based on the new definition of MI (per the ACC/European Society of Cardiology 2000 consensus report), which states that any elevation of biochemical markers, troponin or CK-MB, should be called an infarct if it coincides with ischemic symptoms or ECG changes or coronary intervention. Using this definition, event rates at day 9 ranged from 6.3% (enoxaparin) to 10.1% (fondaparinux 4 mg). There was no significant difference in the event rates associated with 2.5 mg of fondaparinux vs enoxaparin, but the event rate remained significantly better than the 2 intermediate fondaparinux doses (p<0.05).

Revascularization in the first few days was infrequent; at day 9 approximately 2% of patients underwent CABG and about 14.8% to 19.5% PTCA, with no significant difference in revascularization rates among the various study groups.

The investigators concluded that specific Xa inhibition by fondaparinux is at least as effective as enoxaparin in reducing thrombotic events in ACS patients. There is no difference in bleeding complications between fondaparinux and enoxaparin, and there was no clear dose-response either for efficacy or for bleeding.

At 2.5 mg, a dose similar to that used to prevent deep vein thrombosis, fondaparinux appeared to be more effective than enoxaparin. The investigators noted that these findings show that phase III studies in ACS patients are warranted to verify and determine the mechanism of benefit.

Interpretation:

Increasing numbers of individuals worldwide are being seen with ACS, such as those enrolled in PENTUA. Until about 5 years ago, there were no large randomized trials looking at specific therapies for this syndrome. The development of fondaparinux continues recent efforts to inhibit ACS earlier in the coagulation system; instead of suppression of thrombin activity, the most common target of antithrombotic therapy, fondaparinux is part of a class of drugs that actually suppress the generation of thrombin.

These new agents, known as pentasaccharides, are specific inhibitors of activated factor X (factor Xa) in the clotting cascade; factor Xa leads to the formation of thrombin and subsequently to the formation of fibrin as part of the clot. Factor Xa is partly blocked by antithrombin, although this weak inhibition is strengthened when heparin binds to it. However, heparin binds to other clotting factors as well. Fondaparinux was created to bind to offer specific Xa inhibition without interfering with other clotting factors. Early trials were conducted to prevent deep vein thrombosis in orthopedic surgery patients. These trials indicated that fondaparinux reduces venous thrombotic complications by about 50% among patients undergoing orthopedic procedures. Subsequently, investigators wanted to determine whether this drug might be beneficial in patients with coronary artery disease.

During the AHA 2001 annual meeting, discussant Dr. Robert Califf noted that there is no explanation for the absence of a dose effect. Numerous clinical trials have shown that because the coagulation system is so complex, disturbing one component may cause any number of different effects, making it difficult to establish a workable hypothesis. However, to demonstrate whether fondaparinux is showing a differential effect rather than a random effect would require a “daunting” sample size, according to Dr. Califf. Another problem, he said, “There are no valid surrogate endpoints in this field. What we do have are biomarkers and intermediate medical outcomes that can give us probabilities to encourage us to either go on with the study or cut the losses and move on to attack a different biological arena.”

As these phase II results are encouraging but not definitive, certainty about clinical benefit will need to come from a large set of clinical trials. Additionally, studies of this and other drugs in active-controlled, rather than placebo-controlled, trials require a new methodology to deal with all the possible combinations present due to other therapies being used. Current U.S. therapy for ACS involves 2 types of patients: those who receive aggressive therapy (glycoprotein IIb/IIIa inhibition, early catheterization, revascularization), which involves numerous modifying factors, or those who are treated more conservatively. Dr. Califf said that both patient populations will need to be studied in a phase III trial, which also must demonstrate cost effectiveness based on the economical constraints of the current clinical practice environment.

References:

1. Reduced thromboembolism in orthopedic surgery. N Engl J Med 2001;344:619-25.
2. LMWH in ACS treatment. Arch Intern Med 2001;161:1484-90.
3. Phase II safety and efficacy trial (orthopedic surgery). Am Heart J 2001;142:S9-S15.
4. Anticoagulants in treating ACS. Am Heart J 2001;142:S16-S21.
5. Fondaparinux mechanism of action. Am J Health Syst Pharm 2001;58:S14-S17.
6. Review of orthopedic surgery trials. Am J Health Syst Pharm 2001;58:S18-S23.
7. Fondaparinux vs enoxaparin in hip-fracture surgery. N Engl J Med 2001;345:1298-304.
8. Fondaparinux vs enoxaparin in major knee surgery. N Engl J Med 2001;345:1305-10.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Vascular Medicine, Lipid Metabolism, Novel Agents

Keywords: Polysaccharides, Coronary Artery Disease, Myocardial Infarction, Cost-Benefit Analysis, Follow-Up Studies, Thrombin, Troponin T, Electrocardiography, Orthopedics, Fibrinolytic Agents, Consensus, Biological Markers, Enoxaparin, Catheterization, Venous Thrombosis, Probability, Factor Xa, Fibrin


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