OASIS-5: Experts hail the trial, but some questions about details remain

September 23, 2005

Hamilton, ON - OASIS-5 has been hailed by experts and clinicians as a groundbreaking trial in ACS. However, there are some lingering questions about some of the trial's details.

Dr Salim Yusuf

The trial, which was reported for the first time at the European Society of Cardiology Congress 2005 in Stockholm earlier this month, showed dramatically lower rates of bleeding with the new factor-Xa inhibitor fondaparinux than with enoxaparin in ACS patients, which translated into a reduction in major clinical events by day 30. The investigators, led by Drs Salim Yusuf and Shamir Mehta (McMaster University, Hamilton, ON), conclude that these results will make fondaparinux the new antithrombotic of choice in ACS.

Dr Shamir Mehta

Although most cardiologists questioned by heartwire after the presentation of the OASIS-5 results were enthusiastic and believed fondaparinux represented a real step forward in antithrombotic therapy in ACS, there were some who raised questions. Queries have come, not surprisingly, from researchers who have been involved in previous enoxaparin trials.

Their main concern is whether enoxaparin was given in OASIS-5 in a manner that would best minimize bleeding risk; if it was not, the reduction in bleeding with fondaparinux may seem greater than it would have been if enoxaparin had been used "more appropriately."

But Yusuf and Mehta argue that enoxaparin was given exactly as recommended in FDA-approved labeling, and the reduction in bleeding seen with fondaparinux in OASIS-5 was not confined to just one group of patients but was seen "in all subgroups, across the board." They say that this suggests that questions about whether the dose of enoxaparin in certain patients and the use of unfractionated heparin (UFH) in certain patients would have changed the results are "unfounded."

Dr Chris Cannon

Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA), who had no involvement in the OASIS-5 trial and says he has no conflicts in this field, is impressed with the results. He commented to heartwire : "This is a 'practice-changing' trial in that there is a new option for the treatment of unstable angina/non-ST-elevation MI [UA/NSTEMI]. The trial confirmed all the prespecified hypotheses of similar early efficacy, vastly superior safety, and better net clinical benefit. It is simpler because it is once a day, I believe less expensive, and then there is the improved late efficacy—with a significant reduction in mortality.

"When you think of all the therapies for UA/NSTEMI, only an invasive strategy has been shown to reduce mortality in this population; thus, the reduction with fondaparinux is a very important step forward," he said. Cannon also defends the enoxaparin dosing strategy used in OASIS-5, saying: "This regimen is exactly what was done in ESSENCE and TIMI 11B, including the heparin in the cath lab, so it seems pretty reasonable to have used it."

The arguments

One of the most outspoken of those to voice concerns about the way in which enoxaparin was given in OASIS-5 is Dr Marc Cohen (Beth Israel Medical Center, Newark, NJ), who has conducted several enoxaparin trials. He commented to heartwire : "At face value, I have no argument with the OASIS-5 results. Yes, fondaparinux had less bleeding than enoxaparin, but this trial did not use enoxaparin in the best way. This trial shows us very nicely how not to use enoxaparin, but we already knew this from previous studies. Fondaparinux looks like a good drug. It appears to be just as good as enoxaparin, but there is nothing in the OASIS-5 data to show that it is better if enoxaparin is dosed correctly." Yusuf and Mehta strongly refute this suggestion.

Enoxaparin dose in renal insufficiency

One of the issues that Cohen and others have raised is the dose of enoxaparin in patients with renal insufficiency. Cohen says it is normal to reduce the dose of enoxaparin in patients with low creatinine clearance. He explains: "In OASIS-5, the creatinine clearance needed to be more than 3 g/dL before they reduced the dose—that's kind of high. If you have renal insufficiency, five days of exposure to the full dose of a drug that is cleared by the kidneys obviously could be dangerous."

Another person to mention this is Dr Shaun Goodman (St Michael's Hospital, Toronto, ON), who has also worked on enoxaparin and bivalirudin trials. He commented to heartwire : "Some will argue that enoxaparin wasn't given in the optimal fashion; for example, despite the current labeling suggesting 'full' dosing to those with mild to moderate renal dysfunction, it will be important to see how much of the bleeding (and subsequent mortality) difference between the treatment arms is accounted for by those patients with renal clearance in the >30 but <60 mL/min range." He added that although he does not believe this issue should detract from the OASIS-5 results in real-world practice, he was not sure whether either enoxaparin or fondaparinux should be used in patients with renal insufficiency, because both involve renal excretion; he would use UFH in this group.

In response, Yusuf and Mehta note that they followed the FDA labeling with regard to the dosing of enoxaparin. "The enoxaparin dose was reduced to 1 mg/kg once daily in patients with low creatinine clearance, as per its FDA labeling. In patients with creatinine below the median (1.0 mg/dL or 88 µmol/L), major bleeding was reduced by 45%; in those with creatinine above the median, bleeding was reduced by 49%. Thus, renal clearance of enoxaparin cannot explain the benefit of fondaparinux in terms of major bleeding. Bleeding was lower even in those with entirely normal renal function," they point out.

They also offer reassurance about Goodman's concern about using fondaparinux in patients with renal insufficiency. "Fondaparinux is a much friendlier drug than enoxaparin in patients with renal dysfunction—it clearly beat enoxaparin in those with no renal dysfunction, as well as those with mild, moderate, and severe renal dysfunction. The big difference between fondaparinux and enoxaparin is that fondaparinux can be given in much lower doses because of its selectivity for factor Xa, [plus] the fact the drug recycles itself in the circulation," Yusuf and Mehta say.

Dose of enoxaparin in the elderly

Several experts have also brought up the issue of the dosing of enoxaparin in the elderly. Dr Paul Armstrong (University of Alberta, Edmonton) said he believed overdosing enoxaparin in patients older than 65 was "likely a key factor in the OASIS-5 results." Dr Harvey White (Green Lane Hospital, Auckland, New Zealand) noted that when OASIS-5 was designed there was little information available on the appropriate dosing of enoxaparin in the elderly, but data from ASSENT 3 have subsequently suggested that bleeding complications with enoxaparin are higher in the elderly, who may therefore need a reduced dose. He adds that in the EXTRACT trial, which compares enoxaparin with UFH in conjunction with thrombolytic therapy in more than 21 000 patients and is expected to be presented at the American College of Cardiology meeting, the dose of enoxaparin has been reduced substantially in the elderly.

In line with this, many observers have pointed out that the net clinical benefit (end point of death/MI/refractory ischemia/major bleed) was similar for both enoxaparin and fondaparinux in patients under age 65 in OASIS-5.

OASIS-5: Death/MI/refractory ischemia/major bleed at 30 days by age

Age (y) Enoxaparin (%) Fondaparinux (%)
<65 7.5 7.4
>65 15.4 12.1

In response to this, Yusuf notes that although the two drugs did appear to be similar in terms of net clinical benefit in younger patients, "the results of a trial should mainly be judged on its overall data, and subgroups are for consistency." He adds: "From a statistical point of view, in no subgroup was enoxaparin better, and in several subgroups fondaparinux was better. From a practical standpoint, most centers would prefer to stick to one agent for a given condition, unless there is a specific need for another agent. In this case, enoxaparin offers no advantage at all in any subgroup, and overall fondaparinux is clearly the better drug."

Use of UFH in the cath lab

Dr James Ferguson

Another question that has been raised involves the use of UFH in the cath lab. Dr James Ferguson (Texas Heart Institute, Houston), who was the lead investigator of the SYNERGY trial of enoxaparin in ACS, has some concerns about this issue. "The use of open-label UFH appeared to be associated with a doubling of bleeding complications, regardless of treatment assignment; since this was preferentially done in the enoxaparin group, that could be a problem. It certainly parallels what we learned from SYNERGY."

Cohen echoes this view: "We have learned from SYNERGY that if you go to the cath lab and give additional unfractionated heparin on top of enoxaparin before the 12-hour dosing period is over, you get increased bleeding—this is not a smart thing to do," he says.

White also mentions this issue: "In SYNERGY, which showed the effectiveness of enoxaparin to be similar to unfractionated heparin in patients undergoing PCI, there was a modest increase in bleeding in the enoxaparin-treated patients who had PCI >8 hours after subcutaneous enoxaparin—a supplemental dose of a third of the subcutaneous dose (ie, 0.3 mg) was given IV. In OASIS-5, six hours after administration of subcutaneous heparin, a full dose of unfractionated heparin was given. This could explain at least part of the excessive bleeding noted in these patients."

But the OASIS-5 investigators respond that the reduction in bleeding with fondaparinux was observed in those who never received heparin, in those who received heparin before randomization, and in those who received it after randomization. Thus, the background use of heparin did not affect the consistently lower rates of bleeding with fondaparinux. "In those patients who did not undergo PCI (and therefore got no heparin at all), there was a large (42%) reduction in major bleeding, and in those receiving PCI, there was a 54% reduction in major bleeding. The bleeding reduction with fondaparinux was present regardless of whether PCI was performed within six hours of the last enoxaparin dose (when no UFH was given), between six and eight hours, or after eight hours. So any way you look at it, with or without heparin, PCI or no PCI, older patients or younger patients—there were marked reductions in major bleeding. The data are absolutely rock solid in this respect," they say.

Yusuf added: "SYNERGY was a good trial that basically demonstrated no efficacy advantage of enoxaparin over UFH but a clear increase in TIMI major bleeding. The post hoc 'switching hypothesis' is intriguing, but we do not know whether the switch to UFH was because of a bleeding complication due to enoxaparin or whether bleeding occurred after the switch. The overall result of the trial, which clearly showed that enoxaparin was associated with a higher TIMI major-bleeding risk, is probably closest to the real truth."

With regard to the choice of agent in PCI, Mehta said: "Enoxaparin has never been shown to be better than UFH in PCI in an adequately powered randomized trial, is not approved for use in PCI by the FDA, and is not recommended by the AHA/ACC PCI guidelines. The recently released European PCI guidelines go so far as to favor UFH over enoxaparin for use in PCI, even in the setting of ACS. It is therefore not surprising that the overwhelming majority of centers in North America and Europe prefer to use UFH or bivalirudin during PCI."

Resuming antithrombotic therapy after PCI

Another issue raised by Cohen was the restarting of the study drug after PCI in OASIS-5. He explained to heartwire : "We in the US stopped doing that five years ago. Once we have done a successful angioplasty, we immediately stop antithrombotic therapies. So why did they feel they needed to continue antithrombotic agents? This again told us what we already knew—if you give enoxaparin after the cath lab you will get additional bleeding complications." But Yusuf retorts: "The restarting of the study drug after PCI (which was left to the investigator's discretion) cannot explain the reduction in bleeding with fondaparinux. In both scenarios, fondaparinux was associated with lower bleeding."

OASIS-5: Major bleeding after PCI

Group Enoxaparin (%) Fondaparinux (%)
Study drug not restarted 4.3 2.3
Study drug restarted 4.6 1.75
Cath-lab clotting

Several interventionalists have said they will wait for more data on the catheter clotting in PCI patients seen in the fondaparinux arm of OASIS-5 before using the new drug in routine clinical practice. On this issue, Yusuf and Mehta say: "The very small rates of catheter clotting can be virtually eliminated by careful flushing of the catheter and by using a very small dose of UFH. The bleeding risk with fondaparinux is so low that the interventionalist can safely add a reduced dose of heparin (or bivalirudin)."

"Impressive study"

Despite raising concerns, most of these experts were generally positive about the OASIS-5 trial and fondaparinux. Goodman referred to OASIS-5 as "an impressive study with encouraging results," and White described the trial as "a tremendous effort; the results are conclusive in the broad population that was studied." He added that the bleeding results "were a wake-up call as we investigate more and more aggressive antithrombotic regimens." Armstrong said OASIS-5 showed "an interesting result" and that fondaparinux was a "promising alternative to low-molecular-weight heparin."

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