Adding UFH to Enoxaparin for PCI Is Unnecessary, Ups Bleeding Risk

July 23, 2009

July 23, 2009 (Paris, France) Administering unfractionated heparin (UFH) to patients already receiving enoxaparin--a common practice in the cath lab known as stack-on--results in overanticoagulation, putting patients at increased risk of bleeding, and therefore should be avoided, a new French study, STACKENOX, shows [1].

In addition, the results demonstrate that the anticoagulation test commonly used in cath labs--activated clotting time (ACT)--does not detect this excessive anticoagulation.

"The clinical message of our study is be aware of the hemorrhagic risk of the stack-on, whatever the timing of the last administration of enoxaparin," lead author Dr Ludovic Drouet (Hôpital Lariboisière, Paris, France) told heartwire . And "ACT is a potentially misleading test because it's totally blind to this effect, so physicians don't realize the overanticoagulation that is achieved," he stresses. "Enoxaparin is enough, and the additional administration of UFH is not required and is dangerous because of the hemorrhagic risk."

Drouet and colleagues report their findings in the August 2009 issue of the American Heart Journal.

Dr Magnus Ohman (Duke Clinical Research Institute, Durham, NC), who was not involved in the STACKENOX study, told heartwire : "This study provides insight as to why there are worse outcomes with switching from enoxaparin in the cath lab and using heparin.  In fact, the study sets a standard for how one should examine the versatility of anticoagulation that needs to be used in the cath lab."

Significant Risk, Even When UFH Given 10 Hours After Enoxaparin

As background, Drouet and colleagues explain that current guidelines for non-ST-segment and ST-segment elevation acute coronary syndromes (ACS) recommend complex regimens combining the use of different anticoagulants, but the effects of these are not well documented. In practice, says Drouet, at the time of PCI, "physicians are afraid to have patients maintained only on enoxaparin, and they want to give a push of UFH in addition."

To examine the effects of this strategy, he and his colleagues recruited 72 healthy subjects aged 40 to 60 (middle-aged volunteers were chosen as their ages most closely approximate those of ACS patients, Drouet explained). They received a standard, subcutaneous (sc) enoxaparin dose of 1 mg/kg every 12 hours for 2.5 days and were then randomized to receive a 70-IU/kg intravenous UFH bolus four, six, or 10 hours after the final enoxaparin dose. Anticoagulation levels were assessed in subjects receiving enoxaparin alone and after the UFH bolus by monitoring ACT, anti-Xa and anti-IIa activities, and thrombin generation (endogenous thrombin potential [ETP]).

After the final enoxaparin dose, ETP levels decreased by 40%; anti-Xa and anti-IIa activities increased, as expected; and ACT levels did not indicate any anticoagulation effect. Stack-on UFH at four, six, or 10 hours after the last enoxaparin dose significantly increased anti-Xa and anti-IIa activities (p<0.0001) to well above accepted therapeutic levels and resulted in total inhibition of thrombin generation for two hours or more. But ACT levels remained within the range commonly observed in subjects who are receiving only UFH (despite the fact they were also on enoxaparin).

The results show that an additional intravenous UFH bolus given to healthy subjects already receiving standard enoxaparin therapy resulted in complete inhibition of ETP, and this effect was consistent regardless of whether UFH was given four, six, or 10 hours after the last sc enoxaparin dose, say the researchers. This effect was correlated to and was explained by an immediate and prolonged inhibition of factor-Xa and factor-IIa, they add.

"We realized the patients were overly anticoagulated, and the anti-Xa and anti-IIa results reached levels well above the therapeutic range, within the hemorrhagic range," Drouet told heartwire . In addition, the complete inhibition of thrombin generation seen suggests the patients were at significantly increased bleeding risk even when UFH was given up to 10 hours after the last enoxaparin dose.

This appears to represent "more than a cumulative effect," Drouet comments, something more akin to a "potentiation."

ACT Not Appropriate to Monitor UFH and Enoxaparin

"In contrast, measurement of ACT levels reflected only the changes in anticoagulation levels associated with UFH alone and poorly predicted the cumulative effects of enoxaparin and UFH," he and his colleagues explain.

"These data suggest that ACT measurement, although commonly used to monitor anticoagulation in patients undergoing PCI, may not be appropriate to evaluate the combined anticoagulation effects of coadministering enoxaparin and UFH," they observe.

Drouet says the ACT test is commonly used in cath labs in North America and Northern Europe but that in other countries, such as his native France and the rest of Southern Europe, interventional cardiologists often don't even monitor anticoagulation.

Different methods of checking anticoagulation levels are needed, he says, but measuring thrombin generation (ETP) is not feasible for routine monitoring, because it requires the use of skilled technicians and is associated with high reagent costs.

Drouet told heartwire that probably the best test to use would be anti-Xa, because both enoxaparin and UFH inhibit factor-Xa.

Implications for Recent Clinical Trials

The results of the STACKENOX study also have important implications for the interpretation of recent clinical trials where patients receiving enoxaparin were also given UFH, say Drouet et al.

For example, in OASIS-5, bleeding rates were increased in patients receiving enoxaparin and UFH relative to the fondaparinux arm. Given the current findings, this could have been explained by prolonged, excessive anticoagulation levels in patients already fully anticoagulated with enoxaparin and receiving stack-on UFH, they suggest.

To date, no data are available regarding potential interactions and the impact on bleeding risk of administering fondaparinux in combination with other anticoagulants, they note.

Ohman says that a similar study to STACKENOX, using fondaparinux instead of enoxaparin, "would help us better understand what we observe when we have to stack anticoagulation in the cath lab."

Drouet reports receiving grant support from Sanofi-Aventis, Eli Lilly, and GlaxoSmithKline and consulting and lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, the Medicines Company, GlaxoSmithKline, Servier, Cordis, and Boehringer Ingelheim. Coathor Dr Claire Bal dit Sollier (Hôpital Lariboisière) has received grant support from Sanofi-Aventis and Eli Lilly and coauthor Dr Jack Martin (Bryn Mawr Hospital, PA) has received consulting and lecture fees from Sanofi-Aventis.


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