Newer Form of Heparin Drug Of Choice
Duke University Medical Center
Three studies led by Duke Clinical Research Institute (DCRI) cardiologists have shown that the ease and convenience of a newer formulation of the blood-thinner heparin, called enoxaparin, appear to make it the drug of choice for treating patients with suspected heart attacks. Enoxaparin has comparable and sometimes better mortality outcomes than the older formulation, found the researchers.
However, they said, the studies' results did not provide clear-cut evidence of superiority of enoxaparin. Additionally, they stressed that based on their results, patients should not be switched from one formulation to the other during the course of treatment.
Unfractionated heparin is given intravenously and requires continuous monitoring to ensure proper blood levels of the drug. Enoxaparin is given by subcutaneous injection in fixed dosages and does not require blood level monitoring.
The results were published in three reports in the July 7, 2004, issue of the Journal of the American Medical Association.
The DCRI researchers led two multi-national clinical trials and conducted one meta-analysis comparing unfractionated heparin to enoxaparin, the newer low molecular weight heparin. Meta-analyses are those which compile and analyze the results of multiple clinical trials.
Heparin reduces clotting by blocking the action of thrombin, an enzyme important in the process of blood platelet clumping. It is commonly used along with other drugs to treat patients who come to the emergency room with chest pain or symptoms of a heart attack and are likely to be sent to the catheterization lab or operating room.
"In medicine there is often a reluctance to conduct head-to-head trials of similar agents," said Robert Califf, M.D., DCRI director and senior author of the three JAMA articles. "The classical model is to first prove that a drug is better than placebo, and then go out and market the drug. A great example of this trial model involves statins -- many of which have been approved for use in lowering cholesterol but have not been tested head-to-head.
"In this case, the DCRI served as the coordinating center for three different analyses to try to answer some of the same questions about heparin, but in slightly different contexts," Califf continued. "Ultimately we find that there are no great differences in outcomes or side effects between the two drugs, so given the ease of use of enoxaparin, it would appear to be preferred. However, if a physician is comfortable using unfractionated heparin, the differences are not enough to compel change."
The first trial, dubbed SYNERGY, enrolled more than 10,000 patients, while the second trial, dubbed "A to Z," enrolled another 4,000 patients. Additionally, DCRI researchers conducted a meta-analysis by combining data collected in four earlier trials with the unpublished (until July 7, 2004) data from SYNERGY and A to Z, yielding data on almost 22,000 patients. Details on each analysis follow.
"In order to conduct the overview analysis, there was tremendous cooperation amongst the different investigators and trial sponsors," Califf continued. "This degree of cooperation and access to data at the time of primary presentation of trial results is unprecedented and could serve as a model for future investigations.
"Given the recent concerns about publication of results of human clinical trials, we believe this model of alliance among multiple clinicians and academics around the world and industry provides the best chance for full, balanced and rapid public presentation of the results."
Much has changed in the treatment of patients with acute coronary syndromes since the first studies comparing enoxaparin with unfractionated heparin, according to DCRI cardiologist John Petersen, M.D., first author of the meta-analysis published in JAMA.
"Cardiologists now are more aggressive in the use of new medications and procedures to prevent future heart attacks or reduce symptoms of heart disease," Petersen said. "Given that we as are being more aggressive in the treatment of acute coronary syndromes, we wanted see how enoxaparin fared in the 'new world' of cardiology."
The researchers focused on six recent clinical trials. Two of the trials -- SYNERGY and A to Z -- were conducted by the DCRI, which also had the database for a third, the ESSENCE trial, so the datasets were available. With the cooperation of the investigators and sponsors of the three other trials -- TIMI 11B, ACUTE II and INTERACT -- the researchers received access to those datasets as well. In all, the researchers analyzed the clinical data on 21,946 patients worldwide.
"This is one of the first times researchers have had the opportunity to use data from trials prior to publication," Petersen said. "Having access to all this data allows us to get a real sense of the issues involved in using these drugs. In our systematic overview of patients across the spectrum of acute coronary syndromes, we found that enoxaparin is more effective than unfractionated heparin in preventing combined rate of death or heart attack."
The rate of death after 30 days was 3 percent for both enoxaparin and unfractionated heparin. However, when the combined incidence of death or heart attack was used as the prime endpoint, enoxaparin showed a rate of 10.1 percent, compared 11 percent for unfractionated heparin. The difference was statistically significant, Petersen said.
One of the key concerns over using anti-thrombin agents such as heparin is the occurrence of bleeding or the need for a blood transfusion. In his analysis, Petersen found little difference in the rates of major bleeding or transfusion seven days after administration of either enoxaparin or unfractionated heparin.
Within this large group of patients, the researchers identified a subgroup of patients who did not receive either form of heparin prior to being randomized into the trials. For these patients, enoxaparin had an 8 percent rate of death or heart attack, compared to 9.4 percent for unfractionated heparin, a statistically significant difference.
"The substantial and consistent benefits of treatment for those patients who had not received prior antithrombin therapy indicates that enoxaparin may be superior to unfractionated heparin as a first-line agent in this group of patients," Petersen said.
Petersen's analysis was sponsored by Aventis, Inc., Strasbourg, France. Petersen has no financial interest in Aventis.
The SYNERGY trial
While previous trials have demonstrated that enoxaparin was more effective than unfractionated heparin in reducing the occurrence of either death or heart attack in lower-risk heart patients, its effectiveness in sicker patients who would likely be rushed into the catheterization laboratory was not known. To answer this question, DCRI organized a prospective randomized trial known as SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors).
According to DCRI cardiologist Kenneth Mahaffey, M.D., lead author of the SYNERGY paper, this trial was designed to enroll "real world" patients, the type of patients cardiologists encounter every day in their practices. A total of 10,027 patients were enrolled at 467 sites in 12 countries between August 2001 and December 2003.
The trial was designed to compare the rates of death or non-fatal heart attack after 30 days. The secondary goal was to compare the rates of bleeding and stroke.
"We found that enoxaparin is at least as effective as unfractionated heparin," Mahaffey said.
Specifically, death or non-fatal heart attack occurred in 14 percent of patients who received enoxaparin, compared to 14.5 percent for unfractionated heparin. Patients who received enoxaparin experienced higher rates of bleeding episodes -- typically at the site of catheter insertion or drug injection -- but Mahaffey said that these events were not generally associated with major complications for the patients.
"Based on the results of SYNERGY, we believe that enoxaparin is a reasonable alternative to unfractionated heparin, and the advantages of convenience should be balanced with the modest excess of bleeding," Mahaffey said.
One issue facing researchers in interpreting that data was that many patients were receiving one of the agents before being enrolled in the trial, and were then subsequently randomized to the other agent.
"We found that changing anti-thrombin agents in the midst of treatment may be hazardous, with an increase in bleeding episodes and a potential decrease in the effectiveness of the agent," Mahaffey said.
SYNERGY was sponsored by Aventis, Inc. Mahaffey has no financial interest in Aventis.
Phase A of the A to Z Trial
The two-part Aggrastat to Zocor, or A to Z, trial was designed to answer questions regarding safety and efficacy of unfractionated heparin versus enoxaparin along with timing and intensity of statin dosing within the context of current treatment strategies for patients with cardiac chest pain.
In the "A" phase, all patients were treated with tirofiban (trade name Aggrastat) and aspirin and randomized to either enoxaparin or unfractionated heparin. The second Z phase of the trial examined one of two dosing regimens for simvastatin (trade name Zocor), a statin lipid-lowering agent. The results of the Z phase should be available later this year.
The researchers, led by Duke cardiologist Michael Blazing, M.D., did not necessarily set out to prove that enoxaparin was superior to unfractionated heparin, but that it was just as effective. The trial enrolled 3,987 patients from 40 countries between December 1999 and May 2002.
The researchers found that 8.5 percent of patients receiving enoxaparin experienced death, a heart attack or refractory ischemia, compared with 9.5 percent in patients receiving unfractionated heparin. While not statistically significant, the results met criteria for non-inferiority with trends in favor of enoxaparin, Blazing said, adding that if more patients had been enrolled, statistical significance likely could have been achieved.
Additionally, the rates of bleeding were low -- 3 percent for patients receiving enoxaparin and 2.2 percent for those receiving unfractionated heparin. There was a slight one in 200 increased risk of major bleeding with enoxaparin, but only 0.9 percent of the enoxaparin patients and 0.4 percent of the unfractionated heparin patients had major bleeding events. This slight increase in major bleeding did not result in an increase in the transfusion rate as it was nearly equivalent at 1 percent in the enoxaparin arm and 0.8 percent in the unfractionated heparin arm, Blazing said.
"The bottom line is that enoxaparin is a safe drug, with only a slight increase in the rate of bleeding that is more than offset by the trends toward efficacy and ease of use," Blazing said.
For Blazing, the fact that three such important studies are being published at the same time in the same journal is a boon for physicians.
"All the different pieces of the puzzle are together in one place," he said. "Physicians have easy access to the primary data, instead of review articles, which can often reflect the biases of the author. Here they have the data they need to make their own informed decisions."
A to Z was sponsored by Merck & Co., Whitehouse Station, N.J. Blazing has received honoraria as a speaker for Merck.
For more information, or to contact Duke University Medical Center, see their website at: www.mc.duke.edu
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