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Ximelagatran: a new drug to replace warfarin?

Originally Prepared byTammy Kolacny, PharmD Candidate

Re-worked and updated by Sue Ellen Gary, RPh, PharmD Candidate

Update

February 14, 2006

AstraZeneca announced today that it is abandoning all efforts to bring Exanta to market.  There was evidently another case of liver damage in an ongoing test.  This would probably cause a rejection of approval for the drug.  Please look at http://astrazeneca.com/pressrelease/5217.aspx

January 1, 2006

The investigators in the SPORTIV III and SPORTIF V trials concluded that ximelagatran was not inferior to warfarin based on the criteria that were defined before the studies were started.  However, after the studies were completed, it appears that the criteria were changed.  Kaul et al point out 5 areas of disagreement over whether or not the non-inferiority criteria were legitimate. 

1. There appears to have been an unreasonable generous margin of variation potentially biased in favor on non-inferiority.
2. The analytical method use to estimate non-inferiority may have been inappropriate.
3. In making a non-inferiority decision, the ximelagatran would have to retain at least 50% of warfarin’s effect.  Some have doubted that this exists.
4. There was a wide variation of efficacy between the two trials.
5. There is concern that ximelagatran was more toxic to the liver without a corresponding offset in the level of major bleeding.

Therefore these authors concluded that ximelagatran did not show non-inferiority to warfarin.

It does seem unfair that the standards were set and AstraZeneca followed the guidelines and then the target was moved after the studies were completed.

Kaul et al. Trials and tribulations of non-inferiority the ximelagatran experience. J Am Coll Cardiol. 2005;46:1986-95.

 Website editor’s note:  In December 2005, I attended a pharmacists’ convention.  There was very little representation from AstraZeneca.  I talked with several people who have been “in the know” in the past.  Their comments ranged from, “they aren’t saying anything”to “Exanta is dead and buried”.  There is nothing new on the website this year.  If there are any developments, AstraZeneca is not announcing anything.  I tend to be in the “dead and buried” camp but I have been surprised before.

November 12, 2005

The status of research in the US is not being made public.  There are a few studies being reported in other countries, but these consist mainly of analysis of subgroups from earlier studies.  Schulman et al (Ximelagatran for the secondary prevention of venous thromboembolism: a complementary follow-up analysis of the THRIVE III study. Thromb Haemost. 2005 Oct;94(4):820-4) concluded that ximelagatran was superior to placebo for long-term use in deep vein thrombosis prevention.  However, there did not appear to be that much difference in total deaths in the two groups.  Since unpredicted deaths played a big role in the drug not being approved in the US in 2004, I wonder if this study really added anything to our knowledge of ximelagatran.  Eriksson et al (Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran. Thromb Haemost. 2005 Sep;94(3):522-7) reported on the effect of sex, age, body weight, renal function,
malignancy, type of initial VTE event, and history of previous VTE events in ximelagatran-treated people vs people getting placebos.  They concluded that these factors had no effect.  Again, I see a potential problem with the conclusion.  Within the placebo group, risk of recurrent VTE was higher among men than women.  This appears to go against my experience in seeing over 30,000 patient visits.  I am not an expert on study designs, but I wonder what could have caused this to happen.

October 24, 2005

It looks like the next agent in the class of oral direct thrombin inhibitors will be dabigatran.  My sources tell me that there is some hope that this drug will be on the market by 2008.  However, others have said that it is probably more realistic to expect its roll-out to be in 2009 or 2010.

The BISTRO II study published in January 2005 found it to be safe and effective in short-term use to prevent blood clots in hip and knee replacement surgery.  (Eriksson et al. J Thromb Haemost. 2005 Jan;3(1):103-11).

In view of the death from bleeding that could not be reversed in the SPORTIF IV trial, we hope that this issue will be studied further in both ximelagatran and dabigatran.  If it turns out that neither of these drugs can be reversed, should bleeding start, then their uses would appear to be severely limited - probably to very short-term use.

Cohen et al did a meta-analysis of trials comparing ximelagatran with low-molecular-weight heparin for the prevention of clots after major orthopedic surgery.  Six studies with over 10,000 participants were included.  They found no clear advantage for either drug.  Ximelagatran protected from clots with an expense of causing more major bleeding.

 Cohen AT, Hirst C, Sherrill B, Holmes P, Fidan D. Meta-analysis of trials comparing ximelagatran with low molecular weight heparin for prevention of venous thromboembolism after major orthopaedic surgery. Br J Surg. 2005 Oct 20;92(11):1335-1344 [Epub ahead of print]

Colwell et al reported on the EXULT B trial comparing warfarin with ximelagatran for clot prevention after total knee replacement in 1949 patients.  There were four deaths in the ximelagatran group compared with two in the warfarin group.  The authors judged ximelagatran to be superior to warfarin in clot prevention.  The bleeding rates were similar but the ximelagatran group had more major bleeding.   It seems to me that the ximelagatran group usually has a slightly higher number of deaths and more serious bleeding. It may not be statistically significant, but it is troubling.

Colwell CW Jr, Berkowitz SD, Lieberman JR, Comp PC, Ginsberg JS, Paiement G, McElhattan J, Roth AW, Francis CW; EXULT B Study Group. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am. 2005 Oct;87(10):2169-77.

Update

February 25, 2005

 This is largely taken from the AstraZeneca website http://astrazeneca.com/pressrelease/4644.aspx 

The European Union uses a mutual recognition procedure (MRP) to aviod duplication in drug approvals among its members.  The French Regulatory Authority (AFSSAPS) has served as the Reference Member State for Exanta.  Under this procedure, Exanta was approved for prevention of blood clots in people undergoing hip- or knee-replacement surgery in nine countries in May 2004.  At that time AstraZeneca also requested approval for Exanta in preventing strokes among people with atrial fibrillation (AF) and venous thromboembolism (VTE).  However, the regulatory authorities requested more information for giving these approvals for long-term use.   

AstraZeneca’s press release of January 19, 2005 states, “AFSSAPS requested further clinical information confirming the efficacy and demonstrating the safety of Exanta in AF to allow a definitive benefit/risk assessment to be made while, for VTE treatment, the authority does not believe the data presented in the single THRIVE Treatment study provides adequate support for this use of Exanta and is proposing a rejection for this indication.” 

Dr. Hamish Cameron, AstraZeneca’s Vice President and Head of Exanta responded with comments on the unmet needs in this area and confirming that AstraZeneca remains committed to research in this area of medicine. 

AstraZeneca is conducting discussions with the US Food and Drug Administration to see if there is any realistic possibility of marketing this drug in the United States.

THE ITEM BELOW IS MY REPORT OF THE FDA MEETING SEPTEMBER 10, 2004 OF THE FDA ADVISORY COMMITTEE MEETING.

In an astounding rebuke, the Cardiovascular and Renal Drugs Advisory Committee of the United States Food and Drug Administration sent AstraZeneca's Exanta back to the drawing board on September 10, 2004. The charge to the committee was to answer thirteen questions. The vote was resoundingly against Exanta on each of the questions. The committee spent nearly ten hours in session considering the various proposals for Exanta.

Despite the need for a new agent to replace warfarin, the committee let it be known that Exanta was not their choice without further research.

The first three questions dealt with the level of concern for the risk of liver failure with Exanta. Every member felt that the risk was either high or moderate when considered in the setting of prevention of stroke and sytemic embolic events in patients with atrial fibrillation. This was the longest-term use proposed for Exanta. The second question dealt with the prevention of venous thromboembolism (VTE) after a standard treatment with warfarin for six months. Here again, every member expressed their feeling that the risk was either high or moderate. The third question was again about the risk of liver toxicity but this time in the setting of prevention of VTE in patients undergoing total knee replacement surgery. This was the shortest-term use proposed for Exanta. The vote here was slightly more positive with no high-risk votes and everyone voting either moderate or low. Some of the panel members voted against Exanta because they were concerned that patients would probably tend to be left on the drug for longer than was recommended. A few years ago, there was a pain medication called Duract that was withdrawn from the market because physicians did not follow the guidelines and use it only short term. When this happened, there was more toxicity than the clinical trials had shown. Another drug, troglitazone, had only about half the rate of liver damage shown by Exanta in trials and it was withdrawn from the market after a considerable amount of bad publicity. It appeared that with these withdrawals in recent memory, the committee was unwilling to take a chance on Exanta. The next question was closely tied to the first three, " Based on currently available data, is it possible to identify patients who are at risk for developing severe liver toxicity after exposure to ximelagatran?" The majority of the votes were, "No" with a minority saying, "Possibly".

The next question dealt with AstraZeneca's study procedures for monitoring and managing patients with regard to liver function tests. Here the resounding vote was against the company. One committee member noted that under the closely-controlled clinical trial situation , only 70% of the required tests were done. My personal testimony in the open public hearing phase of the meeting dealt with this problem. It has been so widely maintained that Exanta does not need to be monitored that my concern was that physicians and patients would widely disregard this requirement. I encouraged the committee to use strong language in making the requirement for liver function testing known. My testimony assumed that the drug would be approved. Going into the committee meeting I could never have imagined that Exanta would not have gotten some form of approval. In fact, there was a break scheduled before the voting and I was going to ask the people sitting around me how they thought that the voting would go. The committee never took an afternoon break, staying in session for five and one-half hours straight, so I never had a chance to ask.

The next question had two parts regarding the committee members having other safety concerns over the short-term and long-term use of Exanta. On both parts, the members overwhelmingly voted, "Yes". Comments were made about a possible rebound effect causing an increase in the tendency to form clots when the drug was stopped. Evidently AstraZeneca only looked for any rebound effect up to 24 hours after the drug was stopped. Some concern was expressed that the rebound could occur 76 to 92 hours after the drug was stopped. One of the strong points of Exanta is that it is not metabolized by the liver. However, this means that it is eliminated by the kidneys. Many people who would be taking it to prevent strokes are elderly people. This group is the most likely to have decreased kidney function. In the clinical trials for Exanta, people with impaired kidney function were excluded from the trials. But, the ones who developed kidney problems while taking the drug had an increased tendency to bleed. There was also some concern that if people had to have their dose reduced because of poor kidney function that they would then have less protection from a stroke. Why this should be a cause for not approving Exanta is not readily apparent to me. The committee was not voting to replace warfarin with ximelagatran. Anyone with poor kidney function could still use warfarin. The number of patients who withdrew from the study and were totally lost to follow-up also caused some concern. In many studies, people who stop taking the drug are still studied until the end of the trial. More than the usual number seemed to be lost in these studies.

The next question on the agenda was, "Do you recommend additional safety studies with longer follow-up to address the possibility of delayed occurrence of liver toxicity following short-term use?" Here again the vote was a resounding rebuke of the studies done on Exanta thus far. Editor's comment: Exanta has been approved in Germany for short-term use. It has been in use for only about three months but post-marketing data should be coming from there in about another year. While practices in Europe are somewhat different from North America, this data will be "real-world".

Next up was a question about the risk of heart attacks in people who take Exanta short-term for total knee replacement. Here again the vote was overwhelmingly in favor of more studies. Some comments were made in both the open to the public session and from committee members about the advisability of comparing Exanta to warfarin in this setting. However, it seemed to this writer that the main concern was that the people chosen for the studies were relatively low-risk while many people undergoing knee replacement surgery are fairly high-risk, mostly elderly people. Again, post-marketing studies from Germany may help to solve this lack of "real-world" data.

The next question was on the approvability of Exanta - does the benefit outweigh the risk in the setting of short-term use to prevent VTE after total knee replacement? Again the committee resoundingly voted against Exanta.

The following question asked about the approvability of Exanta for long-term use in the prevention of a recurrent VTE after 6 months of standard therapy. This question got the most positive response of the entire meeting with one member voting, "Yes" and one saying that there was not enough information and voting, "Abstain". Not exactly the ringing endorsement that I'm sure that AstraZeneca would have wanted.

The final set of votes centered around the long-term use of Exanta for prevention of stroke and systemic embolic events for people with atrial fibrillation. The first question in the setting was, "Is the non-inferiority margin of 2% compared to warfarin adequate to ensure that ximelagatran is non-inferior to warfarin with respect to efficacy? If, no what should the non-inferiority margin be for the indication of prevention of stroke and systemic embolic events in patients with atrial fibrillation?" The committee voted, "No" . The non-inferiority margin that the committee seemed to agree on was a range of 1.0 to 1.4%. The last question asked about the approvability (benefits outweigh risks) of Exanta for long term-use in atrial fibrillation. Here again there was only one, "Yes" vote.

Before adjourning, members made several comments for the record. One was that AstraZeneca should provide them with a better plan for minimizing risks with Exanta. Another was that approvability might require unequivocal proof of superiority over warfarin. It was this writer's opinion that this request was because of the higher risk of toxicity with Exanta. Another comment was that they needed to do a head-to-head study with warfarin over a sufficient amount of time to show that the risks outweighed the benefits.

The closing comment was that a new molecule does not necessarily mean an advance.

So now we have a dichotomy set between the United States and the European Union. Exanta has been approved for at least short-term use in the EU. It has been rejected, for the present, for any use at all in the US. The stage is set to see which opinion is correct as real-world data accumulates over the next few years.

Remember that the full FDA committee can go against the advisory panel but it is very unusual especially to recommend approval after a negative vote by the advisory committee.

Al Lodwick  September 10, 2004

If you wish to read the entire transcript (414 pages) of the day-long meeting, here is the link http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4069T1.pdf    My testimony begins on page 210.  It is an Adobe Acrobat file.

**Disclaimer: Some information is based on limited, unpublished data from the drug manufacturer and may carry with it bias that would be expected from a party with such vested interests. This product is not approved for use in the U.S. yet and long-term data is limited.  Mr. Lodwick , the owner of this web site has also been a paid consultant for AstraZeneca, the developer of this drug.

Ximelagatran is an oral anticoagulant being developed by AstraZeneca as Exanta™. It is the first oral anticoagulant agent to reach late stage product development since warfarin was marketed  nearly 60 years ago.

Ximelagatran is an oral prodrug of melagatran, a direct thrombin inhibitor. Melagatran is poorly absorbed from the gastrointestinal tract and absorption is affected by food, so it is given as an injection. Ximelagatran, however is about four times as easily absorbed and its absorption is unaffected by food. It is rapidly converted to melagatran (the active drug) after absorption into the blood stream. This is why it is called a prodrug. It is not an active drug the way it is given but it turns to an active drug during metabolism. This is not unique, some other prescription drugs are given in the same manner.

Ximelagatran is termed a "direct thrombin inhibitor" because it slows the coagulation cascade by directly binding to thrombin, a clotting factor essential in the clotting process. If thrombin is blocked, clot formation is delayed (as with warfarin).

Warfarin and ximelagatran both delay clot formation, but they do so in different ways. Warfarin depresses the production of clotting factors  (II, VII, IX, X) within the coagulation cascade to delay the formation of a clot. A major difference between the two medications is the following: warfarin is prevented from working vitamin K and ximelagatran is not. Therefore, ximelagatran is not affected by changes in vitamin K intake from diet or medications. People that are currently taking warfarin, will quickly recognize how this small difference may affect their lifestyle. A person may no longer have to be concerned about bleeding or clotting based upon changes in their diet or vitamin consumption.

According to current studies and manufacturer data, ximelagatran will not involve coagulation monitoring (INR/PT). Unlike with warfarin, dosing and patient response may be more predictable with ximelagatran. Dose proportionality studies have shown that changes in drug dose produce predictable and consistent changes of drug levels in the blood. Therefore, it is expected that ximelagatran may have one dose that is effective for most patients without the variability in dosing that is seen with warfarin.

Manufacturers state that there are "no known pharmacokinetic drug interactions with ximelagatran." Pharmacokinetics is the study of "what the body does to the drug." This process often involves absorption, distribution to tissues, metabolism, and elimination of drugs. The majority of the drug interactions observed with warfarin are due to changes in distribution and/or metabolism as a result of concurrent and often times conflicting drug therapy. Ximelagatran has different drug properties than warfarin that make it less likely to interfere with other medications in this way. Potential drug interactions could include those seen between anticoagulants and other medications that may cause or worsen bleeding effects (such as aspirin or ibuprofen). At this point, drug interaction data is still limited but ximelagatran may be better than warfarin in this regard.  Note this point well - if there is a drug that may cause bleeding on its own, it will still be likely that it cannot be used with ximelagatran.

Clinical trials are still ongoing, but finalized studies indicate that ximelagatran is at least as effective as warfarin and enoxaparin (Lovenox®) when studied for short-term use following total knee and total hip arthroplasty (replacement), respectively. These two orthopedic studies demonstrated ximelagatran efficacy for the prevention of venous thromboembolism such as deep vein thrombosis or pulmonary embolism (clots in legs or lungs, respectively) that was comparable to that observed with traditional agents such as warfarin and enoxaparin.

Long term studies to evaluate the use of ximelagatran in deep vein thrombosis (DVT) treatment, atrial fibrillation (irregular heartbeat), and arterial conditions (following a heart attack) have recently been completed and published.  These studies are often given catchy names so that they can be easily referred to.  When a study is published in a reputable medical journal, it has undergone scrutiny by peers of the authors to weed out false reports and conclusions.  

THRIVE III evaluated the safety and efficacy of ximelagatran for secondary prevention of venous thromboembolism (VTE) in over 1200 patients with documented deep vein thrombosis (DVT) or pulmonary embolism (PE). After 6 months of standard anticoagulation therapy, the patients were randomized to receive either 24 mg of ximelagatran or placebo twice daily for an additional 18 months. In the ximelagatran group, a significantly lower number of patients suffered a confirmed secondary thromboembolic event (VTE) than in the placebo group (2.8% vs. 12.6%). Both groups had similar rates of major bleeding events (less than 1%). The use of vitamin K antagonists, such as warfarin, is associated with an annual major bleeding event risk of 3 – 4%. The researchers concluded that long-term treatment with ximelagatran, without dose adjustment or monitoring of coagulation, is safe and effective in reducing the incidence of recurrent venous thrombosis.

EXULT A compared the safety and efficacy of two different fixed doses of ximelagatran with warfarin in prevention of DVT after total knee replacement. Over 2300 patients were randomly assigned to receive either ximelagatran 24 mg twice daily, 36 mg twice daily, or warfarin adjusted to an INR of 2.5 for 7 – 12 days post surgery. When the study endpoints of DVT, PE, and all-cause mortality were combined, ximelagatran 36mg twice daily proved to be significantly more effective than warfarin, but when each endpoint was evaluated separately, there was no significant difference in safety or efficacy between any of the treatment groups. The study authors concluded that fixed dose ximelagatran, 36 mg twice daily administered without coagulation monitoring, is significantly more effective than warfarin and has a similar incidence of bleeding.

SPORTIF V compared ximelagatran 36 mg twice daily with warfarin adjusted to a target INR of 2.0 to 3.0 in 3922 patients with nonvalvular atrial fibrillation (AF) and one other stroke risk factor (age 75 or older, previous stroke, or history of hypertension or congestive heart failure). Ximelagatran was shown to be "noninferior" to dose-adjusted warfarin in the prevention of all strokes and systemic embolic events. There was no significant difference in rates of major bleeding or intracerebral hemorrhage between the treatment groups. However, when all bleeding was considered ximelagatran did have a lower rate of major and minor bleeding compared to warfarin.

There have been no studies on the safety and efficacy of ximelagatran use for patients with mechanical heart valves or clotting factor abnormalities.

The most common and expected side effect from ximelagatran (and any other anticoagulant) is bleeding. Clinical trials indicate that the bleeding risk associated with ximelagatran is comparable to that of traditional anticoagulants (warfarin and enoxaparin) and is not statistically better or worse than either tested medication. However, bleeding and safety issues will always be a concern for patients on anticoagulant medications.

Elevations in liver enzymes (as high three times normal - that is the level when they start to become worrisome) have been seen in up to 6% of the patients in the first two to six months of treatment with ximelagatran. In most of the patients, enzyme levels returned to normal whether or not ximelagatran was discontinued. Since the significance of this effect on liver enzymes cannot be adequately evaluated until after the drug is released and used in a wider patient population, routine monitoring of liver enzymes would be prudent during the first months of treatment.

Editor's Note:  Since this was written, I have learned that AstraZeneca, in their application for approval of Exanta to the FDA, proposed the following recommendations for liver monitoring: 

Before starting ximelagatran check the liver function by doing an ALT test.  If the results are greater than two times the upper limit of normal, do not start the drug.

After ximelagatran is started check the ALT every month for the first six months, then every two months for the next six months, then periodically.

If any of the results of the ALT test are between two and three times the upper limit of normal, then test the ALT every week.

If any of the results of the ALT test are more than three times but less than five times the upper limit of normal then test the ALT every week.  If the results do not return to normal within four weeks, discontinue ximelagatran immediately

If any of the results of the ALT test are greater than five times the upper limit of normal or if there is any other evidence of liver injury, stop ximelagatran immediately.

An expected date of arrival on the U.S. drug market is unknown. 

Phase III clinical trial results have been published in the United States and the New Drug Application has been submitted. Application for approval of both the injectable (melagatran) and oral (ximelagatran) dosage forms was approved in Europe.  Only the oral dosage form has been submitted for approval in the USA. If approved, it may be available in late 2004.

A patient may want to switch to ximelagatran from warfarin for the following reasons (based on current data):

1. No coagulation monitoring (INR measurements)
2. Fewer drug/food interactions
3. Similar efficacy and safety to warfarin (so far)
4. Better overall quality of life for many patients (due to less monitoring and interactions)
5. Reduced costs from lab tests and visits related to coagulation monitoring

A patient needs to keep the following issues in mind when considering a switch from warfarin to ximelagatran:

1. Limited long-term data to support ximelagatran use
2. Expensive cost of the medication compared to generic warfarin
3. Compliance issues

-Less monitoring and fewer clinic visits may translate (for some patients) into thoughts that the drug is very safe and that missed doses are not harmful (when this can actually be very dangerous).

-Twice daily dosing increases potential to miss doses. Since no monitoring is required, the first indication that a patient is non-compliant could be a serious clotting episode.

4. Potential loss of relations with anti-coagulation provider

-From my experience as a pharmacy student in Al Lodwick’s clinic, I have found that patients come into the clinic for the following reasons: to have their INR measured for warfarin management and to visit with Al.

-Many patients have developed great relationships with their anti-coagulation providers and the loss of monthly visits is certainly a consideration for many patients that may want to switch medications.

5. Overall patient care may suffer from fewer clinic visits

-More frequent provider visits (of any kind) have been shown to play a critical role in preventive healthcare by detecting problems early for better treatment outcomes. Anti-coagulation providers not only give advice about warfarin, but about all types of health conditions and medications (since they are trained healthcare professionals).

6. Safety data is not fully established

-Hesitation and caution need to accompany any anticoagulant therapy changes because of the risk of bleeding or clotting that can result.

- Liver enzyme elevations seen in a small percentage of the patients in the longer term studies may or may not prove to be significant once the drug is released for general use. Patients selected for clinical trial are very carefully screened before being chosen for the study. Once a drug is released for uncontrolled prescribing by the medical community, minor or transient adverse effects may prove to be a major problem. More than one new drug has had to be recalled because of adverse effects that were not seen until after they were being prescribed for the general patient population.

7. There is no known reversal agent (antidote) for ximelagatran so far

-If a patient consumes too much warfarin and providers worry about excessive bleeding, injectable or oral vitamin K can be given to reverse the effects of the warfarin

-Ximelagatran does not stay in the body nearly as long as warfarin so this may not be as much of a concern (because it will be eliminated from the body much faster anyway).

To read about dabigatran, click here.

To read about BAY 59-7939, click here.

 

• References:

• Erikson, BI et al. A Dose-ranging Study of the Oral Direct Thrombin Inhibitor, Ximelagatran, and its Subcutaneous form, Melagatran, Compared with Dalteparin in the Prophylaxis of Thromboembolism after Hip or Knee Replacement: METHRO I. Thromb Haemost 2002 Feb;87(2):231-7

© 2002, 2003 Tamara Kolacny   Used by Permission

© 2003 Sue Ellen Gary  Used by permission

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