RxPG News : Anti-Clotting Drugs

Direct Intraclot Injection of Alteplase - effective treatment for deep vein thrombosis

Tue, 29 Jan 2008 13:25:41 PST

( from http://www.rxpgnews.com ) A novel treatment for blood clots in the legs appears to be safe and effective, according to a pilot study published in the February issue of Radiology. The study found that injecting or “lacing” the clot with a fiber-binding thrombolytic agent effectively treats deep vein thrombosis (DVT) and reduces the risk of subsequent recurrence or bleeding.

“This treatment regimen is able to clear blood clots rapidly and safely, restoring blood flow in the veins of the lower leg, and the results are durable,” said lead author Richard Chang, M.D., chief of the interventional radiology section of the Department of Radiology, Clinical Center, National Institutes of Health (NIH), Bethesda, Md.

DVT is a common and serious health problem in which a blood clot, or thrombus, form in the deep veins, particularly in the lower leg or thigh. Complications occur when the clot breaks off and travels to the lungs, resulting in pulmonary embolism, a potentially fatal condition.

Most patients with DVT are treated solely with anticoagulation therapy (blood thinners) and compression stockings. However, studies have shown that one-third of these patients will suffer from post-thrombotic syndrome, characterized by pain, swelling, or in severe cases by changes in skin color or skin ulceration. Another third are likely to have another clot or pulmonary embolism within five years of their initial DVT.

Treatments with thrombolytic (clot-dissolving) therapy could potentially protect against these occurrences, but can pose a bleeding risk. Therefore, Dr. Chang and colleagues sought to develop a safe, effective and affordable thrombolytic treatment regimen for DVT.

Twenty patients with acute DVT were treated with direct intraclot lacing of the thrombus with a clot-dissolving agent called alteplase and full systemic anticoagulation. Alteplase binds to the clot, so the procedure does not require continuous infusion of the drug, as do some thrombolytic therapies. With this treatment, after lacing one vein segment with alteplase, the interventional radiologist can immediately direct catheters to treat other vein segments to ensure that the entire clot has been adequately treated.

The results of the study showed that blood flow was restored throughout the deep venous system in 16 (80 percent) of the 20 patients during therapy with complete resolution of symptoms in 18 patients (90 percent) after six months of anticoagulation. Alteplase was cleared from the patients’ circulatory system within two hours of treatment, reducing the risk of subsequent bleeding.

There were no serious complications or bleeding during the treatment, and no cases of post-thrombotic syndrome or recurrent clotting during follow-up of 3.4 years.

“With this therapy, pain and swelling resolve rapidly, and, in most cases, the patient is able to resume all normal activity within a week,” said the study’s co-author, McDonald K. Horne III, M.D., from the hematology section of the Department of Lab Medicine, Clinical Center, NIH.

The authors caution that larger clinical trials are required to further support the efficacy of this promising treatment.

Desensitization protocol overcomes allergy to clopidogrel

Fri, 12 May 2006 14:17:37 PST

( from http://www.rxpgnews.com ) A careful desensitization protocol can help patients overcome allergic reactions to anti-clotting medication critical to preventing new blockages inside coronary stents, according to a study being presented at the Society for Cardiovascular Angiography and Interventions (SCAI) 29th Annual Scientific Sessions in Chicago, May 1013.

"Allergic reactions can be quite frightening to patients and physicians, and can lead to discontinuation of the medication," said the study's lead author, Nicholas E. Walker, MD, a cardiology fellow at the University of Iowa, Iowa City. "We showed we could successfully and safely desensitize patients who had just recently had a drug-eluting stent placed. That's a critical population to manage."

Perhaps two out of every hundred patients treated with the anti-clotting medication clopidogrel develop an allergic reaction marked by rash, itching, hives, or swelling of the tongue and airway. A small number of patients even develop an anaphylactic reaction and go into shock.

Physicians generally discontinue a medication that provokes an allergic reaction and prescribe an alternative. However, in the case of clopidogrel, substitute medications are either just as likely to provoke allergy symptoms or markedly less effective. Stopping the medication may be riskier than continuing it: Patients who do not take clopidogrel after stenting--particularly after receiving a drug-eluting stent--face approximately three times the risk of a blood clot blocking the stent and causing a heart attack.

"With widespread use of drug-eluting stents, it's going to be more common to see allergic reactions to clopidogrel, and more critical that we find a way to keep patients on the medication," said Phillip A. Horwitz, MD, a professor of medicine and an interventional cardiologist at the University of Iowa Hospitals and Clinics.

Eight patients with clopidogrel hypersensitivity were treated with the desensitization protocol, which was developed by University of Iowa allergist Mary Beth Fasano, MD. While being monitored in the cardiac intensive care unit, patients were first given a dose of clopidogrel so small it had to be mixed into a drinkable solution. Every 15 minutes over the next several hours they received an additional, higher dose of the drug, until they were able to tolerate a target dose of 75 mg. Altogether, they received nine clopidogrel doses totaling 150 mg.

Patients who developed allergy symptoms during the desensitization process were treated with antihistamines and other anti-allergy medications. All patients were able to complete desensitization and safely take a daily 75-mg dose of clopidogrel at home without experiencing delayed allergic reactions.

Dr. Walker noted that patients who had the most severe form of allergic reaction to clopidogrel--anaphylactic shock--were excluded from the study; therefore, the safety and effectiveness of the desensitization protocol has not been established in such patients.

New 'designer' drugs in anti-clotting technology

Tue, 13 Dec 2005 22:04:38 PST

( from http://www.rxpgnews.com ) Volunteers at the Jack and Linda Gill Heart Institute at the University of Kentucky were the first ever to receive a new anti-clotting therapy. The drug and its antidote are being developed for their effectiveness in preventing blood clots while at the same time providing physicians the ability to rapidly reverse the effects of the blood thinner to help safeguard patients against uncontrolled bleeding.

More than 12 million patients are prescribed so-called "blood thinners" each year to prevent the formation of clots, which can block blood vessels, causing heart attacks, strokes and other debilitating or life-threatening conditions. Blood thinners, or antithrombotics, pose a risk of bleeding, particularly during surgery. The ability to stop the anti-clotting effects quickly could help protect patients from uncontrolled bleeding.

The Gill Heart Institute is one of two sites participating in the Phase 1 trial and is the first site to use the anti-clotting drug and its antidote.

This clinical trial will examine the drug's safety and tolerability in healthy volunteers as well as the antidote's ability to quickly reverse its effects. Although other new antithrombotics are undergoing testing in the U.S., this drug is believed to be the first of its kind.

"This class of drugs is a very promising technology that allows for the development of 'designer' drugs and their antidotes simultaneously," said Dr. Steven R. Steinhubl, the study's principal investigator at UK and director of cardiovascular education and clinical research at the Gill Heart Institute and a UK College of Medicine associate professor of cardiology. "It could have far-reaching implications."

"The research capacity of the cardiology division at UK has skyrocketed in the last year. Millions of dollars in research projects are under way, and we have attracted world-recognized leaders in drug discovery and development, such as Dr. Steinhubl. Leaders of technology and pharmaceutical companies have visited us in Lexington and are entrusting us to pioneer the next-generation of medicines and devices to improve healthcare," said Dr. David Moliterno, professor and vice chair of medicine, and chief, division of cardiovascular medicine, UK College of Medicine, and co-director of the UK Gill Heart Institute.

"Our goal is simple: we want to help patients with heart and vascular disorders by being at the forefront. Our research efforts are clearly bringing Kentuckians closer to the leading edge of the best medicine has to offer," Moliterno said.

FDA Approves Fondaparinux sodium for Prevention of Venous Thromboembolism in Abdominal Surgery

Fri, 27 May 2005 18:59:38 PST

( from http://www.rxpgnews.com ) The anti-thrombotic drug ARIXTRA(R) is now indicated for use in patients undergoing abdominal surgery, GlaxoSmithKline (NYSE: GSK) announced today. The U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for ARIXTRA in the prevention of venous thromboembolism (VTE) in patients undergoing abdominal surgery who are at risk of thromboembolic complications.

"Since many patients undergoing abdominal surgery are at high risk of developing VTE, the FDA's approval of ARIXTRA for this new indication represents an important and exciting medical development," said Kevin Lokay, vice president of GlaxoSmithKline Oncology and Acute Care. "This approval provides these high risk patients, particularly cancer surgery patients, the benefit of VTE protection in a once-a-day anticoagulant."

ARIXTRA is the first selective inhibitor of Factor Xa, a protein central to the coagulation process. ARIXTRA is already approved for the prevention of VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), in
patients undergoing surgery for hip fracture (including extended prophylaxis), knee replacement and hip replacement.

Additionally, ARIXTRA is indicated for the treatment of acute DVT when administered in conjunction with warfarin sodium and for the treatment of acute PE when administered in conjunction with warfarin sodium, when initial therapy is administered in the hospital.

"In addition to demonstrating safety profiles comparable to enoxaparin, dalteparin, and unfractioned heparin, ARIXTRA has not had any reported cases of heparin induced thrombocytopenia (a potentially fatal condition in which
antibodies develop and lead to increased risk of thrombosis) or drug-drug interactions," said Lokay.

VTE is a term that refers to either one or both of two medical conditions: deep vein thrombosis (DVT, which includes blood clots in the pelvic or leg veins), and pulmonary embolism (PE, which is when a clot breaks off and lodges in the lung arteries).

Up to two million cases of VTE develop in the United
States each year.About one-third of patients with symptomatic VTE will develop PE. VTE can be fatal; death occurs in about six percent of DVT cases and about 12 percent of PE cases within one month of diagnosis. Without prophylaxis, up to 25 percent of patients undergoing abdominal surgery will develop DVT, with a 0.5 to 0.8
percent associated risk of PE. In patients undergoing cancer surgery, the risk of VTE and fatal PE is two to four times higher.

The recent approval of ARIXTRA for patients undergoing abdominal surgery is based on the results of the PEntasaccharide GenerAl SUrgery Study (PEGASUS). This non-inferiority study demonstrated that ARIXTRA is at least
as effective as dalteparin in reducing the risk of VTE. In the study, 4.6 percent of patients receiving ARIXTRA experienced a VTE incident versus 6.1 percent of patients on dalteparin. Sixty-nine percent of the patients in the
study underwent cancer-related abdominal surgery with 4.7 percent of patients in the ARIXTRA group experiencing VTE versus 7.7 percent of patients in the dalteparin group. In non-cancer abdominal surgery patients studied, 4.2 percent of patients receiving ARIXTRA experienced VTE versus 2.3 percent of patients receiving dalteparin.

PEGASUS

PEGASUS was a double-blind, non-inferiority study performed in 131 centers in 22 countries. A total of 2927 patients were randomized to receive either subcutaneous ARIXTRA 2.5 mg once daily starting six hours after surgery or subcutaneous dalteparin (2500 IU two hours before surgery; 2500 IU on the evening following surgery; then 5000 IU once daily). Treatment was continued for 7 +/- 2 days and patients were followed-up for 30 +/- 2 days. The main sites of surgery were colonic/rectal, gastric, hepatic, cholecystectomy orother biliary.

The primary efficacy endpoint was the incidence of VTE, including DVT and/or PE, evaluated up to post-surgical Day 10 (4.6 percent for ARIXTRA and 6.1 percent for dalteparin). The primary safety outcome was major bleeding
during the initial treatment period, which was comparable between the two groups (3.4 percent for ARIXTRA versus 2.4 percent for dalteparin). However, in patients treated with ARIXTRA according to the recommended regimen (e.g.,
first dose initiated 6 to 8 hours after surgery), the rate of major bleeding was 2.9 percent.

ARIXTRA Safety Information

For Both Prophylaxis and Treatment:

Spinal/Epidural Hematomas

When epidural/spinal anesthesia or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins, heparinoids or fondaparinux sodium are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events may be higher with postoperative use of indwelling epidural catheters or concomitant use of drugs affecting
hemostasis. Patients should be frequently monitored for signs and symptoms of neurological impairment. (See BOXED WARNING)

Contraindications

ARIXTRA is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), patients undergoing hip fracture, hip replacement or knee replacement surgery and abdominal surgery with body weight
less than 50 kg ( less than 110 lbs), patients with active major bleeding, bacterial endocarditis, patients with thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium, or patients with hypersensitivity to fondaparinux sodium.

Warnings

ARIXTRA is not intended for intramuscular administration.
ARIXTRA cannot be used interchangeably with heparin, low-molecular-weight heparins or heparinoids as they differ in manufacturing process, anti-Xa and anti-IIa activity, units, and dosage.

The risk of hemorrhage increases with increasing renal impairment.ARIXTRA should be used with caution in patients with moderate renal impairment. Renal function should be assessed periodically in patients receiving ARIXTRA and should be discontinued immediately in patients who develop severe renal impairment ARIXTRA, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage.

Thrombocytopenia can occur with ARIXTRA. If the platelet count falls below 100,000/mm3, ARIXTRA should be discontinued.

New Class of Anticlotting Drugs Discovered

Mon, 18 Apr 2005 21:39:38 PST

( from http://www.rxpgnews.com ) Monash University researchers and staff of the Melbourne-based biotechnology company Cerylid Biosciences Ltd, have discovered and developed a new class of anti-clotting drugs that appears to be more effective than aspirin at preventing disease-causing blood clots and has fewer side effects.

Heart attack and stroke are the leading cause of death and disability in the western world and result in the death of about 50,000 Australians each year.

They are typically caused by blood clots that block blood flow to the heart or brain. Patients (except those stroke patients whose illness is caused by bleeding into the brain) are usually treated with aspirin, but this can increase the risk of bleeding and lead to life-threatening haemorrhages.

Associate Professor Shaun Jackson (pictured), from the Australian Centre for Blood Diseases at Monash, said this new class of drugs, called PI 3-kinase inhibitors, may prove to be vitally important in treating heart attack and stroke patients by stopping formation of the problem-causing blood clots without causing excessive bleeding.

"Aspirin is the most widely used anti-clotting drug , however it is only effective at preventing fatal heart attack and stroke for about one in four patients," Dr Jackson said. "There is a major need for safer and more effective anti-clotting drugs. The 'holy grail' in the field is a drug that prevents disease-causing clots whilst not increasing the risk of bleeding."

Animal studies have shown that the drugs, developed by Dr Jackson and colleagues at the Department of Pharmacology at the University of Melbourne, Cerylid Biosciences and the University College of London, do not increase the risk of bleeding.

Phase I trials in human volunteers have also yielded promising results.

The drugs were developed after Dr Jackson and colleagues identified the mechanism that promotes the formation of pathological blood clots (clots that lead to heart attack or stroke) and how it differed from the mechanisms involved in normal blood clotting.

Dr Jackie Fairley, CEO of Cerylid Biosciences, said it was too early to say if the drugs would replace aspirin in treating heart attack and stroke but that at this stage in their development, they had enormous potential.