Study Finds Flaws in New Treatment For Blood Clots Reply

In recent years, catheter-directed thrombolysis (CDT) has been added to the current standard of anticoagulation therapy in some patients with deep vein thrombosis (DVT). The hope was that CDT would help reduce the high rate of post-thrombotic syndrome (PTS), but now an observational study finds no benefits and some important disadvantages associated with CDT.

In a report published in JAMA Internal Medicine, Riyaz Bashir and colleagues analyzed data from more than 90,000 patients hospitalized for DVT, 3649 of whom received CDT plus anticoagulation.

Click here to read the full post on Forbes.

 

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Mixed Results for Thrombolysis in Pulmonary Embolism Reply

The role of thrombolytic therapy for the treatment of pulmonary embolism has been unclear, as it has been difficult to measure the precise balance between enhanced clot-dissolving efficacy and greater bleeding risk produced by thrombolysis when compared with conventional anticoagulation.

A new meta-analysis published in JAMA analyzed data from 16 randomized trials including 2115 patients. Overall, there was a significant, 47% reduction in mortality with thrombolysis relative to standard anticoagulation, but this was accompanied by significant increases in major bleeding, including intracranial hemorrhage.

Click here to read the full post on Forbes.

 

Warfarin Benefits Extended To Patients with Chronic Kidney Disease Reply

Anticoagulation is a cornerstone of therapy for atrial fibrillation because it lowers the heightened risk for stroke in this population. People with chronic kidney disease are also at increased risk for stroke, but the benefits of anticoagulation are less clear in this group, and anticoagulation is used less often in AF patients who have CKD. Now, a large observational study offers some reassurance that anticoagulation in AF patients with CKD may be beneficial.

Researchers in Sweden analyzed data from more than 24,000 survivors of acute myocardial infarction who had AF….

Click here to read the full post on Forbes.

 

FDA Once Again Rejects New Indication For Rivaroxaban Reply

The third time wasn’t the charm. The FDA today turned turned down– for the third time– the supplemental New Drug Application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in acute coronary syndrome patients to reduce MI, stroke or death. In addition, the FDA– for the second time– turned down the sNDA for rivaroxaban in the same population for the reduction of stent thrombosis.

Click here to read the full post on Forbes.

 

FDA Again Rejects ACS Indication for Rivaroxaban (Xarelto) Reply

For the second time the FDA has turned down the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) to treat patients with acute coronary syndrome (ACS).

In a new press release issues on Monday afternoon, the company restated its confidence “in the robustness and results of the ATLAS ACS 2 TIMI 51 trial.” Criticism of ATLAS from the FDA and the advisory panel members had focused on missing data from the ATLAS trial. In today’s press release J&J provided more information about its efforts to address this question:

Click here for the complete story on Forbes.

New Studies Examine Prolonged Anticoagulation For VTE Recurrence Reply

Three studies published in the New England Journal of Medicine provide important new information about the risks and benefits of extended prophylaxis using two of the new oral anticoagulants in patients who have had venous thromboembolism (VTE).

In an accompanying editorial, Jean Connors writes that “deciding how to balance the risks and benefits of extended anticoagulation is difficult” in patients with unprovoked VTE, since the risk of recurrent VTE may reach 40% at 5 years. Patients at low-to-moderate risk of recurrence may benefit from aspirin, which “may be safer than the newer agents,” though “it appears to have less efficacy in reducing recurrent events.” For patients at higher risk, “the new targeted anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favor of extended treatment for this patient population. The wide therapeutic window of this agent enables use of a lower dose that retains great efficacy with no or only a minimal increase in bleeding.”

Click here to read the entire post in Forbes.

The New England Journal of Medicine

 

 

 

Boehringer Ends Phase 2 Trial Of Dabigatran In Mechanical Valve Patients 2

Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.

In October Boehringer told members of its speakers bureau that the post-surgery arm of the trial had been terminated due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time the company said the second arm of the trial would continue.

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomes dabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”
Click here to read the press release from Boehringer…

Prolonged Anticoagulation With Apixaban Found Beneficial In Venous Thromboembolism Reply

A new study suggests that extending anticoagulant therapy for an additional year may be beneficial after patients with venous thromboembolism complete their initial course of therapy. The results of AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment) were presented at the annual meeting of the American Society of Hematology meeting in Atlanta and published simultaneously in the New England Journal of  Medicine.

After completing a standard anticoagulation regimen for 6-12 months, 2,486 VTE patients were randomized to either placebo or apixaban (2.5 or 5 mg twice daily) for an additional 12 months. At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.

The primary endpoint, the composite of death or symptomatic recurrent VTE, was significantly reduced in the apixaban groups, from  11.6% in the placebo group to 3.8% in the low-dose apixaban and 4.2% in the high-dose apixaban groups (p<0.001 for both comparisons).

There were very few major bleeding events: 4 (0.5%) in the placebo group, 2 (0.2%) in the low dose apixaban group and 1 ((0.1%) in the high dose apixaban group. Clinically relevant non-major bleeds occurred in 2.3% of the placebo group, 3% of the low dose apixaban group, and 4.2% of the high dose apixaban group.

The investigators concluded that the results of the study “provide a rationale for continuing anticoagulation therapy” in VTE patients for whom there is uncertainty about the worth of continued anticoagulant therapy. They calculated that 14 patients would need to be treated to prevent one VTE case.

Longer Warfarin Therapy After Bioprosthetic Aortic Valve Replacement May Be Beneficial Reply

Three months of warfarin is the usual standard of care following bioprosthetic aortic valve replacement (AVR),  although the supporting evidence base for this practice is limited. Now a large new registry study published in JAMA suggests that more prolonged warfarin therapy may be beneficial.

Danish researchers identified 4,075 patients who underwent bioprosthetic AVR. As expected, warfarin treatment between 30 and 90 days after AVR was associated with significant reductions in stroke, thromboembolic events and cardiovascular deaths compared with patients not taking warfarin. The benefits continued between 3 and 6 months, though the reduction in stroke was no longer statistically significant. The authors calculated that for every 23  patients not being treated with warfarin between 3 and 6 months, there was one additional cardiovascular death, at a cost of 1 bleeding complication requiring hospital admission for every 74 patients.

“With no randomized trials to guide the length of warfarin treatment, our results call for a review of guidelines in the field to consider an extension of the treatment to 6 months after surgery, especially in patients with an increased risk of cardiovascular death,” the authors wrote.

In an accompanying editorial, Shamir Mehta and Jeffrey Weitz write that, despite the limitations of an observational study, the results support a change in clinical practice in favor of prolonged warfarin therapy for as long as 6 months. They observe that the trial does not provide information about the possible role for the newer oral anticoagulants or about the role of adjunctive aspirin.

Here is the press release from JAMA:

Anticoagulation Treatment For Longer Than Three Months After Aortic Valve Replacement Associated With Decreased Risk of Cardiovascular Death

 CHICAGO – Although current guidelines recommend 3 months of anticoagulation treatment after bioprosthetic aortic valve replacement surgery, a study that included more than 4,000 patients found that patients who had warfarin therapy continued between 3 and 6 months after surgery had a lower rate of cardiovascular death, according to a study in the November 28 issue of JAMA.

“Biological prostheses are preferred to mechanical valves for aortic valve replacement (AVR) surgery in elderly patients older than 65 years because of shorter life expectancy and lack of a need to use anticoagulation treatment in the long-term. Especially in these patients, the tradeoff between thromboembolic complications due to the valve implant and bleeding events as adverse effects from anticoagulation therapy must be balanced. Nevertheless, appropriate duration of anticoagulation treatment postoperatively is yet to be established because the risk of complications when the treatment is discontinued is unknown,” according to background information in the article. The current recommendation of 3 months of warfarin treatment after bioprosthetic AVR surgery is primarily based on results from 1 retrospective study with a limited number of events.

Charlotte Merie, M.D., of the Copenhagen University Hospital Gentofte, Copenhagen, Denmark and colleagues investigated whether discontinuation of warfarin treatment within prespecified periods after bioprosthetic AVR surgery was associated with increased risk of thromboembolic complications, cardiovascular death, and bleeding incidents. Through a search in the Danish National Patient Registry, 4,075 patients were identified who had bioprosthetic AVR surgery performed between January 1997 and December 2009. The researchers determined the incidence rate ratios (IRRs) of strokes, thromboembolic events, cardiovascular deaths, and bleeding incidents by discontinuing warfarin as opposed to continued treatment at 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. Average age of the patients was 75 years; 41 percent were women.

Overall, 361 patients (8.9 percent) experienced a stroke, 615 (15.1 percent) had a thromboembolic event, and 364 (8.9 percent) encountered a bleeding incident after the date of surgery. During the observation period, 1,156 patients (28.4 percent) died, with 879 (76.0 percent) of these deaths related to cardiovascular disease. The IRRs for patients not treated with warfarin compared with those treated with warfarin were 2.46 for stroke; 2.93 for thromboembolic events; 2.32 for bleeding incidents; and 7.61for cardiovascular deaths within 30 to 89 days after surgery; and 3.51 for cardiovascular deaths within 90 to 179 days after surgery.

“Our study demonstrates that discontinuing warfarin therapy within the first 3 months after surgery is associated with a significant increase in the risk of stroke, thromboembolic complications, and cardiovascular death. The novelty of our study is the finding that discontinuing warfarin therapy within 90 to 179 days after surgery is associated with a significant increase in the risk of cardiovascular death,” the authors write.

“International guidelines on anticoagulation after a bioprosthetic AVR have been written with limited data on the appropriate duration of warfarin treatment after surgery. Consequently, our study challenges current guidelines on the duration of antithrombotic treatment after AVR surgery with biological valves by presenting results suggesting that these patients will gain from an additional 3 months of warfarin treatment in terms of reduced cardiovascular death without risking a significant increase in bleeding events.”

(JAMA. 2012;308(20):2097-2107)

Editor’s Note: This work was supported by the Research Fund of the Department of Cardiology at Copenhagen University Hospital Gentofte, Gentofte, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Setback For Trial Studying Dabigatran After Mechanical Valve Surgery 2

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for a newer oral anticoagulant has suffered a setback.

Last year Boehringer Ingelheim announced the launch of the RE-ALIGN trial, a phase 2, open-label, 12-week randomized comparison of warfarin and dabigatran (Pradaxa) in 400 patients who received a mechanical valve. There were two arms in the trial. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Now, following the advice of the trial’s Data Safety Monitoring Board, Boehringer Ingelheim said it had discontinued the first arm of the trial, the post-surgery arm, due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” The trial’s second arm with patients who received a valve more than 3 months before enrollment in the trial is unaffected by this decision and will continue as planned.

Boehringer-Ingelheim said that the  news about RE-ALIGN does “not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication” of stroke prevention in patients with non-valvular atrial fibrillation. “RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.”

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomesdabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”

One clinical cardiologist who did not wish to be identified offered the following perspective:

This is similar to the case reports (with all the usual caveats) where we have seen this signal with the novel anticoagulants…. it’s not intuitively clear why this is the case.  It may be that the dose is not optimized for mechanical valves.  It is worth noting that the drug levels in patients with mechanical valves were lower than anticipated based on pharmacokinetic calculations.  Maybe patients with mechanical valves have a different metabolism of the drug versus those that don’t have mechanical valves?  There may be an interaction with von Willebrand factor in the pharmacokinetics of dabigatran. Or maybe the dose is just too low and patients with mechanical valves need higher doses, just as we use a higher INR in patients with mechanical valves?  The science keeps evolving!

Sanjay Kaul made a similar point:

The anticoagulant dose requirement for mechanical valves is higher even for warfarin (INR targeted for 2.5 to 3.5) compared with atrial fibrillation or VTE indication (Target INR of 2 to 3). It is likely that the dabigatran dose tested in RE-ALIGN was not sufficiently effective early post surgery when the thrombotic risk is the highest.

Click here to read a letter sent by Boehringer Ingelheim to members of its speakers bureau…

High Rate Of Warfarin Discontinuation Observed In Study Reply

One of the many potential problems with warfarin-based anticoagulant therapy is the poor rate of adherence and persistence among patients who are prescribed the drug. Now a new observational study published in Archives of Internal Medicine raises the possibility that the problem may be even worse than many may have previously suspected, as discontinuation rates in clinical trials appear to be much lower than in the real world.

Tara Gomes and colleagues analyzed data from more than 125,000 new users of warfarin in Ontario, Canada and found very high rates of discontinuation over time:

  • 8.9% never filled a second prescription
  • 31.8% discontinued warfarin within 1 year
  • 43.2% discontinued warfarin with 2 years
  • 61.3% discontinued warfarin within 5 years

People at higher risk for stroke, as assessed by the CHADS2 score, were more likely to continue taking warfarin over the course of the study.

In an invited commentary, Whitney Maxwell and Charles Bennett write that the results are consistent with previous observational studies but that warfarin discontinuation can be appropriate and is often initiated by the physician. “Appropriateness of anticoagulation discontinuation is perhaps a more important outcome to evaluate rather than absolute discontinuation rates,” they write. An additional plausible explanation for the study finding is that few patients in Canada were treated at anticoagulation clinics.

Maxwell and Bennett write that any potential problem with anticoagulation discontinuation is not limited to warfarin. In the RE-LY trial, they note, more patients discontinued therapy in the dabigatran arm than in the warfarin arm, and a similar trend was observed with rivaroxaban in ROCKET AF.

Apixaban (Eliquis) For Atrial Fibrillation Gets Positive European Recommendation 2

The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval for apixaban (Eliquis, Pfizer and BristolMyers Squibb) for atrial fibrillation (AF). The drug is already approved in Europe for the prevention of venous thromboembolic events (VTE) following hip or knee replacement surgery. The drug has not yet been approved in the United States.

Here is the CHMP proposed indication for the existing 2.5 mg dose and a new 5 mg dose:

“Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).”

CHMP proposed that apixaban should be contraindicated in patients at high risk for major bleeding and in patients receiving other anticoagulants.

The CHMP decision was based on data from the ARISTOTLE and AVERROES pivotal clinical trials.

Click here to download the PDF of the CHMP summary of opinion.

Click here to read the press release from Pfizer and BMS…

FDA Rejects ACS Indication for Rivaroxaban (Xarelto) 2

The FDA has issued a complete response letter to the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) in patients with acute coronary syndrome (ACS). The action was expected, since last month the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against recommending the new indication, which was based on the pivotal ATLAS ACS 2-TIMI 51 trial.

In a press release a J&J company official said the company remains “confident in the robust results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS. We will continue to work with the FDA to fully address their questions as quickly as possible.” Rivaroxaban is currently approved for the prevention of clots following knee replacement and hip replacement surgery and for the prevention of strokes and blood clots in people with atrial fibrillation.

Click here to read the press release from J&J…

WARCEF: No Advantage For Warfarin Over Aspirin In Heart Failure 1

A new study offers “no compelling reason” to use warfarin instead of aspirin in heart failure patients who don’t have atrial fibrillation. In a paper published in the New England Journal of Medicine, Shunichi Homma and members of the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study group report the results of a trial in which 2,305 patients with left ventricular dysfunction were randomized to warfarin or placebo and followed for up to six years.

No significant differences were observed in the primary endpoint (the composite of death, ischemic stroke, or intracerebral hemorrhage) or its individual components. Warfarin was superior to aspirin in reducing the rate of ischemic stroke, but this advantage was offset by an increased incidence of major hemorrhage in the warfarin group.

  • Primary endpoint: 26.4% for warfarin versus 27.5% for aspirin, HR 0.93, CI 0.79-1.10
  • Ischemic stroke: 1.8% versus 3.5%, HR 0.55, CI 0.32-0.96)
  • Major hemorrhage: 5.8% versus 2.7%, OR2.21, CI 1.42-3.47

The authors concluded:

Given the finding that warfarin did not provide an overall benefit and was associated with an increased risk of bleeding, there is no compelling reason to use warfarin rather than aspirin in patients with a reduced LVEF who are in sinus rhythm.

In an accompanying editorial, John Eikelboom and Stuart Connolly agree with the study authors that there is no justification for the “routine clinical use of warfarin in most patients with heart failure” but write that warfarin is still “most likely to benefit” heart failure patients with atrial fibrillation or with a history of cardioembolic stroke or formation of LV thrombus. They leave open the possibility that warfarin may also benefit heart failure patients with underlying coronary artery disease, and recommend that future studies of anticoagulants in heart failure focus on this population.

FDA Grants Priority Review to Rivaroxaban (Xarelto) for ACS Patients Reply

The FDA has granted a priority review for the supplemental new drug application (sNDA) for rivaroxaban (Xarelto) in combination with standard therapy to reduce the risk of cardiovascular events in acute coronary syndrome (ACS) patients. The news was announced by Bayer and Johnson & Johnson. The FDA will now be required to respond within 6 months instead of 10 months to the December 29 submission of the sNDA.

The application is based upon the results of the ATLAS ACS 2-TIMI 51 study, which was the first trial to show a benefit in ACS with an anticoagulant. Previous trials testing anticoagulants in the setting of ACS had all failed. One key difference highlighted by many experts was the low doses of rivaroxaban used in the trial. The addition of 2.5 mg bid of rivaroxaban to standard therapy resulted in a significant reduction in the combined rate of cardiovascular death, MI, or stroke, as well as a significant reduction in death from cardiovascular causes (2.7% vs. 4.1%, p=0.002) and all-cause mortality (2.9% vs. 4.5%, p=0.002). The last two benefits were not found with the higher dose of rivaroxaban (5 mg bid) also studied in the trial. Rivaroxaban also caused significant increases in bleeding complications, but not fatal bleeding.

Priority reviews are granted to treatments that offer an advance in care or that provide a treatment where no adequate therapy exists, the company said.

Click here to read the press release from Bayer…

Study Explores Role of Periprocedural Dabigatran in AF Ablation 1

Updated with a comment from John Mandrola– As dabigatran becomes more widely used in atrial fibrillation (AF) patients, electrophysiologists are now trying to figure out how to handle anticoagulation in patients taking dabigatran (Pradaxa) for whom AF ablation is planned. In a new study published in the Journal of the American College of Cardiology, Dhanunjaya Lakkireddy and colleagues report on a multicenter, observational study of 290 patients who underwent an AF ablation procedure. Half the patients were taking periprocedural dabigatran and half were matched controls taking warfarin.

There were significantly more thromboembolic  and bleeding complications in the dabigatran group than in the warfarin group:
Click to continue reading…