Saying Sorry May Not Be Good Enough For Novartis Reply

Novartis has issued a formal apology over misconduct relating to valsartan (Diovan) research in Japan, but that apology does not appear likely to satisfy the Japanese Health, Labor and Welfare Ministry, which plans to fully investigate the company’s role in the scandal. If necessary, ministry officials are prepared to raid the company’s offices in Japan.

A Novartis official apologized to the Japanese public for the apparent manipulation of data. David Epstein, the head of the pharmaceutical division at Novartis, met with the Japanese health minister. “We express our deep regret for the concern that the issue has brought to patients, to the medical society as well as the ministry,” Epstein was quoted by Reuters after the meeting. He said the company was “willing to work with” Japanese investigators and will “take additional actions and potential sanctions in order to bring the issue to a good conclusion.”

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Increase In Deaths Linked To First Line Treatment With Sulfonylureas Reply

First-line treatment with sulfonylureas instead of metformin in people with type 2 diabetes is associated with a significantly elevated risk of death, according to results from an observational study presented at the European Association for the Study of Diabetes (EASD) meeting in Barcelona.

Although guidelines do not recommend the use of sulfonylureas for first-line treatment, the drugs are still commonly prescribed this way in many countries. CJ Currie, an epidemiologist at Cardiff University in the UK, said that 7% of diabetics in the United Kingdom receive first-line treatment with sulfonylureas. He presented data from the Clinical Practice Research Datalink (CPRD), which includes 10% of primary care patients in the United Kingdom. Between 2000 and 2012, 76,811 patients with type 2 diabetes began glucose-lowering treatment with metformin, while 15,687 began treatment with sulfonylureas (which include glipizide, glyburide, and glimepiride).

After adjusting for baseline differences, mortality was 58% higher in the sulfonylurea group….

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Study Raises Questions About Digoxin Use Today Reply

Digitalis is one of the oldest medicines in the cardiovascular arsenal. When William Withering identified digitalis as the active ingredient in the foxglove plant more than 200 years ago he was only codifying a longstanding folk remedy for heart failure, or “dropsy” as it was known then.

Digitalis fully entered the modern era with the publication of the DIG trial in 1997. The trial found that digitalis reduced hospitalization for heart failure but did not have an impact on mortality. On the basis of the trial digitalis received recommendations in the US and European guidelines for use in patients with systolic heart failure who remain symptomatic despite optimal therapy. However, the epidemiology and treatment of heart failure have evolved considerably since then. Now the authors of a new study, supported by an accompanying editorial, say that these recommendations need to be reconsidered.

In a study published in Circulation: Cardiovascular Quality and Outcomes, James Freeman and colleagues followed 2,891 patients with newly diagnosed systolic heart failure, 18% of whom received digitalis. After 2.5 years the digoxin users had a higher rate of death and hospitalization for heart failure…

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Using Registry Data, FDA Expands Indication For Edwards’ Sapien Transcatheter Heart Valves Reply

Relying on an important new source of information. the FDA said today that it had expanded the label for the Sapien Transcatheter Heart Valve (Edwards Lifesciences). Previously the Sapien was approved for insertion via the transfemoral or transapical access points in patients not eligible for traditional aortic valve surgery. The new labeling no longer mentions access points and therefore allows for alternative access points such as the subclavian.

The most significant part of the FDA’s announcement may be not the label change itself but the source of the data supporting the claim, the Transcatheter Valve Therapy Registry (TVTR). The TVTR, which is run by the American College of Cardiology and the Society of Thoracic Surgeons, has emerged as an model of cooperation between the FDA, industry, and medical organizations. The TVTR data, according to the FDA, showed no evidence that the access point changed the benefit-risk profile or the device.

Click here to read the full story on Forbes.

 

A Clear-Eyed View Of Statins And Cataracts 1

Past observational studies have turned up conflicting findings about the effects, if any, of statins on developing cataracts. Now a large new observational study finds a small but significant increase in cataracts in statin users, but experts warn that without further support the new finding should probably not influence clinical practice.

In a paper published in JAMA Ophthalmology, Jessica Leuschen and colleagues analyzed data from a military health care system. In their primary analysis they performed a propensity analysis comparing 6,972 propensity-matched pairs of statin users and nonusers. The authors reported a significant…

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Cataract in Human Eye
Cataract in Human Eye (Photo credit: Wikipedia)

 

Editor: “Close to 10% of the papers we receive show some sign of academic misconduct” Reply

Retraction Watch

elsevierThe latest issue of Elsevier’s Editors’ Update is part one of a two-part series on publishing ethics. It contains a bevy of articles on various issues that will be be familiar to Retraction Watch readers, from bias to research misconduct. (Not surprisingly, given the sheer number of journals they publish, Elsevier shows up regularly on Retraction Watch.)

In one of the pieces, Applied Surface Science editor in chief Henrik Rudolph pulls no punches:

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Both Overuse And Underuse Explain Disparities In Heart Procedures Reply

A new study finds that groups who have often been found to receive less medical care– non-whites, women, and people without private insurance or who are from urban and rural areas– are less likely to undergo coronary revascularization. But the same study finds that this disparity may be in no small part due to the fact that these same groups are less likely to receive inappropriate procedures. The study, published online in the  Journal of the American College of Cardiologysuggests, therefore, that the apparent underuse of healthcare in some groups may be partly counterbalanced by overuse in other groups.

In an interview with CardioExchange, Chan said that although “we have come a long way in ensuring that care is delivered equitably and thoughtfully in the US… there is no doubt that underuse in certain populations remains a persistent and huge problem. For policymakers… it highlights the importance of thinking about differences in treatment in a more complex way– as due to underuse and also potential overuse. Therefore, the goal may be to narrow the gap in vulnerable populations in instances where treatment has clearly established benefit rather than assuming that the measured difference is entirely due to a disparity in care.” Chan also said the paper was consistent with the hypothesis that patients for whom physicians are paid more are more likely to undergo inappropriate procedures.

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Younger Women With Acute Coronary Syndromes Less Likely To Have Classic Chest Pain Reply

Younger women with an acute coronary syndrome are slightly less likely than men to present with the classic symptom of chest pain, according to a new study published in JAMA Internal Medicine. In recent years there has been a growing understanding that women with ACS are less likely to have chest pain and, partly as a result, often fail to receive a correct diagnosis in the emergency department. However, there has only been limited data on whether this pattern is also true for younger women.

Nadia Khan and colleagues prospectively analyzed data from more than 1,000 ACS patients 55 years of age or younger– 30% of whom were women– participating in the GENESIS PRAXY study.  When compared with older cohorts in previous studies, patients in the study were more likely to have chest pain, but even in these younger patients women were less likely to have chest pain than men…

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No, Dean Ornish And Elizabeth Blackburn Have Not Discovered The Fountain Of Youth Reply

A very small pilot study offers early evidence that a program of comprehensive lifestyle changes increases telomere length. Telomeres, which have been compared to the plastic caps that prevent shoelaces from unravelling, help protect chromosomes. Telomere length is closely correlated to cellular aging: as we age the telomeres in our cells grow shorter. The new study, published online in Lancet Oncology, is one of the first studies to test whether the Nobel-prize winning research into telomeres has a role to play in assessing the health of humans in typical clinical situations.

The first author of the new paper is Dean Ornish, whose career has been devoted to demonstrating the benefits of a comprehensive lifestyle program consisting of radical changes in diet and exercise, accompanied by stress management and social support. The senior author of the paper is Elizabeth Blackburn, who won the Nobel Prize for her discovery of telomeres and their significance. In the paper Ornish and colleagues report on a long-term followup study in a small group of people with low-risk prostate cancer who agreed to follow Ornish’s rigorous program.

After 5 years telomere length increased in this group and decreased in a group of matched controls. Adherence to the lifestyle program varied among the participants, and some members of the control group made lifestyle changes on their own. The investigators reported that change in telomere length was significantly related to the degree of lifestyle change regardless of the study group. Further, as expected, telomere shortening was independently predicted by age, but the effect of the lifestyle program was independent of age and worked in the opposite direction.

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Dean Ornish

 

Colchicine Found Effective in Acute Pericarditis Reply

Although colchicine has been shown to be beneficial in patients with recurrent pericarditis, which is thought to have a large inflammatory component related to an immune response, until now its efficacy in a first episode of acute pericarditis has been uncertain, as these episodes are thought to usually have a viral component that might benefit from an inflammatory response.

In a study published in the New England Journal of Medicine, 240 patients with acute pericarditis and receiving conventional therapy with aspirin or ibuprofen were randomized to colchicine or placebo for 3 months. Colchicine was found effective in reducing the rate of incessant or recurrent pericarditis (the primary outcome of the trial), as well as symptom recurrence at 72 hours, the number of recurrences per patient, and the rate of hospitalization:

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The New England Journal of Medicine

 

Realistic Expectations For New ‘Breakthrough’ Blood Pressure Technology Reply

Early trials of renal denervation, the innovative new catheter-based blood pressure lowering technology,  have resulted in extremely impressive drops in systolic blood pressure in the range of 30 mm Hg. These results have sparked a great deal of excitement in the hypertension community and stirred the interest of a multitude of medical device companies. Some experts have proclaimed renal denervation a potential “cure” for resistant hypertension, perhaps enabling a significant number of patients to eliminate all drug therapy. Other expanded uses of the technology in more moderate forms of hypertension and other diseases are under active consideration. Now, however, a new analysis of the available data suggests the troubling possibility that renal denervation may not be nearly as effective in cutting blood pressure as had been suggested in the earlier trials. Rather than reducing systolic blood pressure by 30 mm hg, the new analysis suggests that a more realistic estimate of the effect of renal denervation may be a much more modest reduction of about 11 mm Hg.

A paper published online in Heart  demonstrates that the large reductions in blood pressure seen so far in clinical trials of renal denervation may be a consequence of certain key aspects in the design of these trials. The apparent blood pressure lowering effect of renal denervation has been greatly magnified because the trials have been uncontrolled, unblinded, and have utilized office-based blood pressure measurements rather than the far more reliable and consistent ambulatory blood pressure monitoring (ABPM).

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Clear! CPR in the Hospital Is Not Always Good for the Patient Reply

On TV it always seems clear and simple. A patient in the hospital goes into cardiac arrest and the medical team springs into action. After a few tense moments of furious activity, and only after all seems lost, the patient is successfully revived. A few scenes later the smiling and now fully healthy patient thanks the doctor and returns to his or her life as a professional athlete, parent of young children, or criminal mastermind.

Medical professionals know that in real life this is rarely the way it goes. Most patients who undergo cardiopulmonary resuscitation (CPR) are old, frail, and very sick. Many will die and many who survive CPR will die anyway before leaving the hospital. And many survivors will have severe neurological problems.

Now a physician states in JAMA Internal Medicine that hospitals need to change the way they view CPR.

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Lancet Formally Retracts Jikei Heart Study Of Valsartan Reply

The Lancet has formally retracted the Jikei Heart Study paper, originally published in 2007. The retraction had been widely anticipated for more than a month, after a series of news reports in Japan made it clear that the long-simmering controversy over scientific misconduct involving the Novartis blood pressure lowering drug valsartan (Diovan) had come to a full boil. (See our earlier story here.)

As reported previously, the current scandal first began to unfold in late 2011 when a Japanese blogger pointed to a number of apparent errors in publications authored by Hiroaki Matsubara. This ultimately led to a series of retractions of Matsubara’s papers and the retraction of the main paper of the Kyoto Heart Study itself by the European Heart Journal.

In the notice of retraction

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Too Much Emphasis on Door-to-Balloon Time? Reply

One of the great medical advances in recent years has been the improved treatment of acute myocardial infarction. As the enormous benefits of earlier reperfusion became evident, medical systems in many parts of the world aimed to treat increasing numbers of patients in a shorter time frame. The door-to-balloon (D2B) time as a performance measure has emerged as a key part of this initiative. Now a study published in the New England Journal of Medicine finds that in-hospital mortality for acute MI patients receiving PCI has not fallen despite improvements in the D2B time. But some experts fear this finding may be misinterpreted, as it more accurately reflects a growing and changing population receiving PCI than any shortcomings in the D2B initiative.

Using the CathPCI Registry of the National Cardiovascular Data Registry, Daniel Menees and colleagues analyzed data from almost 100,000 hospital admissions for primary PCI between July 2005 and June 2009.

Click here to read the full story on Forbes.

 

New Test Could Speed Heart Attack Treatment In The Emergency Department Reply

Only 1 in 10 patients with acute chest pain in the emergency department turn out to have an actual heart attack (myocardial infarction), yet many are not released from the hospital until after 6-12 hours of cardiac monitoring and multiple ECG and troponin tests. The search for a test that can rule out MI early in the process has proved elusive.

The Biomarkers in Cardiology-8 (BIC-8) trial, presented at the European Society of Cardiology meeting in Amsterdam, was designed to determine the utility of the combination of troponin and copeptin testing. Copeptin is a marker of severe hemodynamic stress. After an acute MI copeptin levels increase rapidly. In earlier observational studies the combination test was found to have a negative predictive value of 99%.

902 patients with suspected ACS who were troponin negative were randomized to standard treatment or an experimental strategy in which patients with a negative  copeptin test were discharged early. At 30 days there were no significant differences in the rate of major adverse cardiovascular events between the two groups:

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Speedy Tour de France Racers Slower To Die Reply

In recent years concerns have been raised about possible adverse cardiovascular effects of intense endurance exercise. Additional concerns have been  raised about sports where performance enhancing drugs are commonly used. However, a new study shows that despite these potential hazards, elite endurance athletes appear to live longer than their contemporaries.

 Xavier Jouven, a triathlete and a researcher at the Sudden Death Expertise Center in Paris, France, gathered mortality information from all 786 French participants in the Tour de France from 1947 through 2012 and compared them to people of the same age in the French general population. The study was presented at the European Society of Cardiology in Amsterdam and published simultaneously in the European Heart Journal.

By 2012, 208 of the French cyclists had died. They had a 41% reduction in mortality compared to their cohorts in the general population (standardized mortality ratio 0.59, CI 0.51-0.68, p<0.0001).

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"Get a bicycle. You will not regret it, if you live." --Mark Twain

“Get a bicycle. You will not regret it, if you live.” –Mark Twain

 

Study Fails To Support Broader Patient Population For Cardiac-Resynchronization Therapy Reply

Cardiac-resynchronization therapy (CRT) has been shown to be beneficial in heart failure (HF) patients with a wide QRS interval. These benefits have not been reproduced so far in patients with narrow QRS intervals, though many such patients have ventricular dyssynchrony. Now a new study, presented at the European Society of Cardiology in Amsterdam and published simultaneously in the New England Journal of Medicine, once again has failed to find benefits for CRT in a broader patient population.

The EchoCRT Study Group randomized HF patients with a QRS duration < 130 msec and left ventricular dyssnchrony upon echocardiography. All patients received a CRT-D device; half the patients were randomized to have the CRT feature activated.

The study was stopped prematurely after 809 patients had been randomized and followed for nearly 20 months.

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Automatic Wireless Monitoring Shows Benefits in Chronic Heart Failure Reply

Following in the wake of studies that failed to find benefits associated with remote wireless monitoring of heart failure (HF) patients, the In-Time trial, presented at the European Society of Cardiology meeting in Amsterdam, is the first trial to show that home monitoring of HF patients may be beneficial.

Gerhard Hindricks, the coordinating investigator of the trial, said that In-Time was designed to test whether automatic remote home monitoring can detect events that precede clinical events and thereby spark interventions to help reduce hospitalizations for HF. In the trial, 664 chronic HF patients with an indication for an ICD were randomized to home monitoring plus standard care or standard care alone.

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Cardiovascular Outcome Studies in Diabetes Drugs Finally Arrive Reply

For many years critics have bemoaned the absence of outcome studies for the many diabetes drugs used to lower blood glucose levels. Now, finally, two large trials with different drugs have been presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in The New England Journal of Medicine. The good news is that the drugs appear safe. Both trials turned up no evidence for the adverse cardiovascular events that some had feared. The bad news is that neither drug appeared to improve cardiovascular outcomes, though cardiovascular disease is the cause of death in most people with diabetes.

SAVOR-TIMI 53

A total of 16,492 people with type 2 diabetes at high risk for a cardiovascular event were studied in SAVOR-TIMI 53. Participants were randomized to the DPP-4 inhibitor saxagliptin (Onglyza, Bristol-Myers Squibb and AstraZeneca) or placebo.

Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE)

In the EXAMINE trial, 5,380 people with a recent acute coronary syndrome (ACS) were randomized to alogliptin (Nesina, Takeda Pharmaceuticals) or placebo.

These trials represent the first round of FDA-mandated cardiovascular outcomes trials for diabetes drugs, a major result of the rosiglitazone controversy. In an accompanying perspective in NEJM, William Hiatt, Sanjay Kaul, and Robert Smith, all members of the FDA advisory committees that debated the fate of rosiglitazone, discuss the complicated recent history of diabetes drugs at the FDA.

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Pretreatment with Prasugrel Not Indicated in NSTEMI Reply

Although current guidelines strongly recommend that dual antiplatelet therapy be administered early in treating patients with non-ST-segment-elevation acute myocardial infarction (NSTEMI), it is unclear whether pretreatment is beneficial,especially with the newer, more potent and more rapidly acting antiplatelet agents prasugrel (Effient, Lilly) and ticagrelor (Brilinta, AstraZeneca). Now a large new study, ACCOAST, presented at the European Society of Cardiology in Amsterdam and published simultaneously in the New England Journal of Medicine, offers strong evidence that pretreatment with prasugrel should not be performed in this situation.

Near the end of the enrollment period, the trial was stopped prematurely on the advice of the independent data and safety monitoring committee because of an increase in major and life-threatening bleeding, but no reduction in cardiovascular events, among patients in the pretreatment group.

A total of 4033 patients scheduled for coronary angiography were randomized to receive pretreatment with prasugrel or no prasugrel. There were no significant differences in the primary endpoint, (death from CV causes, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout at 7 days). However, TIMI major bleeding was significantly more common in the pretreatment group at 7 days. Similar findings were observed at 30 days.

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A Disruptive TASTE of the Future? Getting the Best of Randomized Trials AND Observational Studies Reply

A new study  from Scandanavia may influence the treatment of acute myocardial infarction. But it also may end up having a much bigger impact on the entire field of medicine by pointing the way to an entirely new way of performing randomized clinical trials rapidly and inexpensively. One expert said the trial design may represent “a new paradigm,” and for once the use of the p-word may actually be appropriate.

Thrombus aspiration for ST-segment elevation myocardial infarction (STEMI) has been kicking around for a long time, but its utility has never been definitively evaluated. The procedure uses a dedicated catheter to suck the clot out of the vessel prior to stent implantation. In an accompanying editorial, Robert Byrne and Adnan Kastrati write that thrombus extraction “is an intuitively attractive strategy and one that is simple to carry out.”

The  Scandanavian study has its origins in an earlier study, TAPAS, which found an unexpected benefit on mortality at one year for thrombus aspiration, though the trial was not designed to assess mortality. On the basis of TAPAS, thrombus aspiration was given a level IIA endorsement in both European and U.S. guidelines.

TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) was presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of MedicineThe investigator-initiated randomized trial was performed as part of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which in this case included 1 center each in Iceland and Denmark. After obtaining consent, patients were randomized through “an online randomization module within the SCAAR database.”

A total of 7244 STEMI patients were randomized, representing a striking 60% of all STEMI patients referred for PCI in Sweden and Iceland during the study period. All-cause mortality at 30 days was not significantly different between the two groups:

  • 2.8% in the thrombus aspiration group versus 3% of the PCI-only group (hazard ratio 0.94, CI 0.72-1.22, p=0.63)

A similar result was observed in the per-protocol analysis.

There were no significant differences in the rate of rehospitalization due to reinfarction, stent thrombosis, target-lesion revascularization, target-vessel revascularization, neurological complications, or other clinical outcomes, though there were trends in favor of thrombus aspiration in hospitalization for MI and stent thrombosis. The results were consistent across all major subgroups.

In their editorial, Byrne and Kastrati hold out hope that thrombus aspiration may turn out to be beneficial. They predict that “many interventional cardiologists will continue to perform thrombus aspiration for now,” based on hints of efficacy and the lack of any safety issues found in the trial.

Furthermore, they write, 30-day followup may not be long enough to detect a benefit, since the benefit in the TAPAS trial only emerged at 1 year. They urge the TASTE investigators to report the 12-month findings of their trial, and note that another large-scale randomized trial is nearing completion. “For now,” however, “the hope that this simple, easy-to-use, intuitively attractive technology could save the lives of patients presenting with myocardial infarction remains an unmet aspiration.”

A New Paradigm?

But the sweetest part of TASTE may be that the investigators were able to conduct a rapid and low-cost trial utilizing a new model, “a registry-based randomized clinical trial,” by incorporating the trial within the already existing framework of SCAAR: “The data were monitored and adjudicated as part of the regular registry validation; we did not perform separate, dedicated monitoring and adjudication of the data for the TASTE trial.”

In an accompanying Perspective, Michael Lauer and Ralph D’Agostino, Sr. ask whether randomized registry trials may be “the next disruptive technology in clinical research.” Current trials are expensive and “too complex and difficult to apply.” The usual alternative, traditional observational studies utilizing registries, “lack the rigor of randomization.”

TASTE, they write, represents “a new paradigm… that can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate.”

“The TASTE investigators designed a large-scale trial to answer an important clinical question and carried it out at remarkably low cost by building on the platform of an already-existing high-quality observational registry. With this clever design, which leveraged clinical information that was already being gathered for the registry and for other preexisting databases, the investigators were able to quickly identify potential participants, to enroll thousands of patients in little time…, to avoid filling out long case-report forms, to obtain accurate follow-up with minimal effort, and to report their findings, all for less than the amount of a typical modular R01 grant…”

friet

Disappointing Results with Dabigatran for Mechanical Valves 1

Despite being more durable than bioprosthetic valves, mechanical heart valves are often not chosen because of the requirement for lifelong anticoagulant therapy. It has been hoped that the newer generation of oral anticoagulants might eventually replace warfarin, making anticoagulation more tolerable and better accepted, since these agents don’t require continuous monitoring and have much fewer serious interactions with other drugs and food. So far, however, there has been no convincing demonstration that the the newer agents are as safe and effective as warfarin for this indication.

RE-ALIGN was a phase 2 dose-validation study of dabigatran in patients with mechanical heart valves. Results of the trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine.  Patients in the trial were randomized to dabigatran or warfarin.

After 252 patients had been randomized, the trial was stopped early due to an increase in thromboembolic and bleeding events in the dabigatran group:

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Positive Results for New Anticoagulant From Daiichi Sankyo Reply

A new entrant in the growing oral anticoagulant field shows promise for the treatment of venous thromboembolism (VTE) and pulmonary embolism (PE). The drug, edoxaban, is a new, once-daily Factor Xa inhibitor with a rapid onset of action that is under development by Daiichi Sankyo. Results of the Hokusai-VTE trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine.

The Hokusai-VTE investigators randomized 4921 patients with VTE and 3319 patients with PE to either warfarin or edoxaban. The trial differed from some earlier trials with new oral anticoagulants in that patients were treated following a lead-in period with heparin. In addition, patients were treated for as short as three months or as long as a year at the discretion of the physician, though patients were followed for a full year. Patients with low body weight or renal impairment received a half dose of edoxaban. The investigators said the design was intended to reflect the full spectrum of conditions clinicians see in real life.

Click here to read the full story on Forbes.