Physicians Report Alarming Increase In LVAD Pump Thrombosis Reply

Physicians from three top institutions report an abrupt and highly troubling increase over the last two years in the incidence of pump thrombosis in patients who have received the HeartMate II left ventricular assist device (LVAD) manufactured by Thoractec.

The current investigation, published online in the New England Journal of Medicine, was initially prompted by an observed increase in pump thrombosis at the Cleveland Clinic. This first led to an analysis performed by INTERMACS (the Interagency Registry for Mechanically Assisted Circulatory Support) which found an increase from 2% before May 2011 to 5% afterwards. But, write the NEJM authors, there is reason to believe the INTERMACS analysis may have underestimated the rate of pump thrombosis. (The INTERMACS data, along with other papers about the problem, have been published in a special issue of the Journal of Heart and Lung Transplantation.)

The new paper is based on pooled data from 895 patient who received the HeartMate II LVAD at the Cleveland Clinic,  Barnes-Jewish Hospital, and the Duke University Medical Center . The authors report that after March 2011 the incidence of confirmed pump thrombosis within three months of implantation increased from 2.2% to 8.4% by January 2013.

Click here to read the full story on Forbes.

HeartMate II

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New Anticoagulant From Daiichi Sankyo Works Well In AF Patients Reply

Edoxaban, a direct oral factor Xa inhibitor under development by Daiichi Sankyo, is the latest in the series of new oral anticoagulants seeking to take over the troubled role of warfarin in clinical practice. The results of ENGAGE-AF-TIMI 48 were presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicine. The results of the trial were promising, but edoxaban may have a hard time finding its footing as the fourth new oral anticoagulant to enter the market, following dabigatran (Pradaxa), Boehringer Ingelheim; rivaroxaban (Xarelto), Johnson & Johnson; and apixaban (Eliquis), Pfizer and Bristol-Myers Squibb.

In the trial, more than 21,000 patients with moderate-to-high-risk AF were randomized to one of two regimens of edoxaban or warfarin. Both high-dose and low-dose edoxaban were found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Here are the on-treatment annual rates of stroke or systemic embolism:

Click here to read the full post on Forbes.

 

No Value For Renal-Artery Stenting In CORAL Reply

Previous small studies have failed to find any benefit associated with renal-artery stenting, but the trials have been small and were not powered for clinical outcomes. Now, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial, presented at the American Heart Association meeting and published simultaneously in the New England Journal of Medicine, offers strong and persuasive evidence that renal-artery stenting is not beneficial.

A total of 947 patients with renal-artery stenosis and either systolic hypertension, despite taking two or more antihypertensive agents, or chronic kidney disease were randomized to medical therapy plus stenting or medical therapy alone. There were no significant differences after 43 months in the primary composite endpoint of cardiovascular and renal events (death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy):

Click here to read the full post on Forbes.

 

New Drug For Pulmonary Hypertension Approved By FDA Reply

The FDA today approved a new drug for pulmonary hypertension. Bayer HealthCare’s riociguat (brand name Adempas) was approved for 2 indications:

  1. The treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO* Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class
  2. The treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and delay clinical worsening.

Click here to read the full story on Forbes.

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.

 

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.

Click here to read the full story on Forbes.

 

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:

Click here to read the full post on Forbes.

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.

 

 

New Actelion Drug Found Safe And Effective In Pulmonary Arterial Hypertension– But Does It Save Lives? Reply

Macitentan, a new drug for pulmonary arterial hypertension (PAH), appears to be safe and effective, but it is unclear whether it offers any significant advantages over currently available drugs.  The drug, a dual endothelin-receptor antagonist, is under development from Actelion as an enhanced version of bosentan (Tracleer). The results of a phase 3 trial, SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), have now been published in the New England Journal of Medicine.

In the trial, 742 patients with PAH were randomized to one of three groups: a daily dose of 3 mg of macitentan, a daily dose of 10 mg of macitentan, or placebo. The primary endpoint (the time to the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension) was significantly reduced in the two treatment arms:

Click here to read the full post on Forbes.

Actelion

New Anticoagulant Found Safe And Effective In Acute Venous Thromboembolism 1

In a large clinical trial the new oral anticoagulant apixaban (Eliquis, Pfizer and Bristol-Myers Squibb) was at least as effective as standard therapy and caused fewer bleeding complications in patients with acute venous thromboembolism. The results of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) trial are being presented on Monday at the annual meeting of the International Society on Thrombosis and Haemostasis in Amsterdam and are being published in the New England Journal of Medicine. (The embargo on the trial was lifted early by the Journal after being broken by Reuters.)

Click here to read the full story on Forbes.

 

 

BLOCK HF: CRT Superior To Conventional Pacing In Heart Failure Patients With AV Block Reply

 

Patients with atrioventricular (AV) block generally receive right ventricular pacing; cardiac resynchronization therapy (CRT) has been restricted to patients with a low ejection fraction and a wide QRS duration. However, RV pacing may worsen LV dysfunction in AV block patients with low ejection fractions. Previous studies have raised the possibility that these patients may benefit from biventricular pacing with a CRT device.

Now, results from the Medtronic-sponsored BLOCK HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) trial, published in the New England Journal of Medicine, lend more support for the expansion of CRT devices into this population. Anne Curtis and colleagues randomized 691 patients to standard RV pacing or  biventricular pacing. After 37 months of followup, a primary outcome event– death, urgent care visit for heart failure that required intravenous therapy, or a 15% or more increase in the LV end-systolic volume index– occurred in 55.6% of the RV pacing group versus 45.8% in the biventricular pacing group (HR 0.74, CI 0.60-0.90).

Click here to read the full post on Forbes.

 

Anne Curtis

 

 

 

 

FDA Officials Calm Concerns Over Excessive Bleeding With Dabigatran 1

Concerns over excessive bleeding complications with dabigatran (Pradaxa, Boehringer Ingelheim) as compared with warfarin are most likely due to the heightened sensitivity and vigilance that can accompany a new drug, according to FDA officials in a perspective published online in the New England Journal of Medicine.

“We believe that the large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting,” write Mary Ross Southworth, Marsha Reichman, and Ellis Unger. “In this case, such reporting provided a distorted estimate of the comparative bleeding rates associated with dabigatran and warfarin in clinical practice.”

Click here to read the full story on Forbes.

 

Another Negative Trial With Darbepoetin Alfa 1

Once again a trial testing the erythropoiesis-stimulating agent darbepoetin alfa (Aranesp, Amgen) has produced a negative result. Results of the RED-HF (Reduction of Events by Darbepoetin Alfa in Heart Failure) trial were presented at the ACC in San Francisco and published simultaneously in the New England Journal of Medicine.

A total of 2278 patients with systolic heart failure and mild-to-moderate anemia were randomized to darbepoetin alfa (Aranesp, Amgen) or placebo. As expected, treatment with darbepoetin alfa significantly improved hemoglobin levels. However, no significant improvements in outcomes were associated with darbepoetin alfa.

Click here to read the full 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

 

 

 

‘Somebody has finally twigged that the heart and the lungs are joined up to each other and live in this space called the chest…’ 1

Here are a few gems from Richard Lehman’s weekly cardiovascular literature review. Read the whole thing on CardioExchange.

On a JAMA study showing that ramipril increases walking time in patients with intermittent claudication:

This is the kind of trial that makes nobody millions of dollars, but which we should all be doing in our fields of interest. It took just three interested hospitals in Southern Australia.

On a NEJM study studying rivaroxaban in acutely ill medical patients:

Rule One for selling reprints is that you make the conclusion of the Abstract as favourable as possible, because this is all that most clinicians read…

On Lancet study showing a close association between pneumonia and cardiovascular disease:

Golly, somebody has finally twigged that the heart and the lungs are joined up to each other and live in this space called the chest, or thorax. This could have major implications. We could start thinking of providing services for elderly breathless patients rather than making them wander from chest physicians to cardiologists and back again: we could tackle the problem of the post-hospital syndrome by attending to the cardiovascular risks of chest infections and the right ventricular contribution to heart failure; we could even ask patients what their main problems are and whether they are sufficiently addressed to make them feel safe at home. But all this requires a level of genius far beyond the reach of any known health service.

 

 

YouTube, NEJM, Whitney Houston, and Alpha Male Monkeys 3

Take a close look at this screenshot from YouTube (click to expand):

  • Jim Ware, the legendary New England Journal of Medicine biostatistician: 8 views.
  • Jerome Kassirer, Marcia Angell, and Arnold Relman, former NEJM editors: 36, 28, and 257 views.
  • Whitney Elizabeth Houston Funeral Service: 994,920 views. (And how many more Whitney Houston videos do you think are out there?)
  • Alpha Male Monkey attacks man: 2,135,280 views.

Draw your own conclusions. Here’s just one from me: we need to figure out how we can use social media better than we do now.

Guest Post: More Lessons From the Riata ICD Lead Recall 7

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH. This post is longer and far more technical than most of the content published on CardioBrief. Due to the extraordinary nature of the material, however, I believe this post will likely be of considerable interest to many cardiovascular healthcare professionals.

More Lessons From the Riata ICD Lead Recall

by Edward J. Schloss, MD

In an earlier guest post (What are the Lessons of the Riata ICD Lead Recall?) I summarized points from Robert Hauser’s  important perspective in the New England Journal of Medicine regarding the St. Jude Riata ICD lead recall. In this followup, I’d like to discuss St. Jude’s responses to this piece and place the arguments into a broader context.

Last week Mark Carlson MD, Chief Medical Officer of St. Jude Medical, posted a response to Hauser’s perspective, and he made similar points in a letter subsequently published in NEJM. In the original response, Carlson writes “we believe that there were inaccuracies and omissions in the editorial that are important to recognize in order to more fully understand this issue.”

Major points of disagreement in the two pieces include:

  1. Timing of the initiation of a prospective trial looking at Riata externalizations and failures.
  2. Similarities and differences between the currently marketed Durata lead and it’s recalled predecessor Riata ST.
  3. Robustness of the existing St. Jude lead surveillance systems.

Having looked at this issue in some depth, I feel it would be reasonable for me to weigh in on these matters.

Regarding the timing of the recent trial, Dr. Carlson writes:
Click to continue reading…

ASSERT Sheds Light on the Role of Subclinical AF in Stroke Reply

A new study published in the New England Journal of Medicine sheds some much-needed light on the precise role of subclinical atrial fibrillation (AF) in the prognosis and development of ischemic stroke. ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) followed 2580 patients with a newly implanted pacemaker or ICD and with no previous diagnosis of AF.

At 3 months, subclinical AF lasting longer than 6 minutes had been detected in 10.1% (261) of the subjects. During 2.5 years of follow-up, 51 patients in the study had an ischemic stroke or systemic embolism. Of these, 11 were in the group with subclinical AF by 3 months. Patients with subclinical AF had more than double the risk for stroke or systemic embolism:
Click to continue reading…

No Mortality Benefit Found For Low-Molecular-Weight Heparin in Acutely Ill Patients Reply

Although venous thromboembolism (VTE) is a serious problem for acutely ill patients in the hospital, a new study published in the New England Journal of Medicine failed to find any improvement in mortality associated with thromboprophylaxis.

Ajay Kakkar and the LIFENOX investigators randomized 8307 acutely ill patients to enoxaparin or placebo for 10 days. All patients wore elastic stockings with graduated compression.

There was no difference in 30 day mortality or major bleeding between the groups:
Click to continue reading…