Guest Post: Lessons from the Riata Recall– Part III 1

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.

Lessons from the Riata Recall– Part III

by Edward J Schloss MD

In two earlier posts on Cardiobrief (here and here), I have written in some detail about the St. Jude Riata/Riata ST lead recalls.  In these pieces, I’ve summarized what we know about the design of these leads and their clinical performance. Ultimately I hope this updated information allows clinicians and other interested parties to make intelligent decisions regarding lead follow up and new lead model selection.

This week we’ve seen new important information that sheds additional light on the performance of Riata and Riata ST. As is often the case, new information leads to both new answers and new questions.

Accepted for publication in Heart Rhythm are two new manuscripts that reference these leads.  From frequent contributor Robert Hauser and his group at Minneapolis Heart Institute Foundation comes this review of ICD lead related deaths from the FDA MAUDE database.  Also accepted for publication is a prospective series of Riata and Riata ST leads that underwent fluoroscopic and electrical evaluation from Parvathaneni et al at Vanderbilt.

Hauser’s study has been previously reported on this site (20 Deaths Linked to New Problem with Riata Leads).  It is notable for being one of the first Riata studies focusing on electrical, rather than structural failures.  In the study, 22 (since corrected to 20 by St. Jude review) deaths discovered in the voluntary FDA MAUDE database were linked to failure of the Riata or Riata ST lead.  Interestingly, nearly all deaths appear to be due to failure of the high voltage portion of the lead, and most were directly linked to insulation abrasion.  This is a failure mechanism not commonly seen with other ICD leads, as noted in the article’s comparison to Medtronic Quattro Secure leads (in which failure of the low voltage conductors is the dominant mechanism).  Hauser estimated that failure of the St. Jude leads had an incidence “about 9 times greater than Quattro.”

Close reading of the Hauser data raises some interesting and, at times, troubling points:
Click to continue reading…

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Proof-of-Concept for Bedside Rapid Genotyping Test of CYP2C19 1

A new point-of-care test can rapidly identify people with a common genetic variant associated with impaired clopidogrel function. The authors claim that this is the first study to demonstrate the feasibility of delivering a genetic test at bedside.

In an article published online in the Lancet, Jason Roberts and colleagues report on a new point-of-care test that can identify people who have a common variant of the CYP2c19 gene associated with reduced clopidogrel effectiveness. In their “proof-of-concept” study, 200 patients undergoing PCI were randomized to standard therapy with clopidogrel or to the new test. Patients found to have the CYP2C19*2 allele received prasugrel instead of clopidogrel.

Each group had 23 patients who carried at least one CYP2C19*2 allele. Among these patients, no patients in the test group, and 7 patients (30%) in the control group, were found to have high on-treatment platelet reactivity (PRU) after 1 week of treatment. At 7 and 30 days, there were no ischemic events in either group and no significant differences in major or minor bleeding.

The investigators write that their study “confirms the potential clinical benefits associated with a personalised approach to antiplatelet treatment with selective use of P2Y12 inhibitors in patients at increased risk of adverse events with clopidogrel,” but they also noted that the “major limitation” of their study “was use of a surrogate endpoint to assess clinical efficacy.”

In an accompanying comment, Amber L Beitelshees notes that “.”many clinicians do not know what action to take, if any” until the completion of large trials that are in progress. Earlier studies testing the platelet hypothesis may have failed, she says, because new evidence suggests that benefits of genotyping or platelet function tests may be confined to the PCI population. The new rapid genotyping test will make it easier “for incorporation into clinical care in the catheterisation laboratory.”
Click here to read the Lancet press release…

20 Deaths Linked to New Problem with Riata Leads 1

Electrical malfunctions, not externalized conductors, may be the cause of 20 or more deaths associated with the troubled Riata ICD leads from St. Jude Medical, according to a new report published online in Heart Rhythm.

Robert Hauser and colleagues at the Minneapolis Heart Institute searched the FDA’s MAUDE database and found 22 deaths caused by Riata or Riata ST lead failure. By contrast, only five deaths were caused by failure of the more widely implanted Quattro Secure lead. The authors reported that the Riata deaths “were typically caused by short-circuits between high voltage components. No death was due to externalized conductors.” As reported previously on CardioBrief, Hauser has played an important role in gathering and disseminating information about ongoing concerns about the Riata leads.

“The deaths are rare, but more frequent than you would expect. It’s another example of our flawed regulatory system,” Hauser told the Wall Street Journal. St. Jude told the Wall Street Journal that Hauser’s article contained several errors. Two deaths were counted twice, reducing the total number of lead-related deaths to 20, according to the company. In addition, St. Jude’s chief medical officer, Mark Carlson, said that some of the deaths were “from well-known causes, including wires that were coiled during surgery and ended up rubbing against the defibrillator.”

ASCERT Observational Study Finds Long Term Advantage for CABG Over PCI in High Risk Cases Reply

A very large observational study finds that long-term mortality in high risk patients is lower after bypass surgery than after PCI. The results, which were previously revealed in January at the annual meeting of the Society of Thoracic Surgeons (STS), were presented in final form at the American College of Cardiology by William Weintraub and published simultaneously in the New England Journal of Medicine.

ASCERT (ACCF-STS Database Collaboration on the Comparative Effectiveness of Revascularization Strategies) is an NHLBI-funded study based on linked data from the STS, the ACC, and CMS administrative data. The study population included patients 65 or older with 2 or 3 vessel disease who underwent CABG or PCI in the period from 2004 through 2007. 189,793 patients were followed in the study; 103,549 received PCI and 86,244 underwent CABG. Median followup was 2.67 years.

1 year adjusted mortality:

  • 6.2% for CABG versus 6.55% for PCI (RR 0.95, CI 0.90-1.00)

4 year adjusted mortality:

  • 16.4% versus 20.8% (RR 0.79, CI 0.76-0.82)

The findings, the authors said, were consistent with data from both previous observational and randomized trials. But, they acknowledged, “the potential remains for unmeasured confounders to have influenced the findings.”

In an accompanying editorial, Laura Mauri writes that “it is plausible that, in patients with diffuse atherosclerosis, CABG reduces the risk of fatal myocardial infarction more effectively than does focal treatment.” But she expressed skepticism that CABG could be shown to be better in two-vessel disease or in patients with three-vessel disease with focal lesions. ASCERT also does not reflect either the recent advances in PCI technology or the “modern PCI strategies” which reserve PCI for ischemic lesions, she writes.

Observational studies can provide valuable information “but there is no substitution for randomized trials to eliminate selection bias between treatments.” Mauri concludes: “we must … continue to give priority to randomized trials on the most salient questions regarding treatment strategy.”

What To Do When Federal Investigators Knock On The Door 2

For more than a year now the federal investigation of hospitals suspected of improperly implanting ICDs has been the subject of considerable rumor and speculation. Now, two cardiologists who were involved in a federal audit at one hospital have published a detailed account of their experience.

Jonathan Steinberg and Suneet Mittal are Columbia University-affiliated electrophysiologists who also direct the EP program at a large suburban nonteaching hospital. In a special article published in the Journal of the American College of Cardiology, the two authors describe the audit process and subsequent events in the hope that their experience “might provide valuable lessons” to others involved in similar cases.

The initial government analysis had found that 229 cases, representing 8.7% of all de novo ICD implants for primary prevention between 2003 and 2010, did not warrant coverage. Following a more detailed review of the medical records, the authors report that a much smaller number of cases, 34, representing 1.3% of all implants, were truly not indicated. These cases mostly occurred after bypass surgery in the setting of non sustained VT and/or a positive EP study, according to the authors. By contrast, a small number of cases had a clear secondary prevention indication, but the records for the earlier cardiac arrest or VT event were at another hospital.

Most of the cases were somewhat more ambiguous. Steinberg and Mittal list five common types of cases which were difficult to categorize and which “highlighted the complexity of adjudicating between clinical practice and the contemporary regulatory environment.”
Click to continue reading…

Bariatric Surgery Turns Back the Clock on Diabetes 2

Two new randomized trials offer new evidence that bariatric surgery is highly effective in obese patients with diabetes. The results, according to Paul Zimmet and K. George M.M. Alberti, writing in an editorial in the New England Journal of Medicine, “are likely to have a major effect on future diabetes treatment.”

In the STAMPEDE trial, which was presented at the American College of Cardiology and published simultaneously in the New England Journal of Medicine,  150 obese patients with uncontrolled type 2 diabetes were randomized to medical therapy alone or medical therapy plus either Roux-en-Y gastric bypass or sleeve gastrectomy. Philip Schauer presented the main results.

Percent of patients with glycated hemoglobin level of 6% or less at 1 year:
Click to continue reading…

PARTNER: TAVR Results Appear Durable at Two Years Reply

Two year results of the influential PARTNER trial provide continued support for the growing acceptance of transcatheter aortic valve replacement (TAVR) in clinical practice. Previously, results of PARTNER at one year had demonstrated a similar mortality in high risk patients with aortic stenosis who received TAVR and surgery. The two year results were presented at the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Two year mortality:

  • ITT analysis: 33.9% in the TAVR group versus 35% in the AVR group (HR 0.90, CI 0.71-1.1, p=0.78)

Stroke at 2 years:

  • 7.7% versus 4.9% (HR 1.22, CI 0.67-2.23, p=0.517)

All cause mortality or stroke at 2 years:

  • 37.1% versus 36.4% (HR 0.96, CI 0.76-1.21, p=0.700)

The PARTNER investigators reported that the valve gradients and areas were similar between TAVR and AVR at two years and that they had found no evidence of structural valve deterioration. However, peri-procedural aortic regurgitation was a highly significant predictor of late mortality (p<0.0001).

“We’re most concerned about valve durability, which you have to look at over five to 10 years, but any longer-term information is useful because trends tend to hold true over time,” said Susheel Kodali, who presented the results, in an ACC press release. “We have no evidence that the initial good results in improved valve performance have deteriorated during the follow-up to this time point. TAVR appears to be as durable as AVR.”

“During this follow-up, we observed that significant leakiness around the valve was associated with higher subsequent mortality in TAVR patients, but it’s important to note that overall mortality between the two groups is the same,” he said. “Now we have a target – we know what to fix in the future. TAVR is already comparable to results for AVR in the most experienced surgeons’ hands. If we can reduce these leaks, there’s a good chance we can reduce mortality with TAVR even more.”

The PARTNER investigators concluded that the study “supports the use of TAVR as an alternative to surgery in selected high-risk patients with aortic stenosis.”
Click here to read the press release from the ACC…

Rivaroxaban Found Safe and Effective for Pulmonary Embolism Reply

In recent years rivaroxaban has been found to be effective in the prevention of venous thromboembolism (VTE) after orthopedic surgery, for the prevention of stroke in AF patients, and as additional therapy to conventional antiplatelet therapy in ACS patients. Now, a study presented at the American College of Cardiology meeting in Chicago and published simultaneously in the New England Journal of Medicine offers strong evidence that rivaroxaban is equally effective as standard therapy for the treatment of pulmonary embolism and may cause fewer bleeding complications.

EINSTEIN-PE was a randomized, open-label, non-inferiority study comparing rivaroxaban to conventional therapy with enoxaparin and a vitamin K antagonist in 4,833 patients with pulmonary embolism. Rivaroxaban met the predefined margin for noninferiority to conventional treatment with respect to both clinical efficacy and safety.

Primary efficacy endpoint (first symptomatic recurrent VTE):

  • 2.1%  for rivaroxaban patients versus 1.8% for standard therapy (HR 1.12, CI 0.75-1.68, p=0.0026 for noninferiority)

Principal safety outcome (major or clinically relevant bleeding):

  • 10.3% versus 11.4% (HR 0.90, CI 0.76-1.07, p=0.23 for noninferiority)

Major bleeding was significantly lower in the rivaroxaban group:

  •  1.1% versus 2.2% (HR 0.49, p=0.0032)

Net clinical benefit (VTE plus major bleeding):

  • 3.4% versus 4% (HR 0.85, CI 0.63-1.14, p=0.28)

“Physicians want to know about major bleeding, the most important safety outcome, and rivaroxaban was highly significantly superior. This was our most astonishing finding,” said EINSTEIN chair Harry Buller in an ACC press release. “Rivaroxaban is just as good as standard treatment for PE – these data are pretty convincing – and this is an oral-only approach, which makes it very simple. The subcutaneous injections can be hazardous as well.”

The EINSTEIN investigators concluded that, in conjunction with the earlier EINSTEIN trial in DVT, the EINSTEIN PE trial supports “the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.”
Click here to read the press release from the ACC…

Study Supports CT Angiography to Rule Out CAD in Chest-Pain Patients Reply

Six million people each year in the US go to the emergency department (ED) with acute chest pain. Although only 10-15% of them turn out to have an acute coronary syndrome (ACS), most are admitted to the hospital. Coronary CT angiography (CCTA) has been proposed as a good method to quickly establish the presence or absence of coronary disease and  allow many of these patients to return home sooner.

In a presentation at the ACC and in a simultaneous publication in the New England Journal of Medicine, the ACRIN (American College of Radiology Imaging Network) investigators report the findings of ACRIN PA 4005, the largest trial to date of the strategy to use coronary CT angiography to allow more rapid rule out of coronary disease in patients with possible acute coronary syndrome, in which 1,370 patients with chest pain were randomized on a 2:1 basis to either CCTA or conventional treatment.

The primary outcome was the safety at 30 days of patients with a negative CCTA. Among the 640 patients who had a negative CCTA examination, there were no MIs or cardiac deaths at 30 days.

The investigators also observed that, compared with controls, patients in the CCTA group were more likely to be discharged from the emergency department (49.6% versus 22.7%) and to have a shorter length of stay (18 hours versus 24.8 hours). Coronary disease was also more likely to be detected in the CCTA group (9% versus 3.5%).

Utilization of healthcare resources was similar in both groups. The major drawback to CCTA is radiation, but ACRIN investigator Harold Litt pointed out that the radiation dose received by patients for CCTA is now lower than the dose received during nuclear imaging studies.

“We believe that a CCTA-based strategy can safely and efficiently redirect many patients home who would otherwise be admitted,” the authors concluded.

Study Supports PCI Without Onsite Surgical Backup Reply

Here’s a great example of genuine medical progress: 10% of the first 50 patients who received balloon angioplasty from the developer of the procedure, Andreas Grüntzig, required emergency bypass surgery. By 2002 only 0.15% of PCI patients required emergency surgery, leading many to believe that surgical backup was no longer necessary.

Now a large new study provides strong evidence that PCI can in fact be performed safely and effectively at hospitals without surgical backup. In a presentation at the American College of Cardiology and published simultaneously in the New England Journal of Medicine. Thomas Aversano and colleagues in the Cardiovascular Patient Outcomes Research Team (C-PORT) report  the results of a trial that randomized 18,867 patients to undergo PCI at hospitals with or without surgical backup.

  • 6 week mortality was 0.9% at hospitals without surgical backup versus 1% at hospitals with surgical backup, which was well within the predefined margin of noninferiority of a 0.4% difference in risk (p=0.004).
  • The 9-month composite rate of death, Q-wave MI, or target-vessel revascularization was 12.1% and 11.2%, which met the predefined margin of noninferiority of a 1.8% difference in risk (p=0.05).

The authors noted that high risk patients were excluded from the study, raising the possibility that the study population may differ from the general PCI population.

“The study shows that under certain circumstances, non-primary angioplasty can be performed safely and effectively at hospitals without on-site cardiac surgery,” said Aversano, in an ACC press release.

At an ACC press conference, Aversano discussed the potential impact of the study and warned against interpreting the study as an open invitation to implement PCI without surgical backup:

It doesn’t say you ought to go out and do this and expand it willy nilly, that was not the purpose of this project… These hospitals did not simply buy stents and start doing angioplasty. They went through a formal development program.

 

Eric Peterson to Succeed Bob Harrington as Director of the Duke Clinical Research Institute Reply

The Duke Clinical Research Institute has announced that its new director will be Eric Peterson. The DCRI was founded by Robert Califf, who, as the director of the Duke Translational Medicine Institute (DTMI), will be Peterson’s boss. The DCRI’s second director, Robert Harrington, announced earlier this year that he was leaving Duke to become the chairman of the department of medicine at Stanford.

“Dr. Peterson’s accomplishments in clinical research and quality improvement over the past 20 years have prepared him well for this new responsibility,” said Califf, in the DCRI announcement. “Eric has demonstrated a special ability to expand the reach of the DCRI into areas of outcomes, comparative effectiveness, and implementation that perfectly complement the clinical trials focus of the past few decades, and he has done so by creating local, national, and international collaborations.”
Click to continue reading…

Novel Antiplatelet Agent Reduces CV Events But Increases Bleeding 1

Vorapaxar, the novel antiplatelet agent from Merck, appears to effectively reduce cardiovascular death and ischemic events in patients with MI, ischemic stroke, or peripheral vascular disease, but its potential utility is clouded by bleeding complications, including intracranial hemorrhage. Results from the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial were presented in Chicago on Saturday at the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Results of TRA 2P-TIMI 50 were broadly consistent with the TRACER trial (published last November in the New England Journal of Medicine), which tested the same drug in patients with acute coronary syndromes. In that trial also, vorapaxar effectively reduced negative outcomes but at the cost of an increase in serious bleeding complications. Earlier optimism over the drug had been greatly reduced in January 2011 when the combined data and safety monitoring board (DSMB) of the two trials stopped the TRACER trial and curtailed the TRA 2P-TIMI 50 trial.

TRA 2P-TIMI 50 randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy. Because of an increased risk of intracranial hemorrhage in patients with a history of stroke, at 2 years the DSMB stopped treatment with vorapaxar in patients with a history of stroke.

At 3 years the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but there were also more bleeding events associated with the drug:

CV death, MI, or stroke: 9.3% in the vorapaxar group versus 10.5% in the placebo group (HR 0.87, CI 0.80-0.94, p<0.001)

  • CV death: 2.7% versus 3.0% (HR 0.89, p=0.15)
  • MI: 5.2% versus 6.1% (HR 0.83, p=0.001)
  • Stroke: 2.8% in both groups

Moderate or severe bleeding: 4.2% versus 2.5% (HR 1.66, p<0.001)

  • Intracranial bleeding: 1% versus 0.5% (HR 1.94, p<0.001)

The TIMI investigators reported that in the subgroup of patients with a qualifying diagnosis of MI vorapaxar caused a 20% reduction in the primary endpoint. In light of the heightened risk for stroke patients, the investigators also performed a separate analysis of patients without a history of stroke and found “a significant benefit” in this group.

In an ACC press release, lead investigator David Morrow said: “In the lab, we have seen very compelling science showing the importance of thrombin’s action on platelets causing blood clots in arteries. This is the first study to show definitively that blocking this pathway reduces the risk of suffering another cardiovascular event.”

Click here to download a PDF of the ACC press release for TRA 2P-TIMI 50. Readers should note that the press release does not mention the bleeding complications until the second page of the press release.  In sharp contrast, the press release from Merck discloses the bleeding complications in the first paragraph.

Large Meta-Analysis Finds Very Low Thrombosis Rates for Xience Stent Reply

A large new meta-analysis published in the Lancet provides the best evidence yet that the cobalt-chromium everolimus eluting (CoCr-EES) stents  (Xience and Promus) have a significantly lower rate of stent thrombosis than bare-metal stents BMS) and other drug-eluting stents (DES).

Tullio Palmerini and colleagues analyzed data from 49 randomized trials comparing different stents in more than 50,000 patients.

Odds ratios for 1 year definite ST for CoCr-EES compared with:

  • BMS: 0·23, CI 0·13–0·41
  • paclitaxel-eluting stents: OR 0·28, CI 0·16–0·48
  • permanent polymer-based sirolimus-eluting stents: OR 0·41, CI 0·24–0·70
  • phosphorylcholine-based zotarolimu-seluting stents: OR 0·21, CI 0·10–0·44
  • compared with Resolute zotarolimus-eluting stents: OR 0·14, CI 0·03–0·47

The superiority of the CoCr-EES over BMS emerged within the first month, suggesting that the findings were not simply a reflection of longer duration of  dual antiplatelet therapy. At two years, the CoCr-EESs still had a lower rate of definite stent thrombosis than both bare-metal stents (OR 0·35, CI 0·17–0·69) and paclitaxel-eluting stents (OR 0·34, CI 0·19–0·62). Since concerns were first raised a number of years ago about the higher rate of stent thrombosis with drug-eluting stents, the new results, write the authors, “represent a paradigm shift.”<
In an accompanying comment, John Ormiston and Mark Webster point out that a meta-analysis should only "be regarded as hypothesis-generating," but write that "despite these limitations" the findings are "very reassuring." "CoCr-EES should be regarded as the standard against which future design improvements are compared."
Click here to read the Lancet press release…

Promising Phase 1 Results For New Monoclonal Antibody to PCSK9 Reply

Promising results from very early studies with an experimental new cholesterol-lowering drug, a monoclonal antibody to PCSK9, have been published in the New England Journal of Medicine. Evan Stein and colleagues report the results of two single-dose studies in which the drug, REGN727, was administered intravenously and subcutaneously to healthy subjects. In a third, randomized, placebo-controlled, dose-ranging trial, REGN727 was administered subcutaneously on days 1, 29, and 43 in adults with and without familial hypercholesterolemia (FH).

REGN727 was well tolerated and no subjects stopped taking the drug due to adverse events. Five patients had brief elevations in creatine kinase over three times the upper limit of normal. The drug had a powerful LDL-lowering effect: in the dose-ranging study in subjects already receiving atorvastatin

  • the 50 mg dose caused a 39% reduction of LDL cholesterol to 77.5 mg/dl,
  • the 100 mg dose caused a 53% reduction of LDL cholesterol to 61.3 mg/dl, and
  • the 150 mg dose caused a  61% reduction of LDL cholesterol to 53.8 mg/dl.

In an accompanying editorial, Stephen Young and Loren Fong write that “at this point, the status of PCSK9 therapeutics appears to be full speed ahead.” But they also express caution, noting that much work remains to be done:
Click to continue reading…

Meta-Analysis Adds New Evidence For Cancer Benefits Of Daily Aspirin 1

Although daily aspirin was originally proposed to reduce cardiovascular events, the effects on cancer of daily aspirin have become increasingly apparent while the vascular benefits, especially in primary prevention, have become less clear. Now a new meta-analysis in the Lancet adds significantly new details to our understanding about the effects of aspirin and increases the evidence in support of a long-term beneficial effect of aspirin in preventing cancer.

Peter Rothwell and colleagues analyzed data from 51 primary and secondary prevention trials including more than 80,000 patients. They reported several key findings

  • Daily aspirin reduced deaths from cancer by 15% (p=0·008).
  • After 5 years, there was a particularly striking 37% reduction in cancer deaths (p=0·0005), which largely accounted for a reduction in non-vascular deaths overall (p=0·003).
  • Aspirin was associated with an initial reduction in major vascular events, but this was offset by increases in major bleeding. With longer followup the vascular effects diminished, so that after 3 years only the reduced risk of cancer was significant.

The authors wrote that “in view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting…”

In an accompanying comment, Andrew Chan and Nancy Cook point out that the meta-analysis did not include the two largest primary prevention studies, the Women’s Health Study and the Physician’s Health Study, because they used alternate-day aspirin rather than daily aspirin. Both trials failed to find an effect on cancer. Nevertheless, they write, the researchers “show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect.”

“For most individuals, the risk-benefit calculus of aspirin seems to favour aspirin’s long-term anticancer benefit,” they state. However, current evidence does not support “a definitive conclusion about population-based recommendations regarding routine use of aspirin for cancer prevention.” They conclude that in the future guidelines “can no longer consider the use of aspirin for the prevention of vascular disease in isolation from cancer prevention.”
Click here to read the press release from the Lancet…

Questions Raised About Antiplatelet Therapy in Chronic Kidney Disease Reply

Many people develop chronic kidney disease (CKD) as they grow older, and many people with CKD take antiplatelet agents to prevent cardiovascular events. However, the efficacy of antiplatelet therapy in CKD has not been examined, despite the fact that people with CKD are more likely to die from nonatherosclerotic conditions and are more likely to have bleeding complications due to antiplatelet agents.

In a systematic review and meta-analysis published in Annals of Internal Medicine, Suetonia Palmer and colleagues examined data from   trials that enrolled nearly 10,000 participants with ACS and nearly 12,000 subjects with stable or no cardiovascular disease.

  • In the ACS group, the investigators found that antiplatelet therapy– either glycoprotein IIb/IIIa inhibitors or clopidogrel, increased the risk of serious bleeding but had little or no effect on overall mortality, CV mortality, or MI.
  • In the non-ACS group, the investigators found that antiplatelet agents helped prevent MI but had an “uncertain” effect on mortality and increased minor bleeding.

In both groups, the investigators acknowledged that the evidence was of “low or very-low quality.” They concluded that “bleeding hazards and lack of clear efficacy in reducing cardiovascular morbidity and mortality need to be acknowledged when patients with CKD are being counseled about acute or long-term antiplatelet therapy.”

Merck Drops Development of Oral Vernakalant for Atrial Fibrillation Reply

Merck has discontinued its development of oral vernakalant for the long term prevention of atrial fibrillation (AF) recurrence. Cardiome Pharma, Merck’s partner in the drug, said today that the “decision was based on Merck’s assessment of the regulatory environment and projected development timeline.”

Merck and Cardiome will continue their partnership with the intravenous formulation of vernakalant, Brinavess, which is approved in 37 countries outside the US for the rapid conversion of recent onset AF.
Click here to read the press release from Cardiome…

A Case of Plagiarism Raises Blood Pressures 1

Plagiarism: it’s enough to raise your blood pressure.

An article in Korean Circulation Journal appears to plagiarize from a similar article in the Journal of the American College of Cardiology (JACC). In 2009, Franz Messerli, a well-known hypertension expert at St Luke’s Roosevelt Hospital Center in New York, and Gurusher Panjrath, at Johns Hopkins Hospital, published a Viewpoint and Commentary in JACC: The J-Curve Between Blood Pressure and Coronary Artery Disease or Essential Hypertension: Exactly How Essential?  Less than two years later, two Korean physicians, Chang Gyu Park and Ju Young Lee, published an article with striking similarities to the JACC article: The Significance of the J-Curve in Hypertension and Coronary Artery Diseases.

The Korean article includes some content not included in or published after the JACC article, but a large proportion of the article represents obvious plagiarism. The Korean article fails to even cite the JACC article from which it clearly derives so much of its content, language, and organization. However, it should be noted that the Korean article does not resort to word-for-word copying of the original.

Here are some similarities in the heading and text found in just one paragraph in the papers:

Heading from JACC:

Pathophysiologic Consideration: Coronary Flow and BP

Heading from Korean Circulation Journal:

Mechanism of the J-Curve and the Pathophysiologic Approach

First sentence from JACC:

The coronary circulation is unique in that most of coronary blood flow to the left ventricle (LV) occurs in diastole.

First sentence from Korean Circulation Journal:

Most of the coronary circulation occurs during diastole.

Second sentence from JACC:

During systole, the contracting LV myocardium compresses intramyocardial vessels and obstructs its own blood flow.

Second sentence from Korean Circulation Journal:

During systole, the left ventricular (LV) myocardium contracts and compresses the intramyocardial vessels to impede its blood flow.

Last sentence in paragraph from JACC:

When coronary perfusion pressure is lowered to 40 to 50 mm Hg, the so-called pressure at 0 flow, diastolic blood flow in the coronaries ceases.

Last sentence in paragraph from Korean Circulation Journal:

When the coronary perfusion pressure is lowered to 40-50 mmHg, the blood flow due to coronary perfusion pressure theoretically approaches 0 with exclusion of the LV diastolic pressure.

A careful examination of the papers reveals many similar instances of obvious copying. In addition, the Korean authors use many of the same headings, figures, and references used in the JACC paper.

When the Korean paper was brought to his attention, Messerli attempted to contact the Korean authors and editors.  He also informed Tony DeMaria, the editor of JACC, about the situation. CardioBrief has requested comments from DeMaria, Ho Joong Youn,the editor of Korean Circulation Journal, and the two authors of the Korean paper.

Editor’s note: Marilyn Mann, a well-known blogger and medical watchdog, performed the detailed comparison of the two articles on which this post relies. Once again, I am extremely grateful for her assistance.

Studies Provide Strongest Evidence To Date For Causative Role of Inflammation in Heart Disease 4

Two large new meta-analyses published in the Lancet provide the first strong evidence demonstrating a cause-and-effect relationship between a specific inflammatory protein and the development of coronary heart disease (CHD). Both studies illuminate the role of interleukin-6 receptor (IL6R) by focusing on the common Asp 358Ala variant of the IL6R gene. The variant is known to dampen the inflammatory effect of IL6R.

In the first study, members of the IL6R Genetics Consortium Emerging Risk Factors Collaboration found that Asp358Ala was present in 39% of the population, and was not significantly related to other risk factors. 358Ala increased concentrations of IL6R and interleukin 6 and decreased concentrations of CRP and fibrinogen. Importantly, each copy of 358Ala was associated with a 3.4% reduction in the risk of CHD.

In the second study, members of the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium performed a Mendelian randomization to analyze the impact on CHD of tocilizumab, an anti-inflammatory monoclonal antibody that blocks IL6R, in patients with rheumatoid arthritis (RA). They found that the effect of the 358Ala variant was similar to the effect of tocilizumab in RA trials and resulted in increased levels of IL-6 and decreased levels of CRP and fibrinogen. The investigators also observed a significant reduction in the risk of CHD in a second analysis of more than 25,000 people with CHD people and 100,000 controls. They concluded that IL6R signaling appears to “have a causal role in development” of CHD and that “IL6R blockade could provide a novel therapeutic approach to prevention” of CHD.
Click here to continue reading, including comments from Paul Ridker and Rick Lange…

Achieving CLOSURE: Final Act of PFO Closure Device Reply

You can choose from a myriad of metaphors– closing the book, sealing the deal, fixing a hole– but the story is simple: the publication of CLOSURE 1 in the New England Journal of Medicine is the final act of the long and sad melodrama of the CLOSURE 1 trial. As initially reported at the American Heart Association in 2010, Anthony Furlan and the CLOSURE I investigators randomized 909 patients with crytpogenic stroke to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant difference in the composite endpoint or its components(stroke or TIA in the first two years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):

Composite end point: 5.5% in the closure group versus 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37)

  • Stroke: 2.9% vs 3.1% (p=0.79)
  • TIA: 3.1% vs 4.1% (p=0.44).
  • Deaths at 30 days and deaths from neurological events at 2 years: zero in both groups
As expected there were more major vascular complications related to the procedure in the treatment group, as well as a higher incidence of atrial fibrillation:
  • Major vascular procedural complicaton : 3.2% vs 0% (p<0.001)
  • Atrial fibrillation: 5.7% vs 0.7% (p<0.001)

In an accompanying editorial, S. Claiborne Johnston discusses the troubling issues raised by the trial. Because of off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size of the trial. He continues:

During the 9 years it took for the results of this trial to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.

 

Angioplasty Pioneer Geoffrey Hartzler Dead at 65 Reply

Geoffrey Hartzler, a key figure in the development of interventional cardiology in the United States, has died from cancer at the age of 65. He was one of the first cardiologists to learn the technique of percutaneous transluminal coronary angioplasty (PTCA) from its founder, Andreas Gruentzig. Hartzler then went on to perform the first angioplasty procedure at the Mayo Clinic in 1979.

In 1980 he established the interventional program at the Mid-America Heart Institute in Kansas City, MO. Hartzler retired from clinical practice due to chronic back pain in 1995. Hartzler was renowned for training an entire generation of cardiologists in the then new technique, and helped to expand its clinical application and to develop improved catheters and balloons. Gregg Stone, who had a fellowship with Hartzler, told Heartwire:

Whereas Andreas Gruentzig was responsible for bringing angioplasty to the world, Geoff Hartzler was the single person most responsible for extending its application to the millions of patients who currently benefit each year from interventional cardiology. Whereas Andreas believed PTCA should be restricted to proximal focal lesions, Geoff was the pioneer who brought interventional cardiology (balloons only, no less) to patients with acute MI, multivessel and left main disease, chronic total occlusions, and much more.

Rick Lange recalls the early days of interventional cardiology and Hartzler’s key role in helping it grow:

David Hillis taught me to do PTCA when only 1 brand of guide catheter, 1 type of guide wire and 2 types of balloons were available…..one of which was the Hartzler balloon catheter. I attended Hartzler’s angioplasty course when it was only 1 of 2 offered in the U.S.  For 4 or 5 consecutive years afterwards, Geoff took one of our Parkland cath fellows into his PTCA program (which accepted 2 or 3 fellows/yr).  They were all superbly trained.

The following information is from the Kansas City Star:  Funeral: 11:30 a.m. Friday in Greenwood Chapel, Fort Worth, TX. A memorial service will follow in Kansas City, on a date to be determined. Interment: Greenwood Memorial Park. Visitation: 6- 8 p.m, Thursday at Greenwood Funeral Home. Memorials: In honor of his courageous battle against prostate cancer, gifts in Geoffrey’s memory can be sent to the Prostate Cancer Foundation at www.pcf.org/geoffreyhartzler or the American Heart Association at www.honor.americanheart.org.

Prominent Japanese Cardiologist Accused of Scientific Misconduct 3

Following accusations by independent bloggers in Japan and Germany, the American Heart Association (AHA) has issued an Expression of Concern about five papers published in AHA journals co-authored by Hiroaki Matsubara, a prominent cardiologist and researcher at Kyoto Prefectural University in Japan. In addition to his many papers exploring the basic science of the renin-angiotensin system, Matsubara was the chief investigator of the KYOTO HEART Study, a randomized, open-labeled study studying the add-on effect of valsartan to conventional therapy in high-risk hypertension.

Questions about Matsubara’s work were initially raised last year on a Japanese blog and then pursued in three English language posts (herehere and here) on a German site, the Abnormal Science Blog. Abnormal Science reported evidence of serious scientific misconduct in 12 papers in which Matsubara was the only common co-author. The AHA posted its Expression of Concern on Monday, which was subsequently reported by Retraction Watch.

The three posts on Abnormal Science demonstrate repeated examples of  image manipulation and copying, as well as self-plagiarism. The non-AHA journals cited by Abnormal Science include Kidney InternationalBiochemical and Biophysical Research Communications, and Journal of Molecular and Cellular Cardiology. At least one paper, in Molecular and Cellular Biochemistry, has been  retracted “due to a mistake of duplicating the publication of original data” that already had appeared in Circulation Research. Here is how Abnormal Science summarized its initial findings in several of the papers:

It is apparent that band images from ‘real’ blots may have been digitally reassembled into new blot images pretending to be derived from distinct experimental settings. Since ‘reconfigured blots’ have been densimetrically scanned and the results illustrated in tables and figures, we are presumably confronted with a case of severe data fabrication.

These are the five papers cited by the AHA, including the number of citations as reported by Retraction Watch: