December 2nd, 2013
ACP Recommends Conservative Treatment for Heart Patients with Anemia
Larry Husten, PHD
The American College of Physicians (ACP) is recommending more conservative use of transfusions and erythropoiesis-stimulating agents (ESAs) in anemia patients with heart disease. But the authors of the new clinical practice guidelines, published in the Annals of Internal Medicine, acknowledge that the evidence base is too flimsy to support firm conclusions.
“Overall,” wrote the authors, “despite the epidemiologic and biologically plausible association of anemia with poor outcomes, we did not find consistent evidence that anemia correction improves outcomes in patients with heart disease…” The poor outcomes of heart patients with anemia have prompted aggressive treatment strategies, but “it is unclear whether these strategies improve outcomes.”
Liberal use of transfusions has not been well-tested in clinical trials. Although a possible short-term benefit has been found in a small study in patients with an acute coronary syndrome, this finding has not been confirmed. “In the meantime,” say the authors, “the low-strength evidence suggesting a possible benefit needs to be weighed against the well-known potential adverse effects of blood transfusions.”
“Transfusion may benefit patients with lower hemoglobin levels, less than 7 – 8 g/dL, but the evidence suggests that red blood cell transfusion for milder anemia in patients with heart disease does not improve mortality,” said Molly Cooke, president of the ACP, in a press release.
The authors also offer no endorsement for widespread use of ESAs in this population. “The evidence evaluating the impact of ESAs in patients with heart disease did not show improved health outcomes,” they write. In fact, they write, ESAs “may be associated with serious harms” in patients with mild to moderate anemia and heart disease. More modest hemoglobin targets may possibly be safe and beneficial, “but the lack of any functional or quality-of-life benefits from more aggressive use of ESAs suggests that a potential benefit is unlikely.”
The new guideline offers some support for the use of intravenous iron in patients with heart failure and iron deficiency. Results from one large trial suggest that iron replacement may have short-term benefits, but, the authors warn, “the long-term health implications are uncertain, and harms have not been more widely assessed in this population.”
December 2nd, 2013
Selections from Richard Lehman’s Literature Review: December 2nd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
BMJ 30 Nov 2013 Vol 347
Risk of First VTE in Pregnant Women in Hospital: A population cohort study from England finds that women who are pregnant are at greatly increased risk of thromboembolism if they are admitted to hospital for any reason. The relative risk of VTE is somewhere between 8 and 40 overall – but the article is careful to frame this in subgroups and to give absolute figures too. And it remains elevated in the month after discharge.
December 2nd, 2013
Left Ventriculography: Procedural Variation Writ Large
Seth D Bilazarian, MD
The Dartmouth Atlas Project has documented that the use of many procedures varies widely by region and by institution, raising the question of whether much of the care in high-use areas may be unnecessary. At Palo Alto’s Veterans Affairs Health Care System, where I practice, our cardiology fellows noticed that the use of left ventriculography varied markedly depending on whether coronary angiography was performed at the VA itself (lowest use), at the university hospital by academic staff, or by private physicians (greatest use).
So we conducted a study, now published in Circulation: Cardiovascular Quality and Outcomes, of the use of left ventriculography during coronary angiography across the VA Health Care System nationwide from 2000 to 2009. We found an overall rate of 58% but with dramatic variation: as high as 95% in some facilities and lower than 1% in others. Differences in reimbursement do not explain the variation, given that VA providers are salaried and that most private payers don’t reimburse much for left ventriculography. Other factors must, therefore, be at work.
We have heard, anecdotally, that one VA facility reduced its use of left ventriculography by more than 80% within 8 years despite turnover in just a few interventional cardiologists. However, no published performance measures, guidelines, or appropriateness criteria exist for left ventriculography, so we can’t systematically assess where care is “best.” We did manage to document that even in cases where an echocardiogram was performed in the prior 30 days with no intervening admission for a cardiac cause that might prompt a change in LV ejection fraction, left ventriculography was still performed in 50% of patients. Although that seems like inappropriate use of the procedure, if the clinician does not trust the echocardiogram, he or she may feel compelled to do a left ventriculogram.
So I ask you: Does the variation in use of left ventriculography represent reasonable differences in opinion among clinicians? Or do some of us have unrealistic expectations about the benefits and harms of the procedure?
November 27th, 2013
Physicians Report Alarming Increase in LVAD Pump Thrombosis
Larry Husten, PHD
Cardiac 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 Thoratec.
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. The same pattern was observed at all three hospitals and for multiple surgeons. (In a postscript added during the editing process, the authors state that similar findings were found in an analysis of additional data from the University of Pennsylvania.)
Before March 2011 the median time to pump thrombosis after implantation was 18.6 months and was the result of a constant risk of pump thrombosis of 0.4% per month. After March 2011 the time to pump thrombosis decreased dramatically to 2.7 months, resulting in an early hazard that peaked at 2 months and then fell to a constant 0.6% monthly rate.
Overall there were 72 cases of pump thrombosis in 66 patients. Eleven patients underwent heart transplantation and 19 patients had a pump replacement. Mortality was higher in the patients with a confirmed pump thrombosis.
The authors were unable to identify any predisposing factors or causes for the increase in pump thrombosis. Thoratec said the company had “performed extensive analysis on HeartMate II and have not identified any change that would cause the increase observed in the INTERMACS registry.”
A rise in lactate dehydrogenase (LDH) levels was closely correlated with the increase in pump thrombosis. “We found that a sharp rise in LDH levels occurring within the first weeks after implantation often preceded and heralded confirmed pump thrombosis,” they wrote. An increase in LDH is thought to indicate hemolysis caused by thrombus formation.
The authors acknowledged that LVADs still “provide life-sustaining treatment for many patients with advanced heart failure” but said that “recommendations for LVAD therapy should account for this updated risk-benefit profile.”
Every year nearly 4,000 LVADs are implanted in the U.S. Approximately three-quarters of these are the HeartMate II, according to Wells Fargo analyst Larry Biegelsen. Before getting a transplant, former Vice President Dick Cheney was perhaps the most famous recipient of the HeartMate II.
November 27th, 2013
Reflections on JFK From an Irish Cardiologist in Dallas
John Ryan, MD
Arlington National Cemetery, 2005
The relationship between the Irish and John F. Kennedy is unique. To put it in context, in my grandfather’s kitchen there were two pictures on the wall: one of the Sacred Heart, the other of John F. Kennedy. To the Irish, the Kennedy story is not about Camelot, conspiracies, Cuba, or other controversies. It is about national pride. JFK’s visit to Ireland in the summer of 1963 is seen by many as a turning point in the economic path of Ireland; it coincided with a historic drop in emigration, a shift from an agricultural economy to an industrial economy, and a population movement from rural villages to coastal cities. When JFK spoke to the Irish Parliament in 1963, he observed that “Ireland’s time has come,” an inspirational observation that moved a generation.
I moved from Ireland approximately 10 years ago, not knowing a whole lot about this country, other than what I knew about the Kennedys and had seen on The Sopranos and The Fresh Prince of Bel Air. About 6 months after moving here I went to DC, on a pilgrimage of sorts. My first stop wasn’t the White House or the Lincoln Memorial, but rather Arlington Cemetery where the eternal flame marks Kennedy’s resting place. I must have spent two or three hours there thinking about what it meant to be Irish, and to be in America, and what my future had in store for me. I often think back on that sad and emotional day.
Dallas, 2013
When I heard that AHA 2013 was going to be held in Dallas, I thought this would be a perfect opportunity to visit this important historic site, the last step in this Irishman’s tour of historic Kennedy sites that began when I was four years old at the John F. Kennedy Arboretum in County Wexford. Many emigrants hold on to certain things to keep in touch with our heritage and our upbringing. These act as an anchor, helping to keep us grounded while living overseas. To me those anchors have been the Kennedy family, Irish music, and the Gaelic tongue.
As I stood looking over Dealey Plaza, I took the opportunity to again reflect on what it means to be here, in the US, away from my home country. A lot has changed since I visited Arlington Cemetery in 2005. I have changed. This year marked the start my academic career. My wife and I had our first child. Although I am still Irish, in many regards I am now also American, a dichotomy that I struggle with all the time. As I stood looking at the final road taken by the man felt by millions to be both truly Irish and truly American, I realized that not only can I be both, but more importantly, it’s ok to be both.
November 26th, 2013
Little Difference in Chest Pain Between Men and Women
Larry Husten, PHD
In recent years, the medical community has grown increasingly concerned that women with heart attacks may be less likely to receive prompt and effective treatment. The difference between the sexes in the presentation of symptoms is thought to be a major barrier to better treatment for women. But now a study published in JAMA Internal Medicine finds that a key aspect of these differences — the description of chest pain in the emergency department — may not play as big a role as previously suspected.
European investigators analyzed data from nearly 2500 chest pain patients seen at nine hospitals in Switzerland, Spain, and Italy. Some 18% of the women and 22% of the men were ultimately found to have a myocardial infarction as determined by ECG and troponin tests. The investigators looked at the chest pain characteristics (CPCs) of the men and women in the study and examined whether these characteristics differed according to sex in their frequency or ability to improve the diagnosis of MI.
Most of the 34 characteristics they examined were reported by men and women with a similar frequency, though women were more likely to report several of the CPCs more often. This finding, write the authors, “extends and corroborates” previous studies. But, they note, the previous studies “were unable to address the key question whether attention to any of these CPCs would improve the early diagnosis of AMI in women.”
The investigators then found that most CPCs were not helpful in improving the diagnosis of MI. CPCs “are not powerful enough to be used as a single tool in the diagnosis of AMI and need to be used always in conjunction with the ECG and cTn test results,” they write.
Three CPCs were statistically significantly different between men and women in helping to predict MI, but these differences “did not seem clinically helpful,” say the authors. In addition, because they looked at so many different CPCs, the finding may well have been due to chance. The same pattern emerged when the investigators looks at different combinations of CPCs.
In an invited commentary, Louise Pilote writes that there has been considerable controversy over “whether men and women have fundamentally different presentations of AMI.” The new study “clarifies that presentation of chest pain between men and women is not as different as is commonly thought and provides new knowledge on the value and limitation of chest pain in making a diagnosis of AMI in women as well as in men.” She rejects the Men Are From Mars, Women Are From Venus premise and recommends an alternative view from George Carlin: “Men are from earth, women are from earth — deal with it!”
November 26th, 2013
Edoxaban and the Changing Landscape of Novel Anticoagulants for Atrial Fibrillation
Christian Thomas Ruff, MD, MPH
CardioExchange’s John Ryan interviews Christian Thomas Ruff, a coauthor of the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin in patients with atrial fibrillation. The study was published in The New England Journal of Medicine and presented at the 2013 American Heart Association conference. Click here for CardioExchange’s news coverage of the trial.
Ryan: Where does edoxaban fall on the spectrum of available anticoagulants?
Ruff: Edoxaban is the fourth factor-specific anticoagulant. Both the high- and low-dose exoxaban regimens tested in our trial performed similarly to well-managed warfarin in reducing the total incidence of stroke and systemic embolism, and the higher dose tended to outperform warfarin. However, the lower-dose regimen was associated with a higher rate of ischemic stroke. Both doses were significantly safer than warfarin, yielding substantial reductions in hemorrhagic stroke, major bleeding, and intracranial bleeding. The higher dose was associated with an increase in gastrointestinal bleeding. Both doses were associated with lower cardiovascular mortality. I think the high dose has certainly demonstrated good efficacy and better safety than warfarin. Although the lower dose was associated with an increase in ischemic stroke, it was remarkably safe and could be useful in patients at very high risk for bleeding, especially given the mortality benefit. Edoxaban’s once-daily dosing is also convenient for patients.
Ryan: How should we decide which dose of edoxaban to use in clinical practice?
Ruff: We have to wait for the regulatory authorities, but I can envision the higher dose being indicated for most patients except those at very high risk for bleeding. An important feature of the ENGAGE-AF trial was a very well-defined dose-reduction strategy that allowed more than a quarter of patients to have their dose reduced by 50%. This dose reduction did not sacrifice efficacy but resulted in even less bleeding with edoxaban than with warfarin.
Ryan: Will the introduction of edoxaban start to influence the price points of the novel anticoagulants?
Ruff: I hope that competition does bring down the cost of these medications. Price remains one of the biggest obstacles to widespread use, especially in the United States.
Ryan: Part of the attraction of edoxaban is its reversibility. Is the reversibility available in most hospitals? How long does it take?
Ruff: No reversal agents for edoxaban are currently approved, but several studies have reported exciting preliminary results. Edoxaban is being tested with a potential antidote, PER977, from Perosphere. Results show that PER977 reverses the anticoagulant activity within 30 minutes of IV administration, offering the promise of safe and effective reversal of edoxaban in cases of serious and life-threatening bleeding. Many of the other novel anticoagulants are also testing reversal agents, and it is likely that the same reversal agent may be effective for multiple drugs.
JOIN THE DISCUSSION
Given the data from ENGAGE-AF and Dr. Ruff’s comments, what effect do you think edoxaban will have on how patients with atrial fibrillation are treated in clinical practice?
November 25th, 2013
FDA Removes Restrictions on Avandia
Larry Husten, PHD
In a remarkable climax to a long-running drama, the FDA today lifted major restrictions on rosiglitazone (Avandia, GlaxoSmithKline). The drug has been the subject of intense criticism and controversy since the 2007 publication of the famous Nissen meta-analsysis that first raised the possibility that the blockbuster diabetes drug might increase the risk of heart attack and cardiovascular death.
The FDA said its actions were “consistent with the recommendations of expert advisory committees.” In June of this year an FDA panel reviewed re-adjudicated data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial and concluded that the trial had not found an elevated risk of heart attack or death associated with rosiglitazone.
“Our actions today reflect the most current scientific knowledge about the risks and benefits of this drug,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, in an FDA press release. “Given these new results, our level of concern is considerably reduced; thus, we are requiring the removal of certain prescribing restrictions.”
As a result of today’s FDA action rosiglitzone will be much easier to obtain. Physicians, pharmacies, and patients will no longer have to participate in the stringent Risk Evaluation and Mitigation Strategy (REMS) program.
The rosiglitazone label will also be revised to reflect the FDA’s changed perception of the drug. The current indication for rosiglitazone is severely limited. The new label will be similar to other available diabetes drugs and will state that it may be used to help control blood sugar in type 2 diabetics.
The FDA also said it was “releasing” GSK “from the postmarket requirement to conduct” the TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) trial comparing rosiglitazone to pioglitazone and other diabetes drugs. The FDA said it had “concluded that this trial is no longer necessary or feasible.”
The FDA announcement “is about the FDA’s effort to save face,” Steve Nissen told the Associated Press. “A single reanalysis of a trial does not exonerate a drug where all the other data point to increased cardiovascular risks.” He said he does not think that most physicians will now begin to prescribe the drug again.
Harlan Krumholz offered the following comment:
The turn of events is surprising given that no substantial information has been made available since the original decision. I don’t know how we will ever know the truth until GSK completely releases the Avandia trial data at the patient level.”
November 25th, 2013
Selections from Richard Lehman’s Literature Review: November 25th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
Lancet 23 Nov 2013 Vol 382
DAPT Cessation and Coronary Events After PCI (pg. 1714): This article describes the results of a prospective study of just over 5,000 patients who underwent coronary stenting in Europe and the USA. As the stents were all drug-eluting, everybody received aspirin plus a thienopyridine (usually clopidogrel): this is called dual anti-platelet therapy or DAPT, and was meant to continue for 2 years. But over this period, more than half the cohort gave up DAPT at some point, usually continuing aspirin and dropping the thienopyridine. Now comes the analysis, and I defy anyone to summarise it simply. The take home message seems to be that after the first few weeks it seems to make remarkably little difference to restenosis rates whether or not you comply fully with DAPT, but it’s still just a bit safer to carry on if you can.
Ann Intern Med 19 Nov 2013 Vol 159
Association Between Exposure to Low to Moderate Arsenic Levels and Incident CVD (pg. 649): Funny how some words get people reading. “Arsenic” was one of Agatha Christie’s favourites, and in England at any rate it is hard to think of arsenic without Old Lace. The website of Annals this week features a blackboard with As written in red and surrounded by its atomic properties. And that’s about as good as it gets. The actual study featuring arsenic consists of a single measurement of inorganic and methylated arsenic species in urine at baseline in a cohort of Native Americans, compared with their incidence of cardiovascular disease in subsequent years. That’s it. There might be some association, but the more you adjust for confounding factors, the less it gets. Next: Old Lace.
Comparative Safety of Vascular Closure Devices and Manual Closure Among Patients Having PCI (pg. 660): The closest I ever come to being involved with percutaneous coronary intervention is when I see patients with nasty femoral haematomas following the procedure. This study looks at 85 048 PCIs done in Michigan from 2007 to 2009. It would be interesting to know how many of them were really needed, but that’s not the point of this study. Just over a third of these patients had a vascular closure device placed over the site of femoral puncture, and these patients had fewer complications and fewer transfusions. If you’re an interventional cardiologist, read on for the subgroup effects, etc.
Statins and Cognitive Function (pg. 688): Nine systematic reviewers trawl through the literature to see if there is any evidence to support the FDA’s warning about possible cognitive impairment due to statins. There is not: all the evidence is less than first rate, but none of it supports an association. In particular, “Examination of the FDA postmarketing surveillance databases revealed a low reporting rate for cognitive-related adverse events with statins that was similar to the rates seen with other commonly prescribed cardiovascular medications.” I have no idea why people are currently going to such lengths to suggest that statins have hidden harms and should not be “overprescribed.” Personally I can’t see any reason why anybody should be worried about taking a statin if they so wish, but that may be because I am really a rare example of statin-related cognitive impairment.
November 25th, 2013
FDA Reprimands 23andMe, Grants Breakthrough Status to Factor Xa Inhibitor, and Approves Promus Premier Stent
Larry Husten, PHD
It was a busy morning at the FDA. Three new FDA actions may be of considerable interest in the cardiology universe:
FDA Halts 23andMe Personal Genome Test: The FDA sent a scathing letter to 23andMe ordering the company to stop selling its Personal Genome Service (PGS) test. The FDA highlighted two cardiology-related uses of PGS as “particularly concerning,” including drug responses involving warfarin sensitivity and clopidogrel response. The FDA wrote that
false genotype results for your warfarin drug response test could have significant unreasonable risk of illness, injury, or death to the patient due to thrombosis or bleeding events that occur from treatment with a drug at a dose that does not provide the appropriately calibrated anticoagulant effect. These risks are typically mitigated by INR management under a physician’s care. The risk of serious injury or death is known to be high when patients are either non-compliant or not properly dosed; combined with the risk that a direct-to-consumer test result may be used by a patient to self-manage, serious concerns are raised if test results are not adequately understood by patients or if incorrect test results are reported.”
The FDA said the company had failed to address issues raised by the FDA in 2012 and was therefore withdrawing the earlier 510(k) approval of the test. The unusually harsh FDA letter says that more than five years after 23andMe began marketing PGS
you still had not completed some of the studies and had not even started other studies necessary to support a marketing submission for the PGS. It is now nine months later, and you have yet to provide FDA with any new information about these tests. You have not worked with us toward de novo classification, did not provide the additional information we requested necessary to complete review of your 510(k)s, and FDA has not received any communication from 23andMe since May. Instead, we have become aware that you have initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS’s uses and consumer base without obtaining marketing authorization from FDA.”
FDA Grants Breakthrough Status To Factor Xa Inhibitor Antidote: Portola Pharmaceuticals said that the FDA had granted a breakthrough therapy designation for its investigational Factor Xa inhibitor, andexanet alfa. The designation is intended “to expedite the development and review of drugs for serious or life-threatening conditions,” according to the FDA, which requires “preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.”
Early studies have shown that andexanet alfa can reverse the anticoagulant effect of Factor Xa inhibitors. Phase 2 proof-of-concept studies of andexanet alfa have been completed with apixaban (Eliquis, Pfizer and BristolMyers Squibb) and rivaroxaban (Xarelto, Johnson & Johnson). Additional studies are being completed with enoxaparin and betrixaban, according to the company.
“The FDA’s decision to designate andexanet alfa as a breakthrough therapy reaffirms the urgent need for an antidote to Factor Xa inhibitors, and we believe it demonstrates that andexanet alfa’s properties and data distinguish it from currently used agents or others in development,” said William Lis, the CEO of Portola, in a press release.
FDA Approves Promus Premier Everolimus-Eluting Platinum Chromium Coronary Stent System: Boston Scientific announced that it had received FDA approval for the Promus Premier Everolimus-Eluting Platinum Chromium Coronary Stent System. The company said that the first implantation was scheduled to be performed by Martin Leon at Columbia University in New York City.
“Perhaps the most impressive benefit of the Promus PREMIER Stent System is its unparalleled visibility, which combined with enhanced customized stent architecture, leads to an advance in currently available durable polymer DES,” said Leon, in a Boston Scientific press release.
NEJM Journal Watch — Recent Cardiology Articles- Does Use of Drug-Coated Devices Improve Outcomes in Chronic Limb-Threatening Ischemia?
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