September 26th, 2012
Treading Water During the Post-MI Waiting Period
Harlan M. Krumholz, MD, SM and James Fang, MD
A 60-year-old man was admitted to the hospital with an inferior ST-segment-elevation MI, having arrived an hour after the onset of chest pain. He underwent primary PCI (door-to-balloon time, 30 minutes) and had no signs of heart failure. However, an echocardiogram performed the next day revealed multiple regional wall-motion abnormalities and a left ventricular ejection fraction of 33%.
The doctors recommended that the patient wear a Zoll LifeVest for 90 days and then return for a repeat assessment of his LVEF to determine whether he may benefit from an ICD. The patient was told that their practice routinely uses the LifeVest during this period after an MI for all patients with a depressed LVEF, until they can be assessed further.
Questions:
1. Does your institution use the LifeVest strategy routinely during the waiting period after an MI?
2. What evidence do you use to support or eschew the strategy?
Response:
October 3, 2012
Mortality risk is high during the first few months after acute MI. Routine implantation of an ICD in high-risk patients after acute MI does not lower their overall mortality risk but does reduce the risk for arrhythmia-related death (see the DINAMIT trial).
It is on this basis that some recommend the LifeVest as “bridge” therapy during this high-risk period. The LifeVest may be particularly attractive because, although it cannot reliably address bradyarrhythmias, it is not invasive like an ICD. Also, the risk for sudden death after MI decreases with time-dependent improvements in LVEF from revascularization and meds, and the LifeVest does not commit a patient to potentially unnecessary “permanent” therapy. However, even though the vest may prevent sudden death from arrhythmia, it may not reduce overall mortality risk, given that the extent of the acute infarction may be the key determinant in the patient’s outcome (again, see DINAMIT).
The electrophysiologists at my institution will offer the LifeVest to post-MI patients who appear to have, in addition to a low LVEF, major risk factors for sudden cardiac death (e.g., significant nonsustained ventricular arrhythmias, heart failure, inability to tolerate meds due to bradycardia or hypotension) during the first 40 days after acute MI, when ICD implants are not covered by CMS reimbursement. However, no randomized data support this practice; nor, arguably, does the DINAMIT trial. To my knowledge, the largest published study of the LifeVest is from an observational cohort.
Our electrophysiology service is not routinely asked to provide post-MI assessment of risk for SCD; in general, that remains the purview of our CCU faculty. Some institutions pursue further risk stratification with Holter monitoring, heart-rate variability (HRV) testing, electrophysiology studies, signal-averaged EKG, etc. Notably, in the DINAMIT trial, additional factors (beyond LVEF) were used to identify patients at high risk for SCD (e.g., depressed HRV and increased heart rate).
Finally, after an acute MI, medical therapy must be optimized (statin, beta-blocker, ACE inhibitor, aldosterone antagonist), and LV function should be reassessed over time.
Follow-Up:
October 10, 2012
For a month the patient was bothered by the vest during sleep and by the high price tag. He switched doctors, and an equilibrium radionuclide angiocardiography (ERNA) scan was ordered; it revealed an LVEF of >40%. The vest was discontinued, and the patient finally was able to get a good night’s sleep.
September 26th, 2012
Merck Returns to Cardiome All Rights to Atrial Fibrillation Drug Vernakalant
Larry Husten, PHD
Merck and Cardiome announced today that Merck is returning to Cardiome all marketing and development rights for the atrial fibrillation (AF) drug vernakalant. An intravenous formulation of vernakalant is marketed in Europe as Brinavess. It has not been approved in the United States, though it received a positive recommendation from the FDA’s Cardiovascular and Renal Drugs Advisory Committee in 2007.
Earlier this year, as reported here, Merck announced that it was ending its involvement in the development of an oral formulation of vernakalant.
During a conference call, Dr. William Hunter, the interim CEO of Cardiome, expressed confidence that the company would go forward with vernakalant. He pointed out that “what constitutes an opportunity for Cardiome is probably very different than what constitutes one for a global corporation the size of Merck.” In a press release, Hunter stated: “Cardiome looks forward to continued advancement of the launch of BRINAVESS IV worldwide and welcomes the opportunity to continue development of vernakalant oral worldwide and vernakalant IV in North America.”
September 25th, 2012
AHA Urges More Education and Support for ICD Patients
Larry Husten, PHD
Despite, and perhaps sometimes because of, their life-saving benefits, ICDs are associated with a host of complex psychosocial problems, but clinicians and caregivers receive little training to deal with these problems. In response to these concerns, the American Heart Association (AHA) has published a scientific statement in Circulation to provide a “comprehensive review of what is and is not known about psychological responses and psychosocial care” for ICD patients and their families.
The authors note that many ICD patients and potential ICD patients don’t fully understand the limitations and implications of the device. For instance, they “have a tendency to believe that the device can ‘undo’ the negative consequences of their cardiac condition, overestimate benefits, and underestimate adverse aspects.”
The document provides an overview of psychological responses to ICD therapy and the quality-of-life issues that often come up for ICD patients and their families. The effect of ICD shocks on quality of life is discussed in detail. In addition, the impact on the intimate and sexual relationships of patients and their partners is explored.
Although they represent a small percentage of ICD patients, children are a very important subgroup. The document notes that “few data are available to fully understand the psychosocial impact of the ICD on pediatric and adolescent ICD recipients, and no longitudinal studies of psychosocial response over time are available.”
At the other end of life, the authors discuss the difficult issue of ICD deactivation “as a patient’s clinical status worsens and death is near.” Unfortunately, they note, “clinicians and patients rarely engage in discussions about deactivating ICDs, and most devices remain active until death.” In addition, “most patients are not even aware that deactivation of the shocking function is an option.”
“A shock from an ICD can be lifesaving, but it can also affect a person’s quality of life and psychological state,” said Sandra Dunbar, the chair of the statement writing group, in an AHA press release. “It’s important to look at this issue now because 10,000 people have an ICD implanted each month. They range from older people with severe heart failure to healthy children who have a gene that increases the risk of sudden cardiac arrest.”
September 25th, 2012
Another One Bites the Dust: Diovan Patent Expires but Generic Valsartan Is MIA
Larry Husten, PHD
Although the patent on valsartan (Diovan, Novartis) expired last Friday, a generic version of the popular antihypertensive drug has yet to make it to market. By contrast, a generic version of Diovan HCT, the combination of valsartan and hydrochlorothiazide, was recently launched by generic drug maker Mylan.
As reported on Pharmalot, Ranbaxy, the embattled generic drug maker, holds the exclusive rights to market generic valsartan for 180 days, but has so far been unable to gain FDA approval. The delay, according to Pharmalot, “only adds to the uncertainty surrounding Ranbaxy’s ability to recover from its long-standing manufacturing woes and haggling with the FDA over its ability to resume operations on regular basis in the US.”
According to the Wall Street Journal, the Diovan franchise generated $5.7 billion worldwide in 2011.
September 25th, 2012
Novartis Announces Top Line Results for Phase 3 Trial of New Acute Heart Failure Drug
Larry Husten, PHD
Novartis has announced preliminary results from the RELAX-AHF trial, a phase 3 study of a novel drug, RLX030 (serelaxin), for patients hospitalized with acute heart failure. The company said the trial met one of its two primary endpoints in reducing dyspnea.
Novartis also reported a reduction in all-cause mortality at 6 months. However, it should be noted that the predefined secondary endpoint on ClinicalTrials.Gov was mortality at 60 days, not 6 months. (CardioExchange has requested clarification from Novartis about this point.)
In the trial, 1161 patients hospitalized with acute heart failure were randomized to placebo or an IV infusion of RLX030 for up to 48 hours. By design, the trial had two primary efficacy endpoints measuring dyspnea, but only one of them reached statistical significance, according to the company.
The full results of RELAX-AHF are scheduled to be presented as a late-breaking clinical trial at the American Heart Association meeting in Los Angeles in November.
RLX030 is a recombinant form of the naturally occurring human hormone relaxin-2. The drug was originally developed by Corthera, Inc, which was acquired by Novartis in February 2010.
September 24th, 2012
‘Dramatic’ Increase in Bleeding Accompanies Addition of Oral Anticoagulant Therapy in ACS
Larry Husten, PHD
The newer oral anticoagulants may help reduce ischemic events after an acute coronary syndrome (ACS), but only at the cost of a “dramatic” increase in bleeding complications, according to a new meta-analysis published in the Archives of Internal Medicine.
Hungarian researchers performed a systematic review and meta-analysis of seven trials in which 31,286 ACS patients were randomized to placebo or a new oral anticoagulant, either an anti-Xa or direct thrombin inhibitor. All patients also received antiplatelet therapy. Here are the odds ratios for bleeding events and important clinical endpoints with the newer agents:
- TIMI major bleeding events: OR 3.03 (2.20-4.16)
- Overall mortality: OR 0.90 (0.76-1.06)
- Composite ischemic events: OR 0.86 (0.79-0.94)
- Stent thrombosis (definite or probable): OR 0.73 (0.54-0.98)
“These results suggest that the unrestricted use of new-generation oral anticoagulant agents as an adjunct to dual antiplatelet therapy after an ACS cannot be recommended,” the authors concluded. However, they left open the possibility that the newer oral anticoagulants may be beneficial in the 6%-21% of ACS patients who require long-term anticoagulation for atrial fibrillation and other conditions.
In an accompanying comment, Adrian Hernandez writes that “the conclusions of the meta-analysis seem to be robust.” He points out that the large differences in the relative risk of bleeding and clinical events found in the meta-analysis translate into smaller differences in absolute risk. Nevertheless, he writes, “the benefit is largely canceled by the harm; therefore, the routine use of [novel oral anticoagulants] among patients with ACS is unwarranted.”
September 24th, 2012
Selections from Richard Lehman’s Literature Review: September 24th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections 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.
NEJM 20 Sep 2012 Vol 367
Punishing Health Care Fraud? (pg. 1082): In the next few weeks, we can look forward to dignified murmurs of offended innocence from the pharmaceutical industry in response to Ben Goldacre’s brilliant and damning new book, Bad Pharma. But it is difficult to maintain dignity when caught with your pants down, as GlaxoSmithKline has been over the mis-selling of Paxil and Wellbutrin, and the hiding of safety data relating to Avandia. However, all that’s needed is to pay up $3BN and your pants can quickly be raised and adjusted. Nobody need be called to account, and business can go on as usual: after all, $3bn is about half the profit that these three drugs produced every year while they were being mis-marketed. Here’s a swingeing perspective piece titled Punishing Health Care Fraud—Is the GSK Settlement Sufficient? The answer of course is no. There is nothing to stop fraud continuing as a lucrative business plan, and nothing to bring those responsible to court. And is GSK just a bad apple? No way—there are 25 others who are under special measures, including most of the big names in US pharma.
How Physicians Interpret Research Funding Disclosures (pg. 1119): Take a look at this study of how US medical interns rate hypothetical studies of new drugs: it’s free to everybody courtesy of Jeff Drazen, who also produces an editorial that you can read in full. Lampytinib, bondaglutaraz, provasinab: what fun to make up drug names like that, and trial designs that varied from a proper large RCT to a footling open-label study with no safety data. Not surprisingly, the interns had little difficulty in grading the quality of these mock-ups. But now comes the interesting bit: they were much less inclined to believe the results if the studies were marked as industry funded. This earns them a lofty reproof from headmaster Drazen: “Patients who put themselves at risk to provide these data earn our respect for their participation; we owe them the courtesy of believing the data produced from their efforts and acting on the findings so as to benefit other patients.” Amen to that—but that’s exactly why we mistrust data that have been gathered and interpreted by people with billions of dollars riding on the result—and who have a track record of deceit. If Drazen wants to show true courtesy to the trial participants, he needs to insist that for every trial published in the NEJM there is a full database of raw, de-identified patient-specific data, with the trial protocol and any variations from it, and all other meta-data required to interpret the study, open to all bona-fide investigators. And let’s not forget that the NEJM itself has a vested interest in putting a positive spin on industry-funded trials, as it gets a substantial (undisclosed) proportion of its income from the sale of reprints to pharma companies. There have been some terrific responses to this editorial, especially from Harlan Krumholz and Joe Ross.
BMJ 22 Sep 2012 Vol 345
Systolic and Diastolic BP and All-Cause Mortality in Those Newly Diagnosed with Type-2 Diabetes: “It is refreshing to read an article highlighting the risks of tighter blood pressure control in diabetic patients. But we have to remember that it is a retrospective study, so we don’t know when a patient’s glycaemic index breached the diabetes threshold and when patients were diagnosed. Furthermore, who measured patients’ blood pressures and by what method?” It’s really weird that the BMJ flagged up and printed this rapid response because it is mistaken on almost every count. This is a database study of the blood pressure as measured by UK general practitioners in the first year of diagnosis of type 2 diabetes (from 1990 to 2005), and how it relates to mortality over that period. It tells us nothing about treatment effects. The reason that the glycaemic index of the patients is not reported is presumably because nobody wanted to eat them.
September 24th, 2012
Stress and Coronary Heart Disease: What Role Does Gender Play?
Xiao Xu, PhD
Dr. Xu is a health economist at Yale University School of Medicine. Her research has focused on improving health care delivery and health outcomes of older adults and women, as well as economic evaluation of health interventions.
I am glad to see a growing literature on the link between psychosocial stress and coronary heart disease, as well as an increased interest in the gender differences in this relationship. But the assessment of psychosocial stress from a gender perspective seems to deserve more careful thinking and discussion.
A meta-analysis published in the Lancet last week reported a significant and “broadly similar” association between job strain and incidence of coronary heart disease for men and women. Like many existing studies, this analysis measured job strain based on workload demand and control. While these are two important work-related stressors, they may not adequately capture stress from work-family conflict often encountered by women because of the multiple roles they play in family life and at work. For example, caregiving responsibilities for children and elderly parents often fall on the female members of the family. This can cause major work-family conflict for women and become an important source of stress.
Men, on the other hand, appear to be more affected by job insecurity – another work-related stressor. Just like Dr. Netterstrøm pointed out in the comment accompanying the Lancet article – that “different types of work will have different strain profiles” – there are unique strain profiles for men and women as well. Whether evaluating data or consulting patients, let us all be a little more cautious about the role of gender when assessing stress as a risk factor for cardiovascular diseases.
September 21st, 2012
Apixaban (Eliquis) For Atrial Fibrillation Gets Positive European Recommendation
Larry Husten, PHD
The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval for apixaban (Eliquis, Pfizer and BristolMyers Squibb) for atrial fibrillation. The drug is already approved in Europe for the prevention of venous thromboembolic events following hip or knee replacement surgery. The drug has not yet been approved in the United States.
Here is the CHMP-proposed indication for the existing 2.5 mg dose and a new 5 mg dose:
“Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).”
The CHMP proposed that apixaban should be contraindicated in patients at high risk for major bleeding and in patients receiving other anticoagulants.
The CHMP decision was based on data from the ARISTOTLE and AVERROES pivotal clinical trials.
September 21st, 2012
News Flash! Company Issues Incredibly Boring Press Release
Larry Husten, PHD
Abiomed recently issued a press release (linked below) that was about as dull as a press release can get. The main news of the press release was that the PROTECT II study testing the company’s Impella 2.5 circulatory support device had been published online in Circulation.
The press release provides no details or information about the trial and makes no claims about the clinical benefits of the company’s device. The only remotely interesting items in the press release are generic quotes from the principal investigator of the trial, William O’Neill, and from Michael Minogue, the chairman and CEO of Abiomed:
O’Neill: “Today marks a very significant milestone in providing new clinical insight for cardiovascular disease patients considered too risky for conventional surgery. The PROTECT II publication in Circulation underscores the importance of this study’s observations to the clinical community.”
Minogue: “PROTECT II is a landmark clinical trial and we are grateful to Dr. O’Neill and his colleagues for leading this study. The peer-reviewed publication of PROTECT II in the esteemed Circulation journal is a notable achievement for Abiomed. Most importantly, we believe that this study will advance the treatment for patients with heart failure.”
Now all this would be entirely unremarkable, except for the fact that O’Neill and Abiomed struck a very different tone earlier in the history of this trial.
In December 2010, when the trial was terminated early due to futility, the company issued a press release that contained numerous details about the results of the trial and then portrayed these results as a triumph, despite the fact that the overall trial was negative. Although the full results had not been publicly presented, much less undergone peer review or scrutiny from other physicians or regulators, the CEO said the trial would “pave the way to change the standard of care for PCI requiring prophylactic hemodynamic support.” And O’Neill told Wall Street investors that the trial was “a landmark trial that will impact practice.”
As I wrote then, the press release struck me as a perfect example of how to spin a negative result, relying on cherry-picked endpoints and subgroups. (The original press release was removed from the company website but can be found in my news story.) Rick Lange and David Hillis provided their own critical perspective of the trial on CardioExchange.
The initial press release wasn’t the only problem with the roll-out of PROTECT II. An additional issue became fully apparent a few months later in April 2011 when the full trial results were scheduled for presentation at the American College of Cardiology meeting in New Orleans. Prior to the meeting, the company issued a press release announcing that the study would be presented at a late-breaking clinical trials session, a highly prestigious and much-desired position.
But PROTECT II was not presented at a late-breaking clinical trial session. As I reported shortly before the ACC meeting, the trial “was resoundingly shot down as an ACC late-breaking clinical trial at the selection meeting” because the company had violated the Ingelfinger rule, which prevents publication of trial information that has been previously submitted or reported elsewhere. In other words, the earlier Abiomed press release led the ACC to disqualify the trial for presentation as a prestigious late-breaker.
Circulation is unlikely to lift the veil on its editorial process, but my guess is that the journal played a big role in the final shape of last week’s remarkably modest publication and accompanying press release. The Circulation paper concludes – properly– that “Impella 2.5 did not result in a superior outcome of the primary endpoint at 30 days.” The paper also reports the results of a more promising secondary analysis suggesting a possible benefit for the device at 90 days, but rather than hyping these results as heralding a change in the standard of care, the authors write: “Since the difference in 30 day MAE [major adverse events] did not reach statistical significance for the entire study, the analysis of 90 day events remains exploratory.”
So let’s celebrate genuine progress, in this case represented by a dull scientific paper and an even duller press release.
