July 11th, 2011
OAT Had Little Impact on Clinical Practice
Larry Husten, PHD
Once again, a study finds that cardiologists don’t always pay attention to the literature and guidelines. In 2006, the Occluded Artery Trial (OAT) showed no benefit for routine PCI in patients with persistently occluded infarct-related arteries identified at least one day after an MI. But the study appears to have had minimal impact on clinical practice, according to a report published in the Archives of Internal Medicine.
To assess the impact of OAT, Marc Deyell and colleagues used data from the CathPCI Registry to identify 28,780 patients treated from 2005 to 2008 who met the eligibility criteria for OAT. They found no significant decline in the rate of PCI in their population following the publication of OAT (OR 1.018; CI, 0.995-1.042). Following a subsequent revision of the guidelines (stating that PCI “should not be performed” in these patients), they detected a trend indicating fewer procedures (OR, 0.963;CI, 0.920-1.000). Overall, the crude rate of PCI for total occlusions was 54.2% before the publication of OAT, 52.8% after publication, and 51.9% after the guidelines were changed.
In their conclusion, the authors, led by Judith Hochman, write that the results are “a cause for concern on 2 levels. First, they imply that many stable patients with recent MI and persistent infarct artery occlusion continue to undergo a costly and ineffective procedure. Second, a large public, scientific, and human patient investment in the generation of robust clinical evidence has yet to broadly influence US practice.”
In an invited commentary, Mauro Moscucci writes that the reasons for the lack of response to OAT are “multifactorial.” He cites several potential factors affecting cardiologists, including “personal experience, a perception of low risk of PCI, a desire to please referring physicians, the feeling of a ‘mandate’ to relieve ischemia, the possibility of regret over the possible consequences of not intervening on a lesion, and patients’ expectations and anxiety.” Financial pressures may also come into play, he says.
July 9th, 2011
Will You Still Use Multaq (Dronedarone)? A CardioExchange Panel
CardioExchange Editors, Staff
With the news that the PALLAS study of dronedarone (Multaq) for permanent AF has been stopped early, CardioExchange convened a panel to address a simple question:
What use—if any—do you see for dronedarone given both the cessation of this trial and the recent data on liver toxicity associated with this agent?
Sorry, there are no polls available at the moment.
Stuart Connolly, MD (PI for the PALLAS study)
There is a big difference between the ATHENA and PALLAS trials—with only intermittent AF in the former and only permanent AF in the latter. The results of PALLAS do not negate ATHENA. Because ATHENA had more patients and much longer follow up compared with PALLAS, it had much more statistical power as well. It is still unclear if there is a causal link between dronedarone and liver toxicity. So there still appears to be a good rationale to use dronedarone in intermittent AF.
A basic tenet of treating AF is to avoid making the treatment worse than the disease. Multaq is not only ineffective in controlling AF episodes and often associated with side effects, but now, recent reports suggest it confers an increased risk of cardiovascular and hepatic toxicity. Therefore, I see no role for Multaq in the treatment of AF.
I read the brief announcement on the trial that was stopped, but with no additional data yet available, I plan to continue using dronedarone as I have been for suppressing atrial fibrillation episodes in appropriate symptomatic AF patients. I am routinely adding occasional liver-function tests as part of the follow-up of patients taking dronedarone.
The premature stopping of the PALLAS trial due to unacceptable safety concerns strengthens our previous caveat against off-label, indiscriminate use of dronedarone and narrows the therapeutic window of dronedarone to “low-risk” patients with non-permanent atrial fibrillation/flutter who are unable to tolerate other antiarrhythmic agents including amiodarone. Given its modest antiarrhythmic efficacy, lack of well-established safety advantage over amiodarone, huge cost disadvantage, and potential hepatic toxicity, I see this agent as having a limited role that is far from making dronedarone a “game changer” or an “important milestone” in management of atrial fibrillation.
Finally, this should strike a cautionary note for the guidelines to refrain from making strong recommendations that are not driven by high-quality evidence.
**********************************************************
For those of you on the front lines of AF treatment, who among these panelists do you agree with—if anyone?
July 7th, 2011
Expert Panel: How Often Is PCI Appropriate?
CardioExchange Editors, Staff
The CardioExchange editors have asked a panel of experts to weigh in on a new study published in JAMA. It showed that nearly all the acute percutaneous coronary interventions (PCIs) in the National Cardiovascular Data Registry from June 2009 through September 2010 were warranted, according to “appropriate use criteria” for coronary revascularization. However, the study also revealed that 12% of the nonacute PCIs were inappropriate.
We put these questions to the panel:
Does the study’s major finding support the status quo, or do you see opportunities for improvement? What specifically should be the next steps?
Paul S. Chan (lead study author, U. Missouri–Kansas City): I believe there remain important opportunities to improve patient selection for elective angioplasties. For instance, most inappropriate cases occurred in patients who were either asymptomatic or minimally symptomatic, or who had low-risk stress-test results. Hospitals participating in the CathPCI registry have received reports on their appropriateness rates and their performance relative to other hospitals, as well as a list of patients with inappropriate angioplasties. Hospitals can now be proactive by performing a review of these reports and identifying practice patterns that may lead to inappropriate procedures.
Rita F. Redberg (UC San Francisco):
I congratulate the authors on an important analysis of data from the version 4 Cath PCI NCDR registry: a database that was designed with appropriate use studies in mind.
I think that the study supports that the majority of PCIs are done for appropriate indications. Clearly we can improve on the number of uncertain and inappropriate PCIs. This study indirectly points out the need to reevaluate the definition of “acute indications” (which the ACC views as appropriate by definition). Another recent analysis of NCDR data by some of the same authors found that one third of all patients getting PCI are asymptomatic, yet in this study, 70% of patients getting PCI were considered to have an “acute” indication. What counts as “acute”? For example, should anyone over age 75 years be defined as “acute”?
This study highlights the potential “overuse” of PCI, particularly in the non-acute PCI setting, where only 50% of the procedures were categorized as appropriate. Poor documentation, extenuating circumstances, or patient preferences might explain some of these findings, but true “overuse” is likely a contributor, and possibly a major one.
If the main benefits of non-acute PCI are to improve symptoms (and not to prevent death or MI), then the patient’s values, preferences, and goals should be incorporated through patient-centered shared decision making — where individualized benefits, harms, and quality of life for all therapeutic options (including PCI, CABG, and medical management) are discussed by the patient and clinical team.
Several caveats need to be applied in interpreting this report: it does not inform us about (a) “underuse” of PCI in patients with disparities, (b) the patient outcomes when inappropriate PCIs are performed, or (c) “misuse” when there are knowledge gaps about how to perform PCI. Much more work remains to be done to provide the right care for the right patient, nothing more and nothing less.
John E. Brush (Cardiology Consultants, Ltd.):
The rate of inappropriate PCIs performed in the non-acute setting varies among hospitals from 6% in the lowest quartile to 16% in the top quartile indicating an opportunity for improvement. But look at the big picture: Even though PCI is driven by self-referral, the overall rate of inappropriate procedures in the entire cohort is only 4%.
This analysis was not an outside audit. The analysis was by members of our profession using a registry and appropriateness criteria that were developed voluntarily by the ACC, SCAI, and other professional organizations. The data show that we still have room for improvement, but the entire effort should make us proud of our profession.
How would you answer the questions we put to our experts? And what do you think of their answers?
July 7th, 2011
Multaq’s Off Again, On Again, Then Off Again Ride
Westby G Fisher, MD
CardioExchange welcomes this guest post, reprinted with permission, from Dr. Westby Fisher, an electrophysiologist practicing at NorthShore University HealthSystem in Evanston, Illinois, and a Clinical Associate Professor of Medicine at University of Chicago’s Pritzker School of Medicine. This piece originally appeared on his blog, Dr. Wes.
Today was another tough day for Sanofi’s dronedarone antiarrhythmic medication (marketed as Multaq®) after the prospective randomized PALLAS Trial was stopped early. The PALLAS Trial was a trial that studied the safety and efficacy of patients with chronic atrial fibrillation (as opposed to the already-approved patient population with intermittent [or paroxysmal] atrial fibrillation). It seems there was an increased number of “cardiovascular events” in the drug-treatment arm of the trial and was NOT related to problems with hepatic toxicity as previously reported earlier this year.
Patients with intermittent atrial fibrillation already on the drug are encouraged NOT to stop their drug, but rather “consult your treating physician if you have any questions.”
But Multaq’s path through the drug approval process has been a rocky one. First came the ANDROMEDA Study, a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms. In this study, patients given Multaq had a greater than two-fold increase in mortality. Needless to say the FDA was not too pleased, so the drug failed to gain approval for that indication.
So the drug company decided to try a less sick population and began the ATHENA Trial. The ATHENA trial was the largest anti-arrhythmic drug trial conducted in patients with non-permanent AF/AFL, involving 4,628 patients with a follow-up of 30 months. In this trial, Multaq, on top of standard cardiovascular therapy, significantly reduced cardiovascular hospitalization or death by 24% (p<0.001) when compared to placebo, meeting the study’s primary endpoint. So the FDA granted the drug approval for this indication, provided the patients were carefully screened for heart failure (a contraindication to begin therapy).
All seemed right with the world for Sanofi, at least for a while. Doctors began using the drug but were generally disappointed in its efficacy despite its hype, being an amiodarone cogener and all. Still, plenty of pressure was applied to the writers of our guidelines to make sure this “highly studied” drug was first and foremost of recommended therapies in the latest atrial fibrillation treatment guidelines. In fact, Multaq® is currently available in 32 countries and is recommended as a first line treatment option in the majority of AF patients by BOTH the ESC and ACC/AHA.
Pretty impressive, given its earlier challenges getting approved.
But now we get the news about the PALLAS trial and we have to wonder: if it’s unsafe for older, sicker patients, why should it be okay for our younger ones?
We really don’t know.
But our antennae certainly are at attention now regarding Multaq. I suspect many doctors will now think long and hard before leaping to dronedarone as their “first line” therapy despite the current recommendations of our “guidelines.” More likely, this drug will be used when there are no other options (and there are those cases). Truth be told, most of our pharmachologic therapies to manage atrial fibrillation are problematic for many of our patients for one reason or another: either they have significant side effects or else they just don’t work. This is largely why the more invasive atrial fibrillation ablation procedure has gained favor.
But ablation is not a cake-walk either.
That is why the current NIH-co-sponsored CABANA trial comparing catheter ablation to drug therapy as first line therapy remains so important to continue.
Then maybe, just maybe, we can learn which therapy really does benefit our patients best long-term.
July 7th, 2011
ASCEND-HF: No Harm or Benefit with Nesiritide
Larry Husten, PHD
With the publication of the final results of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial in the New England Journal of Medicine, the once intense controversy over the use — or misuse — of the drug nesiritide in patients with acute decompensated heart failure has finally been resolved. The results, which were first presented last November at the AHA, demonstrate unequivocally that the drug was neither harmful nor beneficial.
CM O’Connor and colleagues randomized 7,141 patients with acute HF to either nesiritide or placebo. The primary endpoin t– the rate of rehospitalization or death within 30 days — occurred in 9.4% of patients in the nesiritide group versus 10.1% of patients in the placebo group (CI −2.1 to 0.7, p=0.31).
The investigators concluded that “on the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure.” Noting the early widespread use of the drug despite the lack of evidence, the authors wrote that “the results of this trial highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions.”
In an accompanying editorial, Eric Topol writes about the “lost decade” from the time of FDA approval of nesiritide to the publication of the trial, in which “well more than $1 billion was wasted on purchasing the drug.”
After the presentation last November of the initial trial results, Eugene Braunwald told CardioExchange: “I don’t see much of a future for nesiritide.”
July 7th, 2011
Dronedarone (Multaq) Study for Permanent AF Stopped Early
Larry Husten, PHD
The PALLAS trial of dronedarone (Multaq) for permanent AF has been stopped early, according to a press release issued by Sanofi. PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) was a double-blind, placebo-controlled, phase IIIb trial of dronedarone in patients with permanent AF.
The company said the discontinuation of the trial resulted from recommendations from the study’s Operations Committee and the Data Monitoring Committee (DMC) following “a significant increase in cardiovascular events in the dronedarone arm.” The company said the study termination “was not related to any hepatic adverse event.” (Earlier this year the FDA warned about liver injury associated with dronedarone.) The company has informed regulatory authorities and has instructed PALLAS clinical investigators to tell patients enrolled in the study to stop taking the study medication. The company said that it remained “committed to Multaq as an essential treatment option for non-permanent AF patients.” (Dronedarone is currently approved for use only in patients with non-permanent AF.)
The trial had two composite co-primary endpoints: major cardiovascular events and cardiovascular hospitalization or death from any cause. According to ClinicalTrials.Gov, the study was started in July 2010 and scheduled to be completed in August 2013 with a planned enrollment of 10,800 patients.
The co-principal investigator of PALLAS, Stuart Connolly, said in the press release that “the PALLAS Operations Committee is very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high risk patient population has been refuted.”
Sanofi said that 400,000 patients worldwide have now been treated with dronedarone.
Click here for previous coverage of dronedarone on CardioExchange.
July 7th, 2011
NCDR Report on PCI Appropriateness: A Slap on the Back…or a Slap in the Face?
Richard A. Lange, MD, MBA and L. David Hillis, MD
According to an analysis of data from the National Cardiovascular Data Registry (NCDR), nearly all (98.6%) acute PCIs (i.e., those done for STEMI, NSTEMI, and unstable angina) were classified as appropriate. For nonacute indications, however, only 50% were classified as appropriate; 38% were of uncertain appropriateness, and 12% were deemed inappropriate.
Dig under the hood and what do you find?
1. Appropriateness could not be determined in 17% of the > 600,000 PCIs in the NCDR because of inadequate data. If these represented low-risk patients, then the rate of inappropriate PCIs in the nonacute setting would be 21%, not 12%.
2. Substantial variation in the proportion of inappropriate PCIs in nonacute settings was noted among hospitals, ranging from 0% to 55%.
3. Of the patients undergoing an inappropriate PCI in the nonacute setting, 99% were asymptomatic or only mildly symptomatic, 72% had low-risk ischemia on noninvasive stress testing, 94% did not have coronary anatomic findings that were judged to be high risk, and 96% were treated with suboptimal antianginal therapy.
4. Although the authors state that it is “unlikely that hospitals inflated their rates of appropriate PCI by reporting more severe symptoms and stress test (results),” recent reports suggest otherwise. Physicians may exaggerate symptom and lesion severity in subjects undergoing unnecessary PCIs, whereas the hospital provides no oversight or turns a blind eye because of the reimbursement involved.
4. Of individuals who allegedly underwent appropriate nonacute PCI, 12% had no or minimal symptoms, 48% did not have high-risk features on noninvasive evaluation of ischemia, and 22% were on no antianginal medications (with another 39% on only one medication). How are these procedures appropriate?
Is this report a slap on the back…. or a slap in the face? Before answering, you may want to read Larry Husten’s take on the ACC President’s response.
Do you really believe that 98.6% of the PCIs performed for MI or unstable angina are truly appropriate?
July 6th, 2011
Lower Sudden Cardiac Death Rates Observed in Women with Healthy Lifestyles
Larry Husten, PHD
It probably won’t come as a big surprise, but a new study finds that women who live a healthy lifestyle have a lower risk for sudden cardiac death (SCD). In a paper published in JAMA, Stephanie Chiuve and colleagues analyzed data from 81,722 women enrolled in the Nurses’ Health Study. They used 4 factors to identify a low-risk lifestyle:
- not smoking
- BMI <25
- exercise lasting 30 minutes or longer per day
- adherence to the Mediterranean diet
Each factor was individually associated with a significant reduction in risk for SCD. Here are the absolute risks and adjusted relative risks for SCD in women with:
- 0 low-risk factors: 22 cases/100,000 person-years, RR=1
- 1 low-risk factor: 17/100,000, RR = 0.54
- 2 low-risk factors: 18/100,000, RR =0.41
- 3 low-risk factors: 13/100,000, RR = 0.33
- 4 low-risk factors: 16/100,000, RR = 0.08
The authors calculated that 4 out of every 5 SCDs may be attributed to “unhealthy lifestyle practices.” They concluded: “Because SCD accounts for more than 50% of CHD mortality, widespread adoption of a healthy lifestyle in the population may make a substantial impact on reaching the American Heart Association’s 2020 Impact Goal of further lowering cardiovascular disease mortality.”
July 5th, 2011
Only Half of Nonacute PCIs Deemed Appropriate
Larry Husten, PHD
Only half of all PCIs performed for nonacute cases have a definite indication, according to a report from the National Cardiovascular Data Registry published in JAMA. Paul Chan and colleagues analyzed data from more than half a million PCI procedures performed between July 1, 2009 and September 30, 2010.
Out of 500,154 PCIs, they found that 355,417 (71.1%) were for acute indications:
- STEMI: 103,245 (20.6%)
- Non-STEMI: 105,708 (21.1%)
- High-risk unstable angina: 146,464 (29.3%)
The remainder — 144,737 (28.9%) — were for nonacute indications.
The vast majority (98.6%) of PCIs for acute indications were classified as appropriate. By contrast, only half (50.4%) of those for nonacute indications were classified as appropriate; 38% were classified as uncertain, while 11.6% were considered inappropriate.
Among the nonacute cases deemed inappropriate:
- 53.8% were in patients with no angina
- 71.6% were in patients who had low-risk ischemia on noninvasive stress testing
- 95.8% were in patients taking fewer than two angina medications.
For the acute cases, there was little variation in the rate of inappropriate procedures across hospitals. For the nonacute cases, however, substantial inter-hospital variation was observed: the rate of inappropriate procedures for nonacute cases ranged from 6% or less in the lowest quartile compared with 16% or greater in the highest quartile. The authors write that the high rate in this group “suggests overuse of PCI in these hospitals and an important opportunity for improvement in patient selection.”
The authors acknowledge that some of the procedures classified as inappropriate “may be explained by extenuating circumstances,” but say such circumstances were unlikely to explain the majority of procedures. In addition, although patient preference may explain some inappropriate procedures, the authors point out that many patients overestimate the benefits of PCI and that most PCIs are performed immediately following diagnostic angiography, allowing little opportunity for a serious discussion with the patient.
The authors conclude that “better understanding of the clinical settings in which inappropriate PCIs occur and reduction in their variation across hospitals should be targets for quality improvement.”
July 4th, 2011
Meta-Analysis: Increased CV Risk Associated with Varenicline (Chantix)
Larry Husten, PHD
The anti-smoking drug varenicline (Chantix, Pfizer) is associated with an increased risk for serious adverse cardiovascular events, according to a new meta-analysis published in CMAJ.
In the meta-analysis, Sonal Singh and colleagues analyzed data from 14 double-blind randomized trials involving 8216 subjects. The rate of serious adverse cardiovascular events was 1.06% (52/4908) among varenicline recipients versus 0.82% (27/3308) among placebo recipients (odds ratio, 1.72; 95% CI, 1.09-2.71). The authors, led by Curt Furberg, estimated that the number needed to treat with varenicline for one additional person to successfully quit smoking was 10, whereas the number needed to cause one additional serious CV event was 28. The authors also noted that varenicline already has a black box warning about adverse neuropsychiatric symptoms.
In an associated commentary, J. Taylor Hays, who has conducted research on varenicline with funding from Pfizer, writes that “the small absolute risk of cardiovascular events associated with varenicline treatment is outweighed by the enormous benefit for reducing cardiovascular morbidity and mortality that can be achieved with successful smoking abstinence.”
The CMAJ paper follows a statement issued by the FDA on June 16, which warned that the drug might increase the risk for cardiovascular events in people who already have cardiovascular disease. “This would have raised a red flag for us if the flag hadn’t already been flying,” said the FDA’s Celia Winchell, in an interview with the New York Times.
The Times also quoted Furberg, who has served as an expert witness in cases against Pfizer: “We have known for many years that Chantix is one of the most harmful prescription drugs on the U.S. market, based on the number of serious adverse effects reported to the FDA. It causes loss of consciousness, visual disturbances, suicides, violence, depression and worsening of diabetes. To this list we now can add serious cardiovascular events.”
In a press release, Pfizer said that the meta-analysis was unreliable and that “the currently available safety data on Chantix… do not support an increased cardiovascular risk associated with Chantix.”
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