September 27th, 2011
Experience Counts in Carotid Artery Stenting
Larry Husten, PHD
According to a new study published in JAMA, experience really does count when it comes to carotid artery stenting (CAS). And that may be a big problem, since the explosive growth in the procedure after gaining FDA approval in 2004 means that most current operators do not have substantial experience with the procedure.
Brahmajee Nallamothu and colleagues analyzed Medicare data from 24,701 CAS procedures performed between 2005 and 2007. The overall 30-day mortality rate was 1.9%, but there was a significant increase in the risk for death among patients treated by the lowest-volume operators.
Here are 30-day mortality rates and adjusted odds ratios based on annual volume of operator:
- High-volume operator ( ≥24 procedures): 71 deaths out of 5127 procedures, OR 1 (reference)
- Medium-volume operator (12-23 procedures): 114/7059, OR 1.2 (p=0.30)
- Low-volume operator (6-11 procedures): 109/5752, OR 1.4 (p=0.06)
- Very-low-volume operator (<6 procedures): 167/6763, OR 1.9 (p<0.001)
Lower-volume operators were also much less likely to use embolic protection devices than higher-volume operators.
In an accompanying editorial, Ethan Halm expresses concern about the growing use of CAS, especially for elderly patients and asymptomatic patients. The 1.9% mortality rate in the study is substantially higher than the 0.7% in CREST. He writes that “relatively high complication rates in real-world practice would substantially reduce and perhaps completely eliminate any long-term expected benefit of revascularization, especially among asymptomatic patients who have much less to gain from the procedure.”
Although the current study shows that “practice makes perfect,” he writes, “it may be that some physicians are ‘practicing too much.’ A procedure performed in a patient who would not be expected to benefit from it is inappropriate and wasteful regardless of how skilled the operator or how low the complication rate.”
CardioExchange’s Interventional Cardiology moderators, Rick Lange and David Hillis, posed some great questions to the lead author of the JAMA study. Click here to read their interview and ask questions of your own.
September 27th, 2011
Carotid Stenting: How Steep the Learning Curve?
Brahmajee Kartik Nallamothu, MD, MPH
In an observational study involving Medicare patients undergoing carotid stenting between 2005 and 2007, Dr. Brahmajee Nallamothu and colleagues showed that low annual operator volume and early experience are associated with increased 30-day mortality. CardioExchange Interventional Cardiology moderators Rick Lange and David Hillis have posed the following questions to Dr. Nallamothu:
RL and DH: Did you find clues about whether the reduced mortality achieved by high volume operators resulted from improvement in their techniques or in their patient selection?
BN: Great question. On a surface level, the more-frequent use of embolic protection devices (EPDs) among experienced operators might be construed as evidence that it was greater technical skill that led to better outcomes. But this could be misleading. Experienced operators could base their patient selection on the likelihood that EPDs will be required or could even turn down cases in which EPDs can’t be used. So we feel that both technical improvements and patient selection are potential explanations for the differences we identified.
RL and DH: Mortality with the most experienced operators in your study (1.4%–1.7%) was substantially higher than was observed in the CREST study (0.7%) and in post-approval studies (0.9%–1.1%). Why?
BN: We believe that our mortality findings largely resulted from a less highly selected patient population than in previous studies. For example, the mean age of patients in our study cohort was 76.2. By comparison, the mean age of patients undergoing carotid stenting in CREST was 68.9. This alone could explain much of the differences you note, particularly with the more-experienced operators.
RL and DH: Is the “cost” of training high-volume operators subjecting patients to low-volume operators initially? Is this acceptable? If so, how is it best done?
BN: Again, great question. There certainly is a “cost” to training new operators to perform complex procedures like carotid stenting. As we note in the article, restricting use to experienced operators early during the dissemination of a new technique could harm long-term access to it. The flip side of this debate is that studies such as CASES-PMS have shown that with good training, new operators can perform the procedure with acceptable outcomes. The significant gap we found could be attributable to the fact that we don’t have formal mechanisms in place to ensure that all new operators go through such rigorous programs. I think we can do better.
RL and DH: In the interest of informed consent, should the physician be required to disclose to the patient how many carotid artery stenting procedures he or she has performed? Do you think physicians would be willing to do this?
BN: As a proceduralist myself, I struggle with this answer. But I think the best perspective on this topic is contained in a commentary by Harlan Krumholz published in JAMA last year. It is hard to read that article and not come away with the feeling that such information should be a part of every informed consent.
RL and DH: Some recommend selectively avoiding less-experienced operators unless they can provide acceptable outcomes data or other convincing evidence of proficiency. Given that 30-day mortality was only 2.5% with the lowest-volume operators in your study, how practical is such a requirement?
BN: This is a major point. A surgeon colleague of mine, Justin Dimick, wrote a wonderful piece for JAMA back in 2004, pointing out that for low-volume procedures with modest complication rates, it is almost impossible to judge operator quality from a statistical standpoint, given the problem of small sample sizes. I think that this could be an issue for carotid stenting. One possible solution is to add rates of stroke, which are much higher and also a measure of proficiency, to outcome assessments. Composite measures that combine risk-adjusted outcomes with volume are also a potential solution.
RL and DH: You found that low-volume operators were less likely than higher-volume operators to use embolic protection devices (EPDs). How would you explain this? Could it be that the importance of EBDs was not appreciated during early experience (procedures done in 2005 vs. 2007)? Some low-volume operators must have used EPDs from the outset. Did they demonstrate such a learning curve?
BN: This is a tough question to answer with certainty. The use of EPDs has grown over the years, especially now that their use is required by CMS for reimbursement. Accounting for the use of EPDs in our mortality models mitigated but did not eliminate the statistical significance of our findings between very-low and high-volume operators. Differences in outcome between patients treated early and late during the experiences of their operators also remained significant even when we restricted our analyses to only those patients who received EPDs. So I think EPDs are an important aspect of this difference, but they cannot entirely explain our findings. As a hypothesis, I wonder if operators who were just beginning to perform carotid stenting might have been trying to keep the procedure as simple as possible by avoiding the use of EPDs.
September 26th, 2011
Statins for Primary Prevention: The Debate Continues
Larry Husten, PHD
Several leading cardiologists have taken issue with the assertion made by Rita Redberg and the editors of the Archives of Internal Medicine that using statins for primary prevention is an example “of the widespread use of medications with known adverse effects despite the absence of data for patient benefit for these indications.”
In a research letter published in the current Archives, C. Michael Minder and colleagues (including Sanjay Kaul and Roger Blumenthal) write that they “believe there is compelling evidence to support the use of statins for primary prevention in patients at high risk… for developing coronary heart disease (CHD) over the next 10 years.” They assert that by focusing on short-term mortality, the Archives editors overlooked the substantial benefits of statin therapy for primary prevention in appropriately selected patients.
Minder and colleagues acknowledge that the evidence for a mortality benefit for statins in primary prevention is “less than robust,” but that when it comes to morbidity the “message is clear.” They cite a Cochrane meta-analysis showing a 34% reduction in revascularizations and a 30% reduction in combined fatal and nonfatal CV endpoints.
The authors argue that it is “paramount to make the distinction between low-risk and high-risk primary prevention cohorts.” They agree that primary prevention is unlikely to benefit people with a 10-year Framingham risk score of less than 10%, but that patients “without known CHD but with diabetes, hypertension, hyperlipidemia, and tobacco use … are likely to benefit from statin primary prevention.”
In response, Redberg and colleagues point out that some of the data in support of primary prevention include patients with known CHD. Furthermore, they state, the authors “do not acknowledge the commonly reported adverse effects associated with statins, including memory loss, muscle pains, weakness, and liver function abnormalities.”
September 23rd, 2011
Former NEJM Editor Questions Decision to Publish ARISTOTLE
Alison Bass, MLA and BA
The following guest post is reprinted with permission from the blog of Alison Bass.
At a Harvard event last night honoring Paul Thacker, a former investigator for Senator Chuck Grassley, someone in the audience wanted to know how the topic of Thacker’s talk — Dollars for Doctors: Who owns your physician? — was related to the soaring cost of medical care in this country. A video of the talk is available here.
As Thacker noted at the outset of his talk, Medicare and Medicaid now consume a larger portion of the federal budget than the Pentagon, and health care now equals 23 percent of all federal expenditures. Part of the problem, he noted, is the fact that our medical system is stacked toward the widespread adoption of expensive new drugs over older generics, even when the new agents are not necessarily safer or more effective than cheaper drugs.
It was left to Dr. Arnold Relman, Professor Emeritus at Harvard Medical School, to showcase a fresh-off-the-page example of how studies that are funded by drug makers and conducted by researchers who have financial ties to the industry present skewed research results that favor expensive new drugs over generics.
His case in point: The New England Journal of Medicine published a study last week concluding that a new anticoagulant known as apixiban (brand name: Eliquis) was superior to the generic drug warfarin in preventing stroke and deaths in patients with atrial fibrillation (abnormal heart rhythm). The study was funded by Bristol Myers Squibb and Pfizer, which jointly manufacture Eliquis, and featured a lengthy roster of authors, many of whom have extensive financial ties to the drug industry (in the form of speaking and consulting fees). At least three of the authors were Bristol Myers Squibb employees, as the fine print at the end of the study disclosed.
The issue Relman, a former editor of the New England Journal of Medicine, raised was how these financial conflicts may have influenced the way the paper itself was skewed in favor of the new drug. He noted two major omissions in the discussion section of the study. One: the anticoagulant showed no efficacy over the much cheaper warfarin generic in the 7,000 patients recruited in Europe (this was a multi-center trial involving 18,000 patients from the U.S., Latin America, Asia and Europe). Two: 35 percent of the patients on warfarin were not taking a therapeutic dose of the drug, which, he said, could explain why they had a higher rate of blood clotting and stroke than patients taking the new anticoagulant.
Yet neither of these key limitations was mentioned in the study’s discussion, a glaring omission, according to Relman. He said that the journal itself was remiss in publishing the study without mentioning these limitations.
“This study was not well peer reviewed,” Relman said. “Neither [Dr. Marcia Angell, also a former editor of NEJM] nor I would have accepted this paper for publication.”
Yet as a result of its publication, many heart doctors will now be steered toward prescribing a much more expensive drug when the cheaper generic would do just as well in many cases.
The study, Relman said, is a prime example of why the disclosure of conflicts of interest (which most leading journals now require) is not enough to curb bad or biased science. He suggested that medical institutions simply prohibit their faculty from doing research on drugs when they are receiving lucrative speaking and consulting payments from the industry. (Research shows a clear link between company funding of a trial and favorable results for that company’s drug — see here and here.)
“The real solution is for medical institutions to get rid of these unethical practices,” Relman said. “Disclosure is not a solution.”
Thacker agreed. The Physician Payment Sunshine Act, which he helped shepherd into law and requires drug companies to disclose all payments to doctors, should be considered a first step, he said.
“It’s a way to get a handle on just how widespread the problem of financial conflicts of interest are, so we can start to make real changes,” he said.
If the documented harm to patients from such conflicts of interest is not enough of a reason, perhaps the unsustainable costs to our overburdened health care system will eventually tip the balance toward change.
September 23rd, 2011
Rivaroxaban (Xarelto) Gets Positive Recommendation for AF and DVT in Europe
Larry Husten, PHD
The European Committee for Medicinal Products for Human Use (CHMP) has recommended that rivaroxaban (Xarelto) be approved for the prevention of stroke and systemic embolism in AF, according to Bayer HealthCare. CHMP has also recommended the drug’s approval for the treatment of DVT and for the prevention of recurrent DVT and PE following acute DVT. Bayer is developing the drug in conjunction with Johnson & Johnson.
Rivaroxaban is already approved in Europe for the prevention of VTE following hip- or knee-replacement surgery. Bayer said that approval for the new indications would make rivaroxaban the first new oral anticoagulant in the EU with all three indications.
The AF recommendation was based on the ROCKET AF study, which was the subject of intense scrutiny and controversy a few weeks ago at the FDA advisory panel. The DVT recommendation is based on the EINSTEIN-DVT study.
September 22nd, 2011
Diet Drugs Get a New Slim Chance at Approval
Larry Husten, PHD
Contrave, the investigational diet pill combination of naltrexone and bupropion, has been granted a possible new lease on life by the FDA. In January of this year, the FDA issued a complete response letter to Orexigen, the drug’s sponsor. Now Orexigen says that it has received guidance from the FDA that could lead to approval of the drug in 2014.
The FDA has “identified a very clear and feasible path forward for this important therapy,” said the company president and CEO.
To gain approval, Orexigen will have to perform a cardiovascular outcomes trial. The trial will enroll less than 10,000 patients and could lead to conditional approval after about 2 years, the company said. At the interim analysis, which would take place after about 87 events had occurred, the trial would have to rule out a hazard ratio of 2.0 At trial completion, it would need to rule out a hazard ratio of 1.4. The company said it hoped to initiate such a trial in the first half of 2012 after discussions with the FDA.
Writing in Forbes, Matt Herper pointed out that even if the trial is successful, approval is far from guaranteed:
The FDA told Orexigen, in writing, that “if the interim analysis meets the specified criteria to exclude an unacceptable increased cardiovascular (CV) risk, the drug could be approved.” That “could” is pretty important — the FDA might consider the results of such a trial and decide that Orexigen’s risks still don’t outweigh its benefits.
Sanjay Kaul, who was a member of the Contrave advisory panel, sent this comment:
It is heartening to hear the FDA is moving in the right direction with regards to establishing a regulatory standard for approval of obesity drugs that is modeled after the diabetes guidance. Greater clarity in outlining the metrics for a favorable benefit-risk assessment, including weight loss, improvement in cardiometabolic profile, and ruling out unacceptable cardiovascular risk a priori would help reduce the regulatory ambiguity. This is a good development for sorely needed therapeutics in this arena.
In a separate development, last week Vivus said that the FDA would allow it to resubmit its NDA for topiramate (Qnexa), another diet drug placed in limbo by the FDA, possibly leading to an FDA decision in 2012. Because of concerns about birth defects in women taking the drug, Vivus said it would seek an initial indication that would exclude women of child-bearing age.
A third diet drug, lorcaserin, has also been delayed, in this case due to findings of cancer in animals. In August Arena Pharmaceuticals said that it planned to resubmit its application by the end of the year.
September 22nd, 2011
Follow the Fellows: The Fellows Get Their Sealegs
Aaron C. Earles, DO, William Kent Cornwell, MD, Erica Sarah Spatz, MD, MHS and Kathryn Jesseca Lindley, MD
For our new series at CardioExchange, “Follow the Fellows,” we have invited physicians from various cardiology fellowship programs to document their course through their training. In their second post, the fellows continue to discuss their initial concerns and experiences soon after entering fellowship. You can read their first post here.
Bill Cornwell — Being “immersed” in the ICU, I have been given the task of managing complex patients while orienting to a new hospital, working seemingly longer hours than ever before, and wondering how my family is getting along in a new city. As I hope for some dust to settle, residents approach me for advice just as I once sought out my fellow, who always seemed so knowledgeable, confident, and able. I am stretched thin, my mind in several places all at once, and I must remind myself to focus on the task at hand. Am I the only one who feels this way, or are the other fellows facing a similar challenge?
Over a quick lunch we commiserate, share some quick anecdotes and I discover that I am not alone. This line of work demands a certain degree of fluidity to respond well to ever-changing conditions and be comfortable amidst some chaos. The terms may be clichéd, but this truly seems to be a trial by fire, and success requires quick adaptation. Onlookers might counter that this is an overreaction but I believe that anyone who has walked down this path knows what I mean.
Aaron Earles — Every fellow I spoke with has told me that they too had the same fears and hesitation about becoming a specialist. The first ECHO board review session I attended with the seniors was one of the most intimidating events I have encountered to date. I was completely lost. The session leaders seemed to be speaking a different language. But a couple of sessions and a few pep talks from upper-level fellows later, and the concepts started making better sense.
Fellowship, to this point, has been on par with my expectations. My second month was on the consult service which took some adjusting. I have said “I don’t know the answer to that” more often than I feel comfortable, but my attendings have been wonderful. I have never once felt intimidated by asking for help or an explanation. That brings up a good point — everyone knows you are there to learn and not to know how to do everything. I am fortunate to have three wonderful senior fellows to help me acclimate to this new environment. They take time to explain difficult concepts and thus far have given me excellent advice. They look out after me, but give me just enough autonomy to learn.
Kate Lindley — I am getting my sea legs. I respond confidently to pages about patients on my service. I called off a STEMI in the ER with little reservation (I did still run the EKG by my senior afterwards). I have a comprehensive plan for my patients – it might not always be right, but at least I have solid reasoning behind my decision-making. I have a lot to learn, but I have to trust that next July I’ll be ready when I receive my first stat “I’m going to need you” consult from a new first year. Most of the fear and anxiety has now resolved, replaced by excitement for the interesting pathology and rich learning environment I’m submerged in. I look forward to facing novel patient-care questions all day long…and then making it home in the evening in time to hit up the local ice cream joint before my daughter needs to get to sleep!
Erica Spatz — Rarely, do we expose our wounds, humility, fear, shame — as in “I didn’t know what was going on or what to do” — followed (hopefully) by “I called my attending.” I admit to owning all of these emotions. And while I have faith in our system of training (as evidenced by the confidence exuded by fellows just one year ahead), I have found that my best weapons for taking call are those that have guided me through all of my professional transitions:
Let the patient be your compass. (1) A careful history and examination will always lead you down the right path. (2) There are no ‘bogus’ consults when patient care is at stake. When consulted it is because the resident/clinician needs help taking care of the patient. They may not be able to articulate the appropriate question, but they have exceeded their knowledge or skills.
Communicate; be a team player. (1) Call on others for help, including co-fellows and attendings. (2) Communicate your thoughts by articulating a differential diagnosis; seize every opportunity to contribute something meaningful. (3) Disclose when or what you do not know; it is almost always appreciated by the patient…and certainly by your attending.
Seek wisdom. Learn from mistakes. Days are long. Partners, kids, and friends await. Still, take time to reflect — to reinforce what was learned, to question what does not add up. Seek feedback — take stock of the quality of care being delivered and question whether this is the best we have to offer. Aspire to be a better physician each day.
Chicken soup for call? I hope Mom approves.
September 21st, 2011
More Data but No Answers About Platelet Function Testing
Larry Husten, PHD
The RECLOSE 2–ACS (Responsiveness to Clopidogrel and Stent Thrombosis 2–ACS) trial from Italy provides new information about platelet reactivity but doesn’t answer any of the key questions about the possible role of platelet function testing in clinical practice.
In a paper published in JAMA, Guido Parodi and colleagues report on 1,789 ACS patients who underwent PCI and who had their platelet reactivity measured. Patients found to have high residual platelet reactivity (HRPR) received a larger dose of clopidogrel or were switched to ticlopidine.
- After 2 years’ follow-up, the rate of cardiac death, MI, urgent coronary revascularization, or stroke was 14.6% in the group with HRPR versus 8.7% in the group with low residual platelet reactivity (absolute risk increase: 5.9%; CI 1.6%-11.1%, p=0.003).
- Within the HRPR group, there was no difference in outcome between patients who, after treatment, had an ADP test result below 70% and those with an ADP result of 70% or above.
- Stent thrombosis occurred in 6.1% of patients with HRPR versus 2.9% of those with low residual platelet reactivity (absolute risk increase: 3.2%, CI 0.4%-6.7%; p=0.01).
In an accompanying editorial, Dominick Angiolillo writes that the absence of benefit on the primary endpoint with adjusted therapies “leaves unsolved the pivotal dilemma of whether platelet reactivity is simply a marker of risk or if it is a modifiable risk factor that can affect prognosis.” Platelet function testing, says Angiolillo, remains a research tool: “Currently available evidence cannot support routine use of PFT in clinical practice.”
September 20th, 2011
Significant Declines Observed in Cardiovascular Procedures Performed in Hospitals
Larry Husten, PHD
More evidence is starting to emerge that the overall volume of cardiovascular procedures in U.S. hospitals is in decline. The trend should come as no surprise to those who have been following news about cardiovascular medicine in recent years, as the field has been repeatedly struck by debate, scandal, and controversy related to the potential overuse of expensive and invasive therapies.
A monthly report from Wells Fargo that tracks hospital volume found a 9.37% drop in inpatient cardiovascular surgeries and procedures in July 2011 compared with July 2010. This continues a trend of similar monthly declines in the range of 6%-11% each month this year compared with 2010. The trend is partially offset by a modest increase in some months in outpatient procedures, though in July cardiovascular outpatient procedures also decreased by 6.28%.
The broad trend observed by Wells Fargo is confirmed by HCA, the large private hospital company. In its quarterly financial report, HCA said that overall demand for its cardiovascular services has been declining by approximately 3% each year for several years, despite a slight growth in the hospital chain’s share of the overall market. Samuel Hazen, the president of HCA, said the decline “appears to be consistent with information from cardiac medical device companies’ public reports.”
In its quarterly report, the company included an analysis of a decline in Medicare revenue growth that it attributed to a significant shift from surgical to medical cardiovascular procedures. HCA disclosed that, compared with the same period a year ago, in the second quarter of this year it performed 769 fewer inpatient EP, interventional, cardiothoracic, valve, and vascular surgeries and procedures. By contrast, in the same period it performed 540 more medical procedures. (You can download the HCA slides here, then click on the link to the HCA Second Quarter 2011 Review Presentation Slides.)
I would speculate that a number of major factors play a role in this trend, including:
- Concerns about stent overuse – as indicated most notably in the Mark Midei case, but also in more sober academic studies (such as this one) that have served to at least slow down the previous headlong rush to stent implantation. The COURAGE trial undoubtedly has played a key role here, though its immediate effect appeared to be fairly small.
- The Department of Justice investigation into ICD implants – although few details about this investigation are known, it has undoubtedly had a broad dampening effect on ICD implantation.
- The payoff from preventive therapies like statins, aspirin, and antihypertensive therapy.
- The larger economic climate.
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