May 18th, 2012
FAME II: Another Study Abides in Infamy
Richard A. Lange, MD, MBA and L. David Hillis, MD
In FAME II, a prospective study conducted at 28 centers in Europe and the United States, >1200 patients with ischemia (as determined by fractional flow reserve [FFR]) were randomly assigned to receive (a) PCI (with a DES) and optimal medical therapy (OMT) or (b) OMT alone. The primary endpoint was a composite of death, myocardial infarction (MI), and unplanned hospitalization leading to urgent revascularization within 24 months of randomization.
Patients were considered to have urgent revascularization if they (a) entered the hospital through the emergency department and their revascularization procedures were performed during the same hospitalization, or (b) presented to clinic with increased angina symptoms.
The study was halted prematurely by the data safety monitoring board (DSMB) because of a difference in the incidence of urgent revascularization in the two study arms; the rates of death or MI were similar. In other words, urgent revascularization was performed for symptom relief, not MI. According to results presented at EuroPCR, the rate of unplanned revascularization within 6 months in the OMT and PCI+OMT groups was 12% and 2%, respectively.
These data can be interpreted in one of two ways. One can conclude that because urgent revascularization was required about 11 times more often in the OMT group than in the PCI+OMT group, PCI in patients with abnormal FFR results in an improved outcome. Alternatively, one can conclude that almost 90% of patients in the OMT+PCI group had an unnecessary (and costly) PCI.
The fact that the DSMB prematurely stopped this trial is troubling for several reasons.
1) Fewer than 40% of the patients had been followed for 2 months or longer before the study was stopped.
2) The trial was discontinued on the basis of a “soft endpoint” (i.e., symptom-prompted revascularization). Participants who did not undergo PCI experienced no “real” harm (i.e., death or MI).
3) Randomizing patients with ischemia to OMT alone is problematic. Because of the perception — held by both physicians and patients — that ischemic myocardium should be revascularized, PCI is almost always performed in such patients. In these individuals, any symptom becomes angina or an anginal equivalent and, as a result, PCI is indicated.
It is well known that trials that are stopped early because of an apparent treatment difference are prone to exaggerate the true effect of the intervention. They often stop on a “random high,” whereas the observed difference might well have regressed to the true effect if they had been continued for a longer time period.
Would you have considered it unethical to continue this trial, or would you have allowed it to continue?
May 18th, 2012
Standing Up for What You Believe: The Story Behind an Editorial
Harlan M. Krumholz, MD, SM
I had an experience the other week that reminded me that speaking your mind has its challenges. I was approached by someone with influence who asked me to cease my discussions on a particular topic. The reason was oblique – and I was told that people are viewing me negatively because my views are strong and wondering if there are conflicts of interest that are influencing me. In essence, I was told that people are whispering about me – though no names were given.
Now this topic was part of a scientific debate that has strong implications for guidelines and performance measures – and, well, patients. It is a situation where I am questioning conventional wisdom – and the long held beliefs by many individuals. I am trying to do so respectfully – and through the use of evidence – but still it is questioning dogma.
This conversation prompted me to write a message to my younger colleagues urging them to stand up for what they believe – and be willing to speak truth to power. I quote my friend Victor Montori, who eloquently advised a junior colleague about how to manage a concern about whether to express an opinion that was likely to be viewed negatively by her superiors. That person had been told to hold opinions tight until he had more grey hair. Victor starts by saying: ‘I have struggled with this issue for years. Turns out that this is a common struggle for those who find themselves unable to stay silent in the face of waste, error, low integrity, or abuse.’
In any case, take a look. Here is the link: http://circoutcomes.ahajournals.org/content/5/3/245.full
I would be interested in your thoughts.
May 17th, 2012
FDA Approves Generic Clopidogrel as Plavix Loses Patent Protection
Larry Husten, PHD
For the second time in the past 6 months, a cardiology mainstay drug has lost patent protection and gone generic. Today, the FDA announced that it had approved several generic versions of clopidogrel (Plavix), the antiplatelet drug that for many years was the second best-selling drug in the world. Last November, the best-selling drug of all time, Lipitor (atorvastatin), another cardiology mainstay, went off patent, though it wasn’t until earlier this month that multiple generics became available.
The FDA said that it had approved 300-mg formulations of clopidogrel from Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals and 75-mg formulations from Apotex Corporation, Aurobindo Pharma, Mylan Pharmaceuticals, Roxane Laboratories, Sun Pharma, Teva Pharmaceuticals, and Torrent Pharmaceuticals.
In recent years, the FDA approved two newer antiplatelet drugs that had been designed to take over the central role of Plavix in treating acute coronary syndromes. However, these drugs – prasugrel (Effient) and ticagrelor (Brilinta) – have been struggling in the marketplace and at this point appear very unlikely to command a significant share of the market.
May 17th, 2012
Large Meta-Analysis Finds Statins Effective in Low-Risk Patients
Larry Husten, PHD
A very large meta-analysis provides strong evidence that the relative reduction in vascular risk with statins is at least as great in low-risk patients as in high-risk patients. The finding, write the authors, provides evidence that expansion of guidelines to lower-risk populations should be considered.
In their paper in the Lancet, the Cholesterol Treatment Trialists’ (CTT) Collaborators analyzed data from 134,537 patients in trials comparing statins with control therapy and 39,612 patients in trials comparing low- and high-dose statins. They examined the impact of statin therapy according to the baseline 5-year risk for a major vascular event on control therapy. Statin therapy caused a consistent reduction in the relative risk for major vascular events and all-cause mortality independent of other factors, including age, sex, baseline LDL cholesterol, or established CV disease.
Here are the rate ratios for major vascular events across five levels of risk at baseline (note that 1 mmol of LDL cholesterol is equivalent to about 39 mg/dL of LDL):
5-Year Risk Rate ratio per 1.0 mmol/L of LDL reduction
- <5% 0·62 [99% CI 0·47–0·81]
- ≥5% to <10% 0·69 [99% CI 0·60–0·79]
- ≥10% to <20% 0·79 [99% CI 0·74–0·85]
- ≥20% to <30% 0·81 [99% CI 0·77–0·86]
- ≥30% 0·79 [99% CI 0·74–0·84]
The meta-analysis found no evidence for harm associated with statin therapy, including cancer or other nonvascular mortality.
The authors note that current guidelines do not recommend statin therapy for people in the lowest two risk categories in the study, who are expected to have a 5-year event rate lower than 10%. As generic statins are highly cost-effective, they write, the study “suggests that these guidelines might need to be reconsidered.”
In an accompanying comment, Shah Ebrahim and Juan Casas ask whether everyone over the age of 50 should take statins. They calculate that, in the U.K., adoption of a threshold of 10% would classify 83% of men over age 50 and 56% of women over age 60 as needing statins.
May 17th, 2012
Coffee — Lots of It — Associated with Reduced Mortality
Physician's First Watch, CardioExchange Staff
Coffee drinking is inversely associated with mortality in a dose-dependent manner, according to a New England Journal of Medicine study. Mortality risks were actually higher until the researchers adjusted for smoking — common among coffee drinkers.
Over 400,000 people aged 50 to 71 were followed for roughly 14 years after completing an extensive questionnaire on diet and lifestyle. All were initially free of cancer, heart disease, and stroke.
After adjustment, those who drank one cup per day or less had hazard ratios for mortality that were comparable to those who didn’t drink coffee (0.99 for men; 1.01 for women). At the highest levels of consumption — six cups or more per day — the ratios were 0.90 for men and 0.85 for women.
The authors say the results may not reflect a cause-and-effect association, but they provide “reassurance with respect to the concern that coffee drinking might adversely affect health.”
NEJM article (Free abstract)
May 17th, 2012
Study Casts Doubt on Protective Effects of Raising HDL Cholesterol
Physician's First Watch, CardioExchange Staff
A genetics-based analysis finds that raising HDL will not necessarily lower risk for myocardial infarction. Reporting in the Lancet, researchers describe a two-pronged approach.
First, they searched for the presence of a specific allele (LIPG Asn396Ser, associated with higher HDL levels in carriers) in a large cohort of subjects with and without MI. The allele’s presence should have lowered MI risk by about 15%, but no such association was found.
Similarly, testing for the presence of an array of HDL-raising gene variants (and assigning a score on the basis of the number of variants in each subject) failed to find an association of lower risk with higher scores.
The authors conclude that raising HDL, whether with lifestyle interventions or drugs, “cannot be assumed ipso facto to lead to a corresponding benefit with respect to … myocardial infarction.”
Lancet article (Free abstract)
Lancet comment (Subscription required)
May 17th, 2012
Azithromycin Associated with Cardiovascular Death
Physician's First Watch, CardioExchange Staff
The antibiotic azithromycin — which may have proarrhythmic properties — is associated with increased risk for cardiovascular death, according to a retrospective cohort study in the New England Journal of Medicine.
The study, in a Medicaid population, included nearly 350,000 azithromycin prescriptions, 1.4 million control periods without antibiotic prescriptions, and 1.8 million prescriptions for other antibiotics, mostly amoxicillin.
Azithromycin conferred a nearly threefold increase in risk for CV death and a nearly twofold increase in all-cause mortality during the 5 days of therapy, relative to no treatment. When azithromycin and amoxicillin were compared, there were 47 excess CV deaths per 1 million courses of azithromycin. For patients with the highest CV risk at baseline, there were 245 excess deaths per 1 million azithromycin treatments, compared with amoxicillin.
Azithromycin also posed greater risk for CV mortality compared with ciprofloxacin, but not compared with levofloxacin.
In HIV and ID Observations, Dr. Paul Sax writes: “If there’s a silver lining to this report … it’s that clinicians will stop prescribing azithromycin for conditions that clearly don’t need it — which is just about every uncomplicated outpatient respiratory infection. … Hey, we can dream, can’t we?”
NEJM article (Free abstract)
HIV and ID Observations blog (Free)
May 16th, 2012
Robert Hauser, ICD Watchdog, Offers Viewpoint On Riata Controversy At HRS
Edward J. Schloss, MD
The St. Jude Riata ICD lead controversy took center stage at last week’s Heart Rhythm Scientific Sessions in Boston, as previously reported here. Near the end of the meeting a leading figure in the field, Dr. Robert Hauser, of the Minneapolis Heart Institute, summarized the current state of the Riata crisis and discussed its broader implications. Hauser has played key roles in the Riata and several other similar, highly disturbing cases, including those involving the Sprint Fidelis ICD leads and the Prizm 2 DR ICD device malfunction.
In a troubling revelation near the end of his talk, Hauser suggested that St. Jude’s problems may not end with the now discontinued Riata leads, and that the company’s Durata leads may have failure mechanisms not previously reported.
Hauser first discussed an abstract from Steinberg and associates from Quebec. These investigators used chest x-rays rather than fluoroscopy to detect Riata externalizations:
They, like others, found a far higher incidence of externalized conductors than what has been reported by St. Jude Medical. And frankly, this and other reports presented at this meeting raise serious questions about the accuracy of the data that the manufacturer has communicated to us. What we learned today is that this externalized cable process is time dependent. It seems to be occurring more frequently in the 1580 leads, particularly in the 8 French, and that with time we are going to see progression. The fact that these investigators were able to use special chest radiographs to identify externalized conductors is interesting and deserves further study by comparing the sensitivity and specificity of their technique to high-resolution cine-flouroscopy
Hauser then discussed the Riata extraction experience from Royal Victoria Hospital in Belfast, and then offered some practical advice:
[these investigators] stunned us all last summer at the European Society of Cardiology in Paris with their report of a 15% incidence of Riata externalized cables. Previously we saw them in isolated case reports. We are certainly in their debt for this important communication. Today, Dr. Rebecca Noad and colleagues reported their excellent results with extracting Riata and Riata ST leads with and without insulation breaches. There was one complication, and that was a tear in the superior vena cava. Everyone should take note that this patient survived that complication because the procedure was performed in the operating room with a surgeon immediately on standby. Veteran extractors have emphasized the difficulties encountered in extracting Riata leads, particularly with externalized cables, with frequent need for 16 French sheaths, which we know increase procedural risk. Importantly, these investigators point out that it may not be possible to pass a locking stylet beyond the insulation breach to the lead tip. And we saw that the stylet actually provoked externalization of the cable. Perhaps we should all be passing a stylet down a Riata lead at the time of PG change, even if the externalized cables are not visible on fluoroscopy.
Next up was the Danish Pacemaker Registry experience presented by Dr. Jens Johansen confirming, as have others, the inferior long term performance of ICD leads with small diameters (including Medtronic Sprint Fidelis and St. Jude Riata):
This finding raises the question: can a small diameter lead be sufficiently robust to perform reliably over years of biologic exposure and mechanical stress in the human body? Hopefully, small diameter leads like Riata ST Optim and Durata are up to the challenge and will do well.
Amplifying this theme was the experience from Dr. Rordorf and coworkers from Pavia, Italy again showing poor performance of thin ICD leads. Hauser’s compelling conclusions followed:
Again this study poses the provocative question: is it possible to produce a small diameter lead that is durable. Presently we do not know the answer. Perhaps we have pushed lead design to the limits of what can be accomplished with current designs and materials. Maybe it is time for us to stick with what works. We have defined acceptable lead performance as a lead that has a failure rate of 0.5% per year over 10 years. Available leads appear capable of achieving this level of reliability. Not perfect, but leads will never be perfect. But is it good enough? I say yes. For the time being at least, until a new technology is proven in long-term clinical trials to be superior to the leads we are implanting today, we should stick with what we have. This field needs to put the era of lead and pulse generator problems behind us. Industry should stop innovating to gain market share, and innovate and focus on product reliability and longevity. Remember the saying “the enemy of good enough is better.”
Hauser then summarized a talk by Dr. Mark Carlson, the Chief Medical Officer of St. Jude Medical, who presented the last study in the place of Dr. Steven Greenberg:
Unfortunately, Dr. Greenberg was unable to attend today, but St. Jude’s Dr. Carlson stood bravely in the breach (no pun intended) to describe the performance of St. Jude’s 3500+ Durata leads in its OPTIMUM registry. Follow up was 2.4 years, and my only comment is that 2.4 years in my view is an early experience, not a mid-term experience. The event free survival was >99%. Excluding dislodgments and perforations, which may be operator dependent, there were only 5 lead mechanical problems, namely conductor fractures, in over 8400 implant years. Now this is truly spectacular. There were no inside-out insulation abrasions and no all-cause abrasions. But I have to say, that the Durata leads that I have been looking at in the FDA’s MAUDE database must not have been included in this study.
Although only hinted in the presentation quoted above, Hauser confirmed in the post session question and answer that he has submitted a manuscript for peer review on Durata failures in the MAUDE database. He could not confirm the publication date, but implied that the paper would challenge St. Jude’s assertions about the reliability of the Durata lead. Wrapping up the session, Hauser circled back to challenge the cardiac device community to improve post market surveillance and prioritize safety:
A few closing comments: We need good data for all life-saving and life-sustaining medical devices. I believe that every pulse generator, every ICD pulse generator, and every lead should be registered and followed, at least annually. We need to apply sophisticated techniques to these registries to uncover potentially defective devices before they are implanted in a large number of patients. It is a goal we the caregivers should accept and drive toward. Lastly, and perhaps most importantly, patient safety should become the overarching goal of this society. Thank you.
Photo of Durata promotional truck at HRS courtesy of Dr. Wes
May 16th, 2012
Changes in Air Pollution During Beijing Olympics Tied to Inflammatory Biomarkers
Nicholas Downing, MD
Reductions in air pollution during the Beijing Olympics were associated with decreases in certain biomarkers of inflammation and thrombosis in healthy young adults, according to a JAMA study.
Researchers measured levels of air pollutants in 2-week periods before, during, and after the Olympics, and also measured blood levels of cardiovascular disease biomarkers in 125 healthy medical residents during the same three periods.
Overall, air pollutants decreased during the Olympics, reflecting the government’s measures to limit pollution during the games. At the same time, participants had significant improvements in markers of platelet adhesion and activation — namely, soluble P selectin and von Willebrand factor. As pollutant levels returned to pre-Olympic levels after the games, so did these biomarkers (soluble P selectin actually was worse after the Olympics than before).
Editorialists say the study “provides evidence supporting the hypothesis that exposure to higher levels of air pollution leads to a prothrombotic response.”
May 15th, 2012
No Benefit Found for Exercise Echocardiography in Asymptomatic Patients Following CABG Or PCI
Larry Husten, PHD
Routine exercise echocardiography in asymptomatic patients after revascularization does not lead to better outcomes, according to a new study published in Archives of Internal Medicine. Although guidelines generally discourage the practice, post-revascularization stress tests are still commonly performed.
Serge Harb and colleagues performed exercise echocardiography on 2105 patients after CABG surgery or PCI and followed them for a mean of 5.7 years. Some 13% of the subjects were found to have ischemia; of these, one third underwent repeat revascularization. Nearly half (49%) of the patients without ischemia on the initial test underwent further exercise testing. Overall, 17% of patients in the study underwent repeat revascularization. However, revascularization had no significant impact on mortality.
Mortality was higher in patients who had ischemia at any time than in patients with no ischemia (8% vs. 4.1%, p=0.03). However, the authors reported that “clinical and stress testing findings, but not echocardiographic features, were associated with both all-cause and cardiac mortality.” This finding, according to the authors, suggests “that risk evaluation could be obtained from a standard exercise test rather than exercise echocardiography.”
The authors write that “careful consideration is warranted before the screening of asymptomatic patients is considered appropriate at any stage after revascularization.”
In an accompanying commentary, Mark Eisenberg writes that the study makes “a compelling argument that routine periodic stress testing in asymptomatic patients following coronary revascularization is of little clinical benefit.”
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