June 6th, 2012
Selections from Richard Lehman’s Literature Review: June 6th
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.
Lancet 2 Jun 2012 Vol 379
Meta-analysis of cIMT and Clinical Outcome (pg. 2053): The massacre of the surrogates continues, and it is tempting to stand by and gloat, like King Herod or Genghis Khan. But there was a time when I really wanted to believe in these things, as the short cuts that medicine needed to move faster. This wishful thinking was widespread, and much encouraged by the pharmaceutical industry – which is busy inventing new surrogates to this day, hoping to avoid the lengthy trials needed to achieve true knowledge based on hard outcomes. How nice it would be if all that we needed to predict cardiovascular outcomes was the progression of carotid intima-media thickness. But contrary to popular belief, this measurement has no useful predictive value. The conclusion of this meta-analysis of individual patient data is unusually clear: “The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.” So how come the entire medical community fell under this delusion?
BMJ 2 Jun 2012 Vol 344
Scoring the Risk Scores: John Ioannidis leads his Stanford team in an exploration of 20 different articles on cardiovascular risk scores. So which scores as the Score of Scores in this score of scores? Impossible to say, he concludes, as they are all derived in different ways and have only one characteristic in common: “authors always reported better area under the receiver operating characteristic curves for models that they themselves developed.” If someone as sharp as John can’t pick a favourite, what hope for the rest of us? I guess my own for UK use is QRISK2, but don’t all pelt me with tomatoes. I will do whatever you say.
Door- vs. Onset-to-Balloon Times: An observational study from 26 tertiary hospitals in Japan confirms common sense and previous evidence: the thing that matters in ST elevation myocardial infarction is not door-to-balloon time but onset-to-balloon time – and that beyond 2 hours, there is little difference in outcomes of death and heart failure at 3 years.
Sundry Reviews: As there is so little original research in the journals this week, forgive me for puffing two superb pieces by friends in this week’s print BMJ: Preventing overdiagnosis: How to stop harming the healthy by Ray Moynihan, Jenny Doust, and David Henry; and The drug industry is a barrier to diabetes care in poor countries by John Yudkin. Putting these pieces behind a paywall is also a barrier to care in poor countries.
CVD Death by Chocolate: Finally, in response to a specific plea, I am travelling to the BMJ website to comment on the already famous paper about chocolate consumption in people with high cardiovascular risk. Ever since delicious solid chocolate was invented in Britain in the late 1840s, people have used it for modelling. This has given rise to the highly inventive Yorkshire term of derision, “Ee, th’art as much use as a chocolate fireguard.” This paper takes the process a step forward. It uses a Markov model to predict the effects of dark chocolate on cardiovascular outcomes over 10 years in high-risk individuals, based on the known effects of chocolate on blood pressure and lipids over a period of 2 to18 months. Now at least you can eat a chocolate fireguard, as my wife was quick to point out. But it’s impossible to swallow this Markov model, however hard you try. Henceforth we will be able to call all modelling studies that make wild extrapolations “as much use as a chocolate Markov model.” And although this is written up as a serious study, I wonder if the Australians who wrote it didn’t have their tongues firmly in their cheeks. Maybe they are now all laughing into their Fosters at pulling one over so many credulous Poms and Yanks.
June 5th, 2012
Troponin T Test Helps Assess Mortality Risk Following Noncardiac Surgery
Larry Husten, PHD
A new study in JAMA finds that postoperative troponin T (TnT) tests can independently improve 30-day-mortality risk assessment among patients who have undergone noncardiac surgery.
The VISION (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) study investigators evaluated the prognostic power of postoperative fourth-generation TnT testing in 15,133 patients. Overall mortality at 30 days was 1.9%.
Some 11.6% of patients had peak TnT values greater than 0.02 ng/mL. These patients had an increased risk for death at 30 days:
- TnT <0.01 ng/mL (reference group): 1% mortality at 30 days
- TnT 0.02 ng/mL: 4.0%, adjusted hazard ratio 2.41 (1.33-3.77)
- TnT 0.03-0.29 ng/mL: 9.3%, HR 5.00 (3.72-6.76)
- TnT >0.30 ng/mL: 16.9%, HR 10.48 (6.25-16.62)
The VISION investigators report that peak TnT value was the strongest predictor of 30-day mortality. A population- attributable risk analysis found that 41.8% of deaths were explained by elevated TnT levels. The findings suggest that postoperative patients with elevated TnT levels may benefit from aspirin and statin therapy, but this strategy has not been tested in clinical trials, the authors note. The investigators conclude that “clinical trials are needed to establish whether interventions can alter patients’ risk of death based on an elevated troponin measurement after surgery.”
June 5th, 2012
Subway Meals Get American Heart Association Endorsement
Larry Husten, PHD
The American Heart Association (AHA) announced yesterday that it had initiated a new program to help people choose healthy meals at restaurants. The Subway restaurant chain will be the first to display the Heart-Check Meal Certification logo next to certain selected meals.
In a press release the AHA’s president, Gordon Tomaselli said the program would make “it easy for consumers to make smart choices that are heart-healthy when eating outside the home, knowing they often don’t have the benefit of reviewing the nutrition facts.” The meal certification program is an expansion of the AHA’s Heart-Check Food Certification program, which was established in 1995.
Tomaselli told USA Today that certification can cost companies as much as $700,000 annually. “But it’s not pay-to-play,” he told the paper. “The money is used to make sure what we’re telling the public is correct.”
The AHA certification logo will be displayed on Subway meals that meet the AHA’s nutritional criteria for levels of sodium, calories, cholesterol, saturated fat and trans-fats. But the new program does not mean that all meals certified by the program will necessarily be heart healthy, as noted on the Heart-Check Meal Certification webpage:
Is it still heart healthy to order my meal with mayonnaise or mustard?
- The standard SUBWAY® 6-inch sandwiches that are part of the AHA (adult) certified meal are prepared on 9-grain wheat bread and contain the following vegetables: lettuce, tomatoes, onions, green peppers and cucumbers.
- These sandwiches were evaluated without the addition of condiments such as mustard or mayonnaise. Adding condiments containing sodium (such as mustard) or fat (such as mayonnaise) may result in the meal no longer meeting AHA meal criteria.
- Condiments such as mayo and mustard add saturated fat, sodium and cholesterol that can easily be avoided. These small choices throughout the day can help keep eating habits on track.
- Additions such as pickles, cheese, and olives also make the sandwich less healthy.
- Considering the freshness of the bread and the flavor and juiciness provided by the vegetables, these sandwiches are tasty without the addition of other toppings or condiments.
Subway said that it has been an AHA supporter for 12 years. On the AHA website, Subway is listed as a member of the Industry Nutrition Advisory Panel (INAP). Here is the mission of the INAP, according to the AHA website:
The American Heart Association (AHA) Industry Nutrition Advisory Panel (INAP) is a strategic relationship between the AHA Nutrition Committee and food industry leaders. INAP provides a platform for sharing information and planning cooperative programs in the areas of diet and nutrition and cardiovascular disease.
INAP industry members pay a $10,000 yearly membership fee to participate in meetings with “science representatives” from the AHA and other industry members. Here is the AHA description of the benefits of membership:
The primary benefit of INAP is bringing together industry and science representatives to exchange dialogues on areas of mutual interest pertaining to nutrition. Benefits of this dialogue include:
- Networking and relationship building with industry leaders
- Education on relevant topics from the nutrition, physical activity, metabolism and obesity areas
- Members get the latest updates on all AHA initiatives and are given the opportunity to provide input to the AHA regarding statements and positions on these topics
- Direct access to AHA staff involved in nutrition-related issues
- An organized relationship with the Nutrition Committee that allows for open communication on topics of interest
Members also receive one complimentary registration to attend the AHA’s spring science conference and council dinner coordinated by the Nutrition, Physical Activity and Metabolism Council (NPAM) and the Council on Epidemiology (EPI).
In addition to Subway, some of the other members of INAP are Uniliver, Coca-Cola, Dr. Pepper, Frito-Lay, Hershey, Kellog, Kraft, McDonald’s, Sara Lee, The Sugar Association, Welch’s, and Yumi Brands (Taco Bell, KFC, Pizza Hut).
June 5th, 2012
Data, Drugs, and Deception – A True Story
D H Newman, MD
The following guest post by Dr. David Newman is reprinted with permission from his website and blog, Smartem.Org. Dr. Newman is an Emergency Physician and Director of Clinical Research at Mt. Sinai School of Medicine in the Department of Emergency Medicine.
Recently The Lancet published a meta-analysis of 27 statin trials, an attempt to determine whether patients with no history of heart problems benefit from the drugs — true story. The topic is controversial, and no less than six conflicting meta-analyses have been performed — also a true story. But last week’s study claims to show, once and for all, that for these very low risk patients, statins save lives — true story.
Actual true story: the conclusions of this study are neither novel nor valid.
The Lancet meta-analysis, authored by the Cholesterol Treatment Trialists group, examines individual patient data from 27 statin studies. Their findings disagree with an analysis published in 2010 in theArchives of Internal Medicine, and with analyses from two equally respected publications, the Therapeutics Letter and the Cochrane Collaboration.* Despite this history of dueling data the authors of last week’s meta-analysis, in a remarkable break from scientific decorum, conclude their report with a directive for the writers of statin guidelines: the drugs should be broadly recommended based on the new analysis.
As an editorialist points out, if implemented, the CTT group recommendations in the United States would lead to 64 million people, more than half of the population over the age of 35, being started on statin therapy — true story.
Where is the magic, you ask, in this latest effort? What is different? In some ways, nothing. Indeed just a year and a half earlier The Lancet published a meta-analysis of 26 of the same 27 studies, with the same results, by the same authors (true story, and an odd choice on the part of the journal). So the findings aren’t new. They are, however, at odds with other meta-analyses. Why? It is the way they calculated their numbers. This meta-analysis, like the earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL)”, in common U.S. terms, a roughly 40-point drop in LDL.
That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.
Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.
But LDL drop cannot be predicted. Some won’t drop at all, some will drop just a bit, and some may drop more. Therefore the numbers here tell an interesting story about certain patients who took statins, but they have no relevance to patients and doctors considering statins. And yet, the latter group is the target of the study’s concusions.
True story: in prior meta-analyses that found no mortality benefit the investigators simply looked at studies of patients without heart disease and compared mortality between the statin groups and the placebo groups. No machinations, no acrobatics, no per-unit-cholesterol. They took a Joe Friday approach (just the facts, ma’am), and found no mortality benefit.
Perhaps never has a statistical deception been so cleverly buried, in plain sight. The study answers this question: how much did the people who responded well to the drug benefit? This is, by definition, a circular and retrospective question: revisiting old data and re-tailoring the question to arrive at a conclusion. And to be fair they may have answered an interesting, and in some ways contributory, question. However the authors’ conclusions imply that they answered a different, much bigger question. And that is not a true story.
Guideline writers, doctors, patients, journalists, and policy makers will all have to pay close attention to avoid the trappings of deceptive data, dressed up as a true story.
——————–
*The Cochrane Collaboration analysis reports an overall mortality benefit with statins (RR=0.86), however their summary suggests that statins should be used for primary prevention “with caution.” In particular on p.12, after a discussion of the biases in many of the trials that led to their numerical finding, they clearly state that using statins for patients with anything less than a 2% per year risk of coronary events “is not supported by existing evidence.” This cutoff encompasses virtually all people that would be considered candidates for primary prevention.
June 4th, 2012
Observational Study Finds Possible Long-Term Mortality Advantage for Rhythm Control Drugs in Atrial Fibrillation
Larry Husten, PHD
Challenging a decade-old influential trial, a large observational study of patients with atrial fibrillation (AF) suggests that rhythm control drugs may outperform rate control drugs after 4 years.
Raluca Ionescu-Ittu and colleagues analyzed data from 26,130 patients 66 years or older diagnosed with AF in Quebec, Canada. Patients were followed for a mean of 3.1 years and for a maximum of 9 years. In apparent agreement with the AFFIRM trial, the investigators observed a small early increase in mortality associated with rhythm control therapy, followed by similar mortality between the groups until year 4. After year 4, however, mortality was lower in the rhythm control arm.
Total unadjusted mortality
- Rhythm control: 48.3%
- Rate control: 50.1%
Unadjusted mortality at 5 years:
- Rhythm control: 41.7%
- Rate control: 46.3%
Adjusted hazard ratios for rhythm control at:
- 6 months: 1.07 (1.01-1.14)
- 1 year: 1.03 (0.95-1.11)
- 3 years: 0.95 (0.90-1.02)
- 5 years: 0.89 (0.81-0.96)
- 8 years: 0.77 (0.62-0.95)
The authors point out numerous differences between their study population and the AFFIRM study population, including the fact that their subjects were older, were more likely to be female and to have CHF, and were more likely to receive beta-blockers in the rate control group. Acknowledging the limitations of observational studies, they write that “the long-term benefits of rhythm control drugs in AF found in this study need to be assessed in future studies.”
In an accompanying editorial, Thomas Dewland and Gregory Marcus write that the results of the observational study are “provocative” but “insufficient to recommend a universal rhythm control strategy for all patients with AF.” They remind their readers, however, “that no clinical trial has definitively shown that maintenance of sinus rhythm is inferior to rate control, and expert consensus recommends a rhythm control strategy for individuals with arrhythmia-attributable symptoms.”
May 31st, 2012
Women at Increased Risk for Stroke in Atrial Fibrillation
Larry Husten, PHD
Among patients with atrial fibrillation (AF), women have a higher risk than men of having a stroke, according to a new study published in BMJ. The increased risk was mostly found in women over 65 years of age and in women with multiple risk factors.
Leif Friberg and colleagues analyzed data from more than 100,000 Swedish patients with AF. Women had a 47% higher rate of ischemic stroke than men (6.2% vs. 4.2% per year, P<0.0001). After adjusting for multiple risk factors, women still had an increased risk (HR 1.18, CI 1.12 – 1.24). Women with CHA2DS2-VASc scores of 2 or less had no increased risk of stroke and there was no significant difference (p=0.09) in women under 65 years of age with no vascular disease.
The authors noted that women are less likely to receive intensive anticoagulation therapy than men after a stroke or MI, but adjusting for this difference did not substantially alter the result. They write that when the decision “to give anticoagulation treatment” is unclear, “we suggest that female sex should probably tip the scale towards initiating treatment.”
In an accompanying editorial, Eva Prescott writes that a “major concern” in this observational study “is the selection of patients to be included and why they were given anticoagulants.” She concludes that women are at increased risk for stroke, “but when differences in age and risk factor profile are taken into account the excess risk is low.” She agrees with the authors that women under 65 years of age with no other risk factors do not require anticoagulation.
May 31st, 2012
Reality Check: Stem Cell Science According To Perez Hilton
John Ryan, MD
Celebrity Blogger Perez Hilton recently ran a news story about stem cell research with the headline: “Scientists Convert Skin Cells Into Beating Heart Muscle!” According to the report, “the tissue could one day be used to treat” heart failure.
Sites such as PerezHilton.com (which is among the top 150 most visited sites in the US), and Patientslikeme.com (with over a 150,000 patient members) reach a far wider audience than sites such as CardioExchange or even the highest impact factor journal. However, they can also provide excess optimism and oversimplify the data. In fact, the accompanying Reuters report on the stem cell paper, which was originally published in the European Heart Journal, quoted Professor John Martin from University College London as saying, “The chances of translation are slim and if it does work it would take around 15 years to come to clinic.”
Patients and the public have both a need and an interest to learn about advances in science and medicine, but healthcare professionals have not filled this void. Thus more reliable voices such as Perez Hilton have become the surrogate educator of our patients. The casual nature of the report and the attractive 3-D imagery makes this a very understandable resource, which fails to address the complexities or limitations of these studies.
- How do you respond to patients when they ask you about health “facts” that they have read online?
- How can physicians better prepare the public so that physicians and societies become the go-to resource for patients, rather than bloggers and private companies?
May 30th, 2012
Reality Check: Do Reporters Spin Trial Results?
Harlan M. Krumholz, MD, SM
Do reporters spin trial results – or do some reporters just not understand the science well enough to report results accurately?
I was thumbing through Nature Reviews/Cardiology when I happened on this headline in the section on Research Highlights: Vorapaxar beneficial in setting of prior MI, but not in patients who have experienced stroke. This long headline caught my attention because I thought that TRA 2P-TIMI 50, the trial that is being reported, was positive at the cost of a substantially higher risk of bleeding.
Vorapaxar is a novel antiplatelet drug that Merck inherited from Schering-Plough. It selectively inhibits the actions of thrombin. TRA 2P-TIMI 50 showed that in patients with a history of MI, stroke or PVD, vorapaxar produced an absolute 1.2% reduction in the composite of death from cardiovascular disease, myocardial infarction or stroke – and a 1.7% increase in moderate or severe bleeding and a 0.5% increase in intracranial bleeding.
With the disappointing TRACER study, which showed that in patients with acute coronary syndrome, this drug did not produce a significant reduction in a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization and did significantly increase intracranial bleeding – this drug seems unlikely to garner much support.
In this context, the headline seems to be a little misleading. Is that really the major message from this trial? How do you know which research summaries you can trust? I’d also like to hear from anyone who thinks I misinterpreted this trial.
May 29th, 2012
Selections from Richard Lehman’s Literature Review: Week of May 28th
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.
JAMA 23 May 2012 Vol 307
Treating Obstructive Sleep Apnoea (pg. 2161): Daytime sleepiness is one of the main reasons for treating obstructive sleep apnoea, another one being the risk of cardiovascular events and hypertension in untreated OSA. Continuous positive airway pressure is the standard treatment, and observational evidence suggests that as well as keeping people more alert by day, it may also reduce adverse cardiovascular consequences. I hadn’t realized before reading this paper (and the associated editorial) that there is no evidence for this from randomized trials. The Spanish Sleep and Breathing Network considered that it would be unethical to do an RCT in symptomatic OSA: instead they selected people with OSA but without daytime sleepiness and randomized them to a prescription of CPAP versus no prescription. Many of the CPAP group found the fiddle of using it all night long too much, and rarely did, so that on an intention-to-treat basis this trial could prove nothing: in those who were compliant, there was a trend to better outcomes.
The same Spanish team also offers an observational study showing that OSA is associated with hypertension, and in those who use CPAP it seems to progress less.
NEJM 24 May 2012 Vol 366
Aspirin for VTE (pg. 1959): Ah, Perugia! Town of my dreams, the very epitome of Italian civilization, cradle of Raphael, home to Perugino and Pinturicchio, a hill covered with miraculous architecture, including an ancient University, from which this paper originates. What a neat little study this is, enrolling just so many subjects as were needed to prove that taking low dose aspirin for two years following unprovoked venous thromboembolism reduces recurrence by nearly a half without an increase in significant episodes of bleeding. And now it is time for lunch – the linguine with black truffle shavings are so good – and a siesta – and then we must visit the astounding Palazzo dei Priori, taking in the annual chocolate festival a little later. One day soon, perhaps.
BMJ 26 May 2012 Vol 344
Prothombotics: Drugs which inhibit thrombosis get an airing pretty well every week in these columns, but the pro-thrombotic drug tranexamic acid languishes on the sidelines, despite some startling evidence of benefit in certain situations, such as early use in bleeding trauma patients (CRASH-2). There have been lots of trials in elective surgery too, and this systematic review and cumulative meta-analysis demonstrates that there is a sound body of evidence for a substantial reduction in blood transfusion in a variety of procedures. What is not so certain, unfortunately, is the rate of thrombotic events or the effect on total mortality.
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