December 13th, 2013
Dispatch From the Wild Frontier of the Statin Wars
Larry Husten, PHD
The long simmering controversy over the relative benefits and harms of statins has heated to a high boil with the release of the new AHA/ACC U.S. guidelines. But nowhere is the battle more intense right now than in Australia, where, according to the National Heart Foundation, a TV show may be the cause of 2,000 heart attacks and strokes over the next five years.
The show was a two-part documentary (click here for part one and part two) broadcast in October on the Australian ABC network about dietary fat and cholesterol.
The program, wrote Amy Corderoy, the health editor of the Sydney Morning Herald, “claimed the causal link between saturated fat, cholesterol and heart disease was ‘the biggest myth in medical history’… [and described statins] as toxic and potentially deadly.”
Catalyst delved into a raging debate: has dietary guidance telling us to avoid fats pushed us towards more harmful sugar and carbohydrates instead?
But the program also went a step further, arguing cholesterol was just an innocent bystander in the body’s attempts to deal with the sugar-damage. It was not a big leap to claim statins were dangerous, and the research supporting them fraudulent.
…
Catalyst focused heavily on the opinions of U.S. experts – one of whom believes vaccines can cause autism and another who promotes chiropractic and chelation for heart problems – while downplaying the conclusions of other expert groups.”
The program contained numerous quotes from cardiologist Rita Redberg, who has been a leading critic of statin overuse, especially when used for primary prevention. Redberg made clear that statins may be valuable for some patients who already have heart disease. But her views were accompanied by “experts” who were much more removed from the mainstream, including lengthy appearances, with little or no counterbalance, from extreme cholesterol skeptics like Beatrice Golomb and Stephen Sinatra.
The show initially came in for criticism from the Australian National Heart Foundation. Now, the Heart Foundation reports that “an alarming number of people with high cholesterol have stopped or changed their cholesterol medication as a direct result of” the program. The Heart Foundation surveyed more than a thousand Australians receiving statins and recorded alarming findings:
- 22% stopped, stopped then restarted, or reduced their medications.
- 12% “started taking natural remedies.”
- 9% completely stopped taking their medication.
“…almost half of those who completely stopped their medications didn’t consult their GP,” said the CEO of the Heart Foundation. “What is most worrying is that of the people who have stopped taking their medication, one in four have previously had a heart event, such as a heart attack or stroke… It should be clear that statins are life saving for people who have already had a heart attack, and people should not go off their medication without seeing their GP.”
Extrapolating from the survey findings, the Heart Foundation calculated that as many as 55,000 Australians may “have stopped their medication as a direct result of the show.” Of these, about 40% had either had a heart attack, a stroke, established heart disease, or have multiple risk factors for heart disease.
The Heart Foundation said that the estimate of 2,000 or more additional heart attacks and strokes was “a very conservative estimate.”
Statins For Primary Prevention Get A Boost
On the heels of the news from Australia, a comprehensive review in JAMA lends strong support to the use of statins in primary prevention. The review by Fiona Taylor and colleagues concluded that
When used for primary prevention, statins are associated with lower rates of all-cause mortality, major vascular events, and revascularizations compared with placebo. Statin therapy is not associated with increased rates of life-threatening adverse effects such as cancer.”
Here are the relative risks, 95% confidence intervals, and the number need to treat for 5 years:
- All-cause mortality: RR 0.86, CI 0.79- 0.94, NNT 138
- Combined fatal and nonfatal CVD RR 0.75, CI 0.70-0.81, NNT 49
- Combined fatal and nonfatal coronary heart disease events: RR 0.73, CI 0.67-0.80, NNT 88
- Combined fatal and nonfatal stroke: RR 0.78, CI 0.68-0.89, NNT 155
In an accompanying editorial, Jennifer Robinson writes that “the accumulated evidence should convince those with a philosophical aversion to statin therapy for primary prevention to reconsider their stance.”
In a viewpoint published earlier this month in JAMA, John Ioannidis discussed the implications of the new guidelines and the expanded population now eligible for statins that “eventually would lead to massive use of statins at the population level; i.e., ‘statinization.’ It is uncertain whether this would be one of the greatest achievements or one of the worst disasters of medical history.”
Hat tip: Marilyn Mann
December 12th, 2013
FDA Panel Gives Support to Left Atrial Appendage Closure Device
Larry Husten, PHD
The FDA’s Circulatory System Devices Panel yesterday gave a vote of confidence to Boston Scientific’s Watchman left atrial appendage closure device for the prevention of stroke in atrial fibrillation patients. By a large majority, the panel agreed that the device was effective, that it was safe, and that the benefits outweighed the risks. In each case the vote was 13-1.
The panel decision may herald a change in fortune for the device, which has had a long and difficult history. In 2010, the FDA issued a complete response letter and earlier this year a scandal broke out when the American College of Cardiology cancelled a prestigious late-breaking clinical trial presentation of the PREVAIL trial after the company broke an embargo by giving trial results to investors.
The FDA is expected to make a decision whether to allow the Watchman to enter the U.S. market in the second half of 2014. Approval now seems likely, but the lopsided voting may not provide a full indication of lingering concerns about the device by panel members. Committee discussions focused on the data from two randomized control trials, PROTECT AF and PREVAIL, and from the continued access protocol registry.
During the long session on Wednesday, panelists repeatedly expressed concern about the potential for overuse of the device. Although panel members generally agreed that the Watchman was equivalent to standard treatment with warfarin, they acknowledged that the data to support this view was difficult to interpret. In addition, they noted that the device has not been compared with the newer oral anticoagulants which have begun to replace warfarin as initial therapy in some patients. The FDA is likely to take these concerns into account when developing the label for the device.
Rick Lange, who was the sole panel member to vote against approval, offered the following comment:
Despite the “warts” of the PROTECT AF trial, the panel thought that the totality of the data (including followup of 5 years) showed that the Watchman left atrial occluder device was non-inferior to warfarin therapy. I was the lone dissenter, voting against approval because the PREVAIL trial, which was designed to address the shortcomings of PROTECT AF, had collected endpoint data on only 28% of their patients. As a result, I didn’t think we had sufficient information to determine if the Watchman device was noninferior to warfarin therapy. Regardless, the entire panel was concerned that the device would be overused, and that patients would not be sufficiently informed that its use is not associated with a lower risk of major bleeding or ischemic stroke than warfarin therapy.”
December 11th, 2013
Inside The KDIGO Guideline On Lipid Management In Patients With CKD
Marcello Tonelli, MD, SM and Harlan M. Krumholz, MD, SM
Recently the Kidney Disease Improving Global Outcomes (KDIGO) Lipid Management in Patients with Chronic Kidney Disease Guideline was published in Kidney International. Now a synopsis has appeared in the Annals of Internal Medicine. Harlan Krumholz spoke with the co-chairman of the guideline, Marcello Tonelli.
Krumholz: Like the new US Guidelines, the KDIGO Guideline abandons targets. Were you aware of the US Guidelines or did your group come to that conclusion independently?
Tonelli: Our guideline was published on November 1. We had been anticipating the release of the US guidelines but had no idea what they would say, as we had no contact with the US guidelines panels. As an individual, I don’t agree with all aspects of the US guidelines — but as the KDIGO co-chair, it is nice to see that they abandon LDL-C targets, which will facilitate implementation of our guideline in kidney patients.
Krumholz: Many people outside the kidney community may not be familiar with KDIGO. Can you tell me about this organization?
Tonelli: KDIGO has been producing international practice guidelines about the care of people with kidney disease or kidney failure since 2003. KDIGO makes guidelines on multiple topics relevant to kidney patients, including anemia, bone disease, hypertension, and CKD care. This is the first lipid guideline. Any funds from industry must support KDIGO’s overall mission, and cannot be used to support specific guidelines. In addition to industry support, KDIGO receives financial and/or in-kind support from several (independent) national nephrology societies, which in my view adds an additional layer of credibility. KDIGO has an international board of directors and two co-chairs who at present are from the UK and the US. The board, executive committee and co-chairs select topics based on stakeholder input, and then select workgroup co-chairs (in this case, Dr. Wanner and myself). The workgroup co-chairs then propose workgroup members who in turn are approved by the KDIGO co-chairs. Further details on KDIGO are available at the KDIGO website.
Krumholz: Unlike the US Guidelines, you state that the statin/ezetimibe combination or statins are acceptable for patients with chronic kidney disease. The US FDA declined to grant Merck, the producer of ezetimibe, an indication, so in the US you are making an off-label recommendation. What was your thinking in deciding to include the combination?
Tonelli: KDIGO makes guidelines for an international audience, and so although we’re certainly interested in US regulatory decisions, they’re not directly relevant to the majority of our users. I can’t comment on the rationale for the US guideline panel’s decision, but here is our thinking: SHARP was the largest randomized controlled trial (RCT) ever done in CKD patients and the only one to show a convincing benefit of lipid lowering in people with advanced CKD. It compared simvastatin/ezetimibe versus placebo and found a clinically relevant benefit. Unlike the situation in the general population, there are no RCTs showing benefit of statin monotherapy in advanced CKD. It doesn’t seem rational to recommend a statin alone in patients with advanced CKD even though it was combination therapy that showed benefit in the best available trial. But of course, the available data from post hoc analyses of trials in moderate CKD plus the tremendous body of clinical and experimental evidence suggests that statin monotherapy would be beneficial too. So we recommended for either statin monotherapy or combination therapy in advanced CKD, which seems most consistent with the evidence. You will note that in less advanced CKD (the patients who were not included in SHARP) we recommended for statin monotherapy and not combination therapy. The rationale for all of these judgments is presented in more detail in the full guideline.
Krumholz: When I first read the recommendation I had concerns about whether Merck had a role in the Guideline. I wrote you and I want to give you an opportunity to share with readers what you told me. So let me ask you directly, did Merck have a role and what did you do to protect your guideline process from potential conflicts of interest.
Tonelli: Evaluating the quality of guideline processes is difficult — but our guideline achieves high scores using the AGREE-2 tool, which is the accepted criterion for judging rigor of guideline development. Regarding commercial bias — KDIGO is funded by a basket of sponsors (listed below). The list does not include Merck. Although BMS is a sponsor they had nothing to do with this guideline — they obviously made a financial contribution to KDIGO but it was not tied to any specific guideline or topic. I didn’t realize that BMS had provided funds as I had never carefully read the sponsors list until you emailed to ask — it has simply not been relevant to our work on this guideline. From an administrative perspective, KDIGO paid for the travel of the guideline panel and all costs related to guideline production and guideline meetings. Neither we nor the independent evidence review team had any dealings with anyone from industry during guideline development.
The Annals synopsis includes COI information that can be found by clicking on the “Article and author information” link and describes the COI for the panel members. This information is also available on the KDIGO website. You will note that Dr. Wanner and I have both done work for Merck. I donated these honoraria (like all of the honoraria that I receive from industry) to charity, and if possible I ask the company to pay the charity directly– although this is much harder than it used to be. I accept that both my honoraria and Dr. Wanner’s are potential conflicts of interest that should be considered when reading our guideline.
Here are the published disclosures:
Financial Support: KDIGO is supported by a consortium of sponsors and no funding is accepted for the development of specific guidelines. KDIGO’s founding sponsor is the National Kidney Foundation. Support for KDIGO is also provided by Abbott, Amgen, Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole Food Company, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, International Society of Nephrology, JC Penney, Kyowa Hakko Kirin, NATCO—The Organization for Transplant Professionals, National Kidney Foundation (NKF)-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma, and Wyeth.
Grant Support: Dr. Tonelli was supported by an AHFMR Population Health Scholar award and a Government of Canada Research Chair in the optimal care of persons with chronic kidney disease.
Potential Conflicts of Interest: Dr. Tonelli reports provision of technical and administrative assistance from KDIGO, and consultancy/speaker honoraria from Merck that were donated to charity. Dr. Wanner reports speaker honoria from Astellas-Pfizer (Japan), Merck, and Merck Sharp & Dohme.
December 10th, 2013
Co-Chairs of CVD Risk Guidelines Discuss a Difficult Case
Eric Lindley, MD, Donald M Lloyd-Jones, MD, ScM and David C. Goff, Jr., MD, PhD
University of Utah cardiology fellow Eric Lindley presents a challenging case to the co-chairs of the new 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: David Goff, Dean of the Colorado School of Public Health, and Donald Lloyd-Jones, Chairman of the Department of Preventive Medicine at Northwestern University.
Lindley: My patient is an asymptomatic 38-year-old white male who comes to the office concerned about his future CV risk. He is a lifetime nonsmoker and takes no medications. Asymptomatic and very active, he frequently rides his bike to and from work, and spends his weekends hiking and camping. By trade, he is a horticulturist, eats out of his garden in Oregon, and eats red meat approximately once a week.
The patient has a significant family history of early atherosclerotic disease. His father, uncles, and grandfathers had either an MI or a CABG when they were in their mid-to-late 40’s. His physical exam is unremarkable, with a normal BMI and blood pressure (systolic blood pressure <125 mm Hg). His total cholesterol has ranged over the last five years from 200-240, with his LDL <190, and his HDL hovering around 35-40.
He is reluctant to start a statin at this age, as he doesn’t want to start a medicine he’ll need for life unless the benefits truly outweigh the risk. Using the new lipid guidelines and risk calculator, his lifetime CVD risk is estimated at 50%. However, until he is age 40, no 10-year risk is calculated. Estimating for him in the future, and only changing his age in the calculator, leaving all other numbers the same, his 10-year CVD risk isn’t above 7.5% until he’s 53. Yet a significant number of his relatives have already had their events by the time they were 53.
Would you start a statin based on his lifetime risk alone?
Goff: I would be reluctant to recommend a statin based on his lifetime risk estimate alone, primarily because he expresses reluctance to take a life-long medicine at this point, he appears committed to a healthy lifestyle, and his short-term risk and short-term benefit are both estimated to be low. I would reinforce a healthy lifestyle and try to help him reduce his cholesterol further. You stated that his blood pressure is normal. If it were higher than optimal, that is, higher than 120 systolic or 80 diastolic, I would include an emphasis on the blood-pressure lowering benefits of more intensive lifestyle change to motivate adherence.
Lloyd-Jones: This is a very interesting scenario, and this is the kind of patient I encounter very frequently in my preventive cardiology clinic. First and foremost, we must respect his family history. This kind of premature CVD family history is not particularly well represented in any risk assessment approach from the broad population. He must be congratulated on trumping as much of his inherited risk as possible by following the healthy lifestyle he follows. He sounds like he is quite active and currently asymptomatic at a good workload. That he has stayed lean (“normal BMI”) is a good sign. If he wants to avoid medication, he should certainly be offered a referral to a nutritionist or dietician to explore options, explicitly including a vegan diet. But, at this point, I would not start a statin based solely on the lifetime risk estimate.
Would you wait until his 10-year risk exceeded 7.5% to start a statin?
Goff: Given his strong family history, I am concerned that the risk calculator might under-estimate his risk. All risk estimates are averages for people with the same values of the risk factors that are included in the model, but no one really has 7.5% of a heart attack or stroke. The patient will either have an event or not during the 10-year period. From that point of view, it is all or nothing!
The challenge is that it is difficult to predict who will have the event and who will not in a group with any specified level of risk, and when we examined the contribution to risk prediction of information regarding family history, that added value was quite small for the general population. Of course, most people don’t have the very strong family history of this patient. For him, I would be interested in discussing disease screening, especially if we were not able to achieve substantial reductions in his cholesterol through lifestyle change.
Lloyd-Jones: Let’s think about his risk. I would start by plugging in his risk factor levels with an age of 40. Recognizing that we have not quantitatively considered his family history, I get 10-year risk estimates in the range of 1.4% to 2.4% (if he were black it would be as high as ~3.1%). Lifetime risks are in the range of 46-50%. This is not where we prescribe a statin per the guidelines (despite what the media seems to think), this is where we start the risk discussion. And this is very much how I practice.
As you know, the guidelines provide 6 different things that should potentially be considered to color in our risk assessment. In this framework, the first 3 questions to ask, before we consider any additional testing, are:
- Is his LDL >160? Sounds like it sometimes is, so I would take this as an indicator that we should consider a statin now.
- Does he have a strong family history of premature CVD? Unequivocally, yes. This, for me as his physician, would provide strong justification for a statin now.
- Does he have a higher lifetime risk? I would say unequivocally, yes.
At this point, I would provide him with all of this information, answer any questions, and indicate that, on balance, I would favor starting a statin now. But first I would tell him my read on the statin safety data.
Would you do further testing such as an hsCRP or CAC score to determine his risk and possible need for a statin?
Goff: The Risk Assessment and Cholesterol Guidelines provide advice on how to proceed when one is uncertain about a risk-based treatment decision. We recommend that clinicians consider using information about several factors: family history of premature CVD, LDL-C > 160, lifetime risk, hsCRP, ABI, and CAC.
I am especially intrigued by the potential value of disease screening using CT to detect CAC. We know that people without CAC are at very low risk for clinical events, and people with CAC are at much greater risk. If he were interested in pursuing additional testing, I would consider getting a CAC score. Even without the CAC score, he has a very strong family history and a fairly high lifetime risk. If his LDL-C were to remain greater than 160 despite focus on a healthy lifestyle, the guidelines provide support for a decision to start statins. The risk-benefit discussion will be critical for this patient, because his short-term benefit is likely to be low, but his long-term benefit is likely to be great.
Lloyd-Jones: If he is still reluctant to take a statin, or would like to make our decision-making a little more concrete, here is what I would do next:
- Although these tests are mentioned for potential consideration in the guidelines, I would not personally measure CRP (too nonspecific) or ABI (very low yield at this age) in him.
- Off guidelines, I would next offer him a Lp(a) measurement. If that is high (>30 or so; which I suspect will be the case, given his family history), I would urge statin therapy. Lp(a) is actually our highest yield test for heritable premature CVD and I believe it would indicate intensive statin therapy if high in this scenario.
- If the Lp(a) is not elevated, or he is not convinced enough to start a statin in the instance that Lp(a) is high, I would offer him a CT scan for CAC scoring. This would be an important test, in many ways definitive for decision-making in such a scenario. In fact, this is the situation when I tend to use CAC scores. The average white male develops CAC at an age of 53 years, so if he has CAC now he is way ahead of his age/sex/race cohort and it would indicate a sufficient burden of coronary atherosclerosis to consider him at very high risk in the nearer term. If his CAC score is zero, this would be very reassuring that he should be at very low risk (<1%) for the next 5-10 years. I would feel compelled to tell him that he will have to pay out of pocket for the CAC score (typically $75-$300) and that there is some radiation exposure, typically equivalent to ~2 chest x-rays). If we can buy him 5 years, there might well be other medication options for risk reduction other than statins.
If, after all of this, he still does not want to take a statin, I would at least feel I had offered him the best possible information to help him make his decision. Regardless of his decision, optimal lifestyle modification must remain a critical component of his prevention regimen.
December 9th, 2013
European Air Pollution Standards May Need to be Strengthened
Larry Husten, PHD
A large new analysis published in the Lancet has found a strong association between long-term exposure to air pollution and the risk of dying. The results suggest that European standards for air quality may need to be strengthened.
The European Study of Cohorts for Air Pollution Effects (ESCAPE) analyzed data from 22 European studies, including 367,251 participants followed for an average of 13.9 years. Nearly 30,000 deaths from natural causes occurred during followup. ESCAPE is the first large multicenter study to examine long-term exposure to air pollution and mortality across many different European settings. The authors adjusted their findings to account for a broad range of confounding factors, including smoking, socioeconomic status, physical activity, education level, and body-mass index.
Overall, the investigators found a consistent 7% increase in mortality (hazard ratio 1.07, CI 1.02-1.13) for every 5 μg/m3 increase in air pollution (particulate matter with diameters smaller than 2·5 μm). This association remained significant even when air pollution levels were well below the existing European Commission air quality standards, which uses a threshold of 25 μg/m3. The WHO and the U.S. — with thresholds at 10 and 12 25 μg/m3, respectively — have considerably stronger standards.
“A difference of 5 µg/m3 can be found between a location at a busy urban road and at a location not influenced by traffic,” explained the study leader Rob Beelen (Utrecht University, NL), in a Lancet press release. “Our findings support health impact assessments of fine particles in Europe which were previously based almost entirely on North American studies.”
One striking and unexplained finding was that the increase in mortality was found only in men. The Lancet publication focuses on overall natural-cause mortality. A second paper will focus on cause-specific results, but the authors briefly report that they found significant increases in the incidence of lung cancer and stroke mortality, but, surprisingly, not for mortality from ischemic heart disease or respiratory disease.
In an accompanying comment, Jeremy Langrish and Nicholas Mills write that “despite major improvements in air quality in the past 50 years” the new study highlights “the continuing effects of air pollution on health. These data, along with the findings from other large cohort studies, suggest that further public and environmental health policy interventions are necessary and have the potential to reduce morbidity and mortality across Europe. Movement towards more stringent guidelines, as recommended by WHO, should be an urgent priority.”
December 9th, 2013
Selections from Richard Lehman’s Literature Review: December 9th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 5 Dec 2013 Vol 369
Targeted Temperature Management at 33°C vs. 36°C After Cardiac Arrest (pg. 2183): Respect: this trial collected nearly a thousand patients who survived out-of-hospital cardiac arrest and ended up in one of 36 intensive care units spread across Europe and Australia. They were then randomised to treatment involving hypothermia to 33 deg celsius—as recommended by current guidelines—or without hypothermia. This logistic feat proved worthwhile, because it shows that hypothermia achieves nothing. This futile procedure can be dropped at once. Cooling is not cool.
Bivalirudin Started During Emergency Transport for Primary PCI (pg. 2207): Although I try to report advances in the management of myocardial infarction for you every week, if I had a heart attack myself I would have only the faintest idea what my options really were and what their relative harms and merits might be. Perhaps as I was sucking on my aspirin tablet, I might ask the paramedic to leave the blood pressure cuff inflated for about five minutes to achieve a bit of ischaemic preconditioning. I might call for a tot of cardioprotective brandy: they say it goes well with diamorphine. Has anyone done a trial of oral alcohol for acute MI? I suppose I would let the ambulance take me to the nearest catheter lab for PCI, although more than an hour might elapse before I even reached the hospital door. What should I accept on the way there? The Medicines Company hope that I would say bivalirudin. In the EUROMAX trial that they funded, 2218 people with AMI were randomised to either receive bivalirudin on the way to a PCI centre, or else a “optional receipt of a glycoprotein IIb/IIIa inhibitor.” A rather odd study design, made even odder by a change in the composite primary end-point after the trial had started. So compared with optional receipt of a glycoprotein IIb/IIIa inhibitor, and using the post-commencement composite end-point of death or major bleeding not associated with coronary-artery bypass grafting (CABG), “Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis.” Is that clear to everybody? Would you ask for bivalirudin in the ambulance?
Lancet 7 Dec 2013 Vol 382
Safety and Efficacy of Drug-Eluting Stents in Women (pg. 1879): The Lancet is a very odd journal, in case you hadn’t noticed. Some weeks it contains pharma-funded phase 2 trials of astounding clinical irrelevance; occasionally it contains important papers heralding major breakthroughs, or reporting massive RCTs; then there are some issues entirely devoted to health in a particular part of the globe you are unlikely to visit; last week the journal was all about sex and the British, in case you are thinking of having sex in Britain; and this week the entire research section is taken up with this analysis the safety and efficacy of drug-eluting stents in women, based on patient-level results from 26 randomised trials; plus a paper on risk stratification at diagnosis for children with hypertrophic cardiomyopathy. We seem to have wandered into the pages of Circulation rather than The Lancet. Anyway, the message from the stents-for-women analysis is that drug-eluting stents are safer than bare metal stents, and that second-generation drug-eluters are better than first generation. This is very much what pharma would like you to believe, so I am inclined to disbelieve it. But then neither I nor you, dear reader, are in a position to re-interrogate the data and the methods of 26 major trials. We must believe what we read, and buy the latest products.
BMJ 7 Dec 2013 Vol 347
Target Cardiovascular Risk Rather than Cholesterol Concentration: For me, the best thing in this week’s BMJ is an editorial by Harlan Krumholz about the new cholesterol-lowering guidelines from the American College of Cardiology and the American Heart Association. Those who read this column regularly will realise that I am quite a fan of Harlan’s work, and in this case he can take some credit for a major change in policy by these organisations. For many years he has pointed out the fact that statins alone among LDL-cholesterol lowering drugs reduce cardiovascular risk, and that using them should depend on the level of risk, not the level of cholesterol. When he and Rod Hayward wrote an open letter to the guideline committee two years ago in Circulation: Cardiovascular Quality and Outcomes, there were dark mutterings about undermining public confidence in medical practice. But now the same people have looked at the evidence and come up with a guideline that embodies a model based on risk, and that acknowledges that cheap generic statins have a solid evidence base that other lipid-lowering drugs lack. Harlan generously acknowledges this change of heart. Nothing is more difficult for authority figures than to change their minds in public: look at the diabetes community, still wriggling around the issue of targets in type 2 diabetes. I think Harlan’s commentary is not only the best written, but also the most persuasive, of all the many that have appeared in the last two weeks. Several others have been excellent, including one by Ioannidis available free on the JAMA website.
December 5th, 2013
Hail Fellows, Well Met!
Andrew M. Kates, MD
CardioExchange welcomes all new and returning cardiology fellows!
What are your thoughts about Match Day?
We hope all are happy with results, but realize not everyone gets his or her first choice. You can tell us that, but we also want to know anything and everything that is on your mind in the aftermath. For example:
What did you think of the process?
How did you evaluate programs?
What did you like or dislike about the structure of interview day?
What made you like or dislike a program?
What feedback did you receive from (or give to) programs?
If you had it to do over again, would you go about things differently?
December 5th, 2013
Large Study Finds Favorable Risk-Benefit Profile for the New Anticoagulants
Larry Husten, PHD
A very large new meta-analysis finds a favorable risk-benefit for the new oral anticoagulant drugs in the setting of atrial fibrillation. The findings, published online in the Lancet, were remarkably consistent for all four of the new agents which have been fighting to replace warfarin, which was the only oral anticoagulant available for decades until the arrival of the new agents. Although warfarin is inexpensive, it has numerous interactions with other drugs and foods and requires regular monitoring and dose adjustments. The new agents can be taken once or twice a day and do not require dose changes.
Christian Ruff and colleagues combined data from the nearly 72,000 patients randomized in the four large mega-trials: RE-LY, which studied dabigatran (Pradaxa, Boehringer-Ingelheim); ROCKET AF, which studied rivaroxaban (Xarelto, Johnson & Johnson); ARISTOTLE, which studied apixaban (Eliquis, Pfizer and BristolMyers Squibb); and ENGAGE-AF-TIMI 48, which studied edoxaban (Daiichi Sankyo).
Compared to warfarin, the new agents were associated with a 19% reduction in stroke or systemic embolic events. The investigators said this finding was “mainly driven” by a significant 51% reduction in hemorrhagic stroke. In addition, they found a 10% reduction in mortality and a 52% reduction in intracranial hemorrhage. However, gastrointestinal bleeding was increased by 25%. There were only small, statistically insignificant reductions in myocardial infarction and ischemic stroke. Here are the relative risks and 95% confidence intervals:
- Stroke or systemic embolic events: 0.81 (0.73–0.91, p<0·0001)
- –Hemorrhagic stroke: 0.49 (0.38–0.64, p<0·0001)
- –Ischemic stroke: 0.92 (0.83-1.02, p=0.10)
- Mortality: 0·90 (0·85–0·95, p=0·0003)
- Intracranial hemorrhage: 0·48 (0·39–0·59, p<0·0001)
- Gastrointestinal bleeding: 1·25 (1·01–1·55, p=0·04)
- Myocardial infarction: 0.97 (0.78-1.20, p=0.77)
The results were consistent across all subgroups analyzed.The new agents were equally effective both in patients who had previously received warfarin and in patients who had not.
In an accompanying comment, Torben Bjerregaard Larsen and Gregory Lip point out that the paper assumes that there is a class effect for the new drugs or that they are “broadly equivalent,” though this has not been tested. The paper also “does not really answer the question of which novel oral anticoagulant is best, whether from an efficacy or safety perspective.” Warfarin, they write, is still a good choice for patients who are likely to achieve a high time in the therapeutic range, “because the main benefits of novel oral anticoagulants compared with warfarin might be only marginal in those with high times in therapeutic range, although the reduction in intracranial hemorrhage is still evident.”
December 3rd, 2013
Stents Lose in Comparisons with Surgery and Medical Therapy
Larry Husten, PHD
Despite the enormous increase in the use of stents in recent decades, there is little or no good evidence comparing their use to the alternatives of CABG surgery or optimal medical therapy in patients also eligible for these strategies. Now two meta-analyses published in JAMA Internal Medicine provide new evidence that the alternatives to PCI remain attractive and that some of the growth in PCI may have been unwarranted.
In the first paper, Ilke Sipahi and colleagues performed a meta-analysis of trials in the modern era that compared PCI and CABG in patients with multivessel disease. They identified six randomized trials, including more than 6000 patients, in which, to reflect contemporary practice, at least one arterial graft was used in the CABG arm and at least 70% of patients received stents in the PCI arm. By themselves, these trials were not powered to detect differences in mortality and other major individual outcomes.
With an average 4.1 years of follow-up, CABG was associated with significant reductions in total mortality, myocardial infarction, repeat revascularization, and the rate of major adverse cardiovascular and cerebrovascular events (MACCE). CABG was also associated with a trend for excess strokes. Here are the risk ratios for CABG:
- Mortality: 0.73, CI 0.62-0.86, p<0.001
- MI: 0.58, CI 0.48-0.72, p<0.001
- Repeat revascularization: 0.29, CI 0.21-0.41, p<0.001
- MACCE: 0.61, CI 0.54-0.68, p<0.001
- Stroke: 1.36, CI 0.99-1.86, p=0.06
Results remained consistent when the investigators looked both at trials that were limited to diabetics and at trials that were not. A similar analysis found no difference in trials using bare-metal stents or drug-eluting stents.
The authors conclude that “CABG should be the preferred revascularization method for most patients with multivessel coronary artery disease.”
In the second paper, Kathleen Stergiopoulos and colleagues analyzed studies that compared PCI plus medical therapy with medical therapy alone in more than 4000 patients with stable coronary artery disease and documented ischemia. With a median 5 years’ follow-up, there were no significant differences in death, nonfatal MI, unplanned revascularization, or angina. Here are the odds ratios for PCI plus medical therapy:
- Mortality: 0.90, CI 0.71-1.16, p=0.42
- Nonfatal MI: 1.24, CI 0.99-1.56, p=0.06
- Unplanned revascularization: 0.64, CI 0.35-1.17, p=0.14
- Angina: 0.91, CI, 0.57-1.44, p=0.67
The results, write the authors, have important implications regarding our understanding of the relationship between ischemia and clinical outcomes. The findings “suggest that myocardial ischemia may be more of a marker for atherosclerotic burden” and that “the relationship between ischemia and mortality is not altered or ameliorated” by a stent in a blocked artery. Stents don’t prevent future clinical events because these are most often due to “new plaque ruptures in distant coronary segments without flow-limiting stenoses.”
“Finally,” the authors write, “these findings call into question the common practice of ischemia-guided revascularization (either using noninvasive testing techniques or FFR) where the presence of myocardial ischemia routinely determines patient selection for coronary angiography and revascularization.” Here is their summary of the situation:
Thus, the lesions that are responsible for most cases of MI and subsequent death are not severe enough to induce ischemia on stress testing, and the lesions responsible for causing ischemia do not tend to rupture. Since intervening on a marker of an outcome that is not in the causal pathway of the subsequent adverse clinical events would not be expected to reduce those events, it should not be surprising that prior clinical trials and meta-analyses consistently demonstrate that PCI fails to reduce death or MI in patients with stable CAD who are concomitantly aggressively treated with contemporary medical therapy for secondary prevention.
Unfortunately, according to the authors, although there are no data to support it, “this ischemia-driven approach to PCI is a cornerstone of daily practice in the evaluation of patients with chest pain or known CAD—endorsed by the American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines.”
December 3rd, 2013
Estimating Prosthesis-Patient Mismatch for Patients Undergoing Bovine Pericardial AVR
Jyothy Puthumana, MD,MS
Harlan Krumholz and John Ryan interview Jyothy Puthumana about his research group’s Circulation: Cardiovascular Imaging study, for which they compared prosthesis-patient mismatch (PPM) prevalence and its impact on survival.
A total of 614 patients with normal systolic function undergoing bovine pericardial aortic valve replacement (AVR) were evaluated using 3 modalities: (1) the ASE guidelines-suggested algorithm (ASE PPM); (2) the manufacturer-provided charts (M PPM); and (3) the echocardiographically measured, body surface area-indexed, effective orifice area (EOAi PPM) measurement. PPM prevalence using the algorithmic-ASE approach was low and correlated well with manufacturer-provided PPM. Independent of assessment method, PPM was not associated with medium-term mortality.
Krumholz and Ryan: PPM is defined as an effective orifice area of the implanted prosthetic valve that is too small for the patient, causing high gradients through a normally functioning valve.
By the ASE algorithm (peak gradient > 3 m/s, dimensionless index > 0.25, and acceleration time <100 ms), you estimate that about 4% of patients have severe (effective orifice area ≤0.6 cm2/m2) PPM. You also find no implication for outcomes. Should we be concerned about mismatch and make it a never event – or is it not really a problem? Or do we not know since you only had 22 patients with severe mismatch?
Puthumana: In our population of patients with normal systolic function who had a pericardial tissue valve implanted (a very homogenous group), the prevalence of PPM is very low by either the ASE algorithm estimates or by the manufacturer estimates. This correlated very well with excellent intermediate-term clinical outcomes, therefore, we feel that clinically relevant PPM is not being missed using this approach.
EOAi estimates for this cohort identified moderate and severe PPM in a significant number of patients (63% of the cohort), without prognostic relevance, causing us to question EOAi as a routine method of PPM assessment in patients with normal systolic function who undergo AVR with a pericardial tissue valve.
Krumholz and Ryan: You evaluated through three different modalities. In an echo lab that can only do one modality, which would you recommend and why?
Puthumana: Based on our outcomes in patients with normal LVEF who undergo AVR with pericardial tissue valves, we feel that the ASE algorithmic approach to quantify the severity of PPM has the best clinical relevance. This correlated with the manufacturer provided estimates, which makes valve selection in the OR easy and practical, and this approach would significantly decrease the risk of PPM and its associated complications during follow up.
EOAi estimates, on the other hand, seemed to overestimate the number of the patients who were identified to have PPM, without adverse prognosis during intermediate duration of follow up.
Krumholz and Ryan: You submitted your paper on May 2, 2013, and it was not accepted until July 26, 2013. What took the paper so long to be accepted?
Puthumana: After initial submission, based on reviewers’ comments, we updated the paper to include near complete follow up for an additional two years and included re-operation for AVR as one of the outcomes. These changes warranted collection of additional data on a few patients, through telephone follow up, etc.
Once this was complete, we performed the data analysis that reconfirmed excellent clinical outcomes for a longer term of follow up and re-submitted the paper.
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