July 31st, 2014
What Does CRISPR’s Success Mean for Cholesterol Control?
Anthony L Komaroff, MD
CRISPR is a new technique for inactivating or editing specific genes. Developed in microorganisms, it also works in mammalian cells, including in vitro human cells and monkey embryos.
About 10 years ago, a gene was identified that is critical to production of the LDL cholesterol receptor (LDL-R): PCSK9. Naturally occurring human mutations that enhance the effect of this gene greatly reduce production of LDL-R in the liver, causing hypercholesterolemia. Conversely, mutations that impair expression of the gene greatly increase production of LDL-R, leading to LDL cholesterol levels that are 40% lower than normal (and coronary heart disease rates that are 90% lower than normal).
In a recent study, a multi-institutional team used CRISPR to knock out the PCSK9 gene in the livers of mice. A single injection of the virus carrying the CRISPR “machinery” to the mouse liver led to dramatic increases in LDL-R and decreases in plasma levels of LDL cholesterol. No adverse effects (such as inadvertently knocking out genes other than the target gene) were noted.
The study authors claim the result should be durable and that a single treatment might confer long-term cholesterol reduction, although they do not present proof of this. If this approach works safely in humans, the implications are obvious and enormous.
As clinicians, what is your response to this report?
This story was adapted from NEJM Journal Watch. You can find the original publication here.
July 30th, 2014
Heart of the Matter: Treating the Disease Instead of the Person
Leana S Wen, MD, MSc
In her popular article originally published for NPR, Dr. Leana Wen confronts the lack of overlap between physicians’ desire for efficient and effective care and patients’ desire to be treated with kindness and compassion. The article has sparked a lot of discussion about patient satisfaction and customer service in the medical field—what are your thoughts?
A 56-year-old man is having lunch with his wife at a seafood restaurant just outside Boston when he develops crushing chest pain. He refuses an ambulance, so the man’s wife drives him to the ER.
What happens next says a lot about the difference that being a doctor or a patient can make in how one feels about the health care system.
First, how did the patient and his wife see the trip to the hospital?
When the man arrives in the ER, he is told to take off his shirt. He lies in the hallway, in pain, naked from the waist up. Strangers surround him. They don’t introduce themselves, and they talk over him, at each other.
Pagers ring and there’s a lot of beeping. Someone else must be really sick, he thinks; that must be why no one is paying attention.
After a few minutes, he signs some forms and finds himself being wheeled into an elevator. Masked figures enter. He feels a cool liquid flowing into his veins. The lights go out.
He wakes up hooked up to machines, uncertain what has happened. It takes several hours for the staff to find his wife, who is still waiting in the ER lobby and has no idea why her husband is in intensive care.
They are both surprised when they find out, two days later, that he’s had a heart attack. As soon as they get home, they file a complaint with the hospital about their terrible experience.
Now, how did the staff at the hospital see it?
A triage nurse greets the patient immediately upon his arrival and finds out that he has chest pain. Within three minutes, he gets an electrocardiogram that shows he is having a heart attack. The ER doctor activates the special heart attack pager, which immediately summons the emergency cardiology team.
The doctors and nurses arrive and bring the patient up to the catheterization suite. There, the attending cardiologist threads a catheter through an artery in his groin and pushes it all the way to his heart, where the doctor sees on an X-ray machine that a vessel is blocked. She inflates a small balloon in the catheter, opening the artery and restoring the flow of blood to the man’s heart.
All told, it took only 22 minutes from the time the man entered the hospital for the cardiology team to clear the blockage. The cardiology team is proud that they beat the national average for what they call door-to-balloon time by 42 minutes. The faster a blockage can be cleared, the better the odds are for a full recovery.
The patient gets well without complications. Two weeks later, he’s back at work and exercising again. The ER and cardiology teams consider the man’s case a resounding success.
Why then are there such different views of the same ER visit? Who’s right? The doctors who believe they delivered exemplary care, or the patient and his wife who feel he was treated badly?
As an emergency physician and advocate for my patients, I frequently hear clashing stories like these. When I review the cases, I find that the doctors and nurses are often surprised by the patient’s complaint because they did everything by the book and made no medical mistakes.
Indeed, in this case, every measure of sound medical care was met: prompt diagnosis, speedy and effective treatment and an uneventful, full recovery.
The objective measures that health care workers focus on are necessary, but they’re not enough by themselves. Every provider in this man’s case had good intentions and was working hard to respond to the medical emergency. But in their rush to open the blocked heart artery, they treated him as a disease to be cured, not a person to be cared for.
Would it have alleviated the patient’s anxiety for the doctors and nurses to introduce themselves, and to ask if he wanted his wife by his side? Would it have helped to assure him that all the activity was happening around him because everyone was trying to take care of him?
I think those simple courtesies would have made a difference.
These instructions aren’t on typical checklists for treatment of heart attack, yet they are part of caring for people as human beings. In modern medicine, we are fortunate to have incredible high-tech options available, but we must not forget the low-tech approaches that can improve communication and quality of care.
Patients and family members can also speak up when they are confused and scared. It’s possible that doctors explained what was happening, but not clearly enough.
What if the patient said he didn’t understand what was going on? What problems could have been avoided if the patient and his wife didn’t wait until after he was discharged to raise their concerns?
The two viewpoints of this ER visit end with one thing in common. Just as the providers were surprised by the patient’s complaint, the patient and his wife were taken aback when the team that I was part of presented them with their doctors’ point of view.
“We had no idea they were trying so hard,” the man said. “It’s too bad we didn’t know that at the time.”
July 30th, 2014
Heart Groups Update Guidelines on Stable Ischemic Heart Disease
Nicholas Downing, MD
The American College of Cardiology and the American Heart Association have issued a focused update to their 2012 guideline on diagnosing and managing patients with stable ischemic heart disease (IHD).
The update, published in the Journal of the College of Cardiology, includes a new section on the role of invasive coronary angiography for the diagnosis of coronary artery disease (CAD) in patients with suspected stable IHD. Angiography is:
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“useful” in patients with presumed stable IHD who continue to have “unacceptable” symptoms despite guideline-directed medical therapy and who are open to, and eligible for, coronary revascularization;
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“reasonable” to determine the extent of CAD in patients with suspected stable IHD who have a high likelihood of severe IHD based on clinical characteristics and noninvasive testing;
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“reasonable” in those with suspected symptomatic stable IHD who cannot undergo diagnostic stress testing when it’s likely that the findings will warrant “important changes to therapy.”
In addition, the groups now say that chelation is of uncertain value in reducing cardiovascular events in patients with stable IHD (the 2012 guideline said chelation was not recommended), and a heart team approach to revascularization is now advised for patients with diabetes and multivessel CAD.
July 29th, 2014
Cardiac Rehab for Heart Failure Patients: The CMS Is Convinced — Are You?
Ileana Piña, MD, MPH and John Ryan, MD
CardioExchange’s John Ryan interviews Dr. Ileana Piña about her work in HF-ACTION and how it relates to the recent approval by the CMS to expand potential Medicare coverage of cardiac rehabilitation by about two million people. Dr. Piña’s work is published here in the Journal of the American College of Cardiology, and the New York Times coverage of the CMS approval can be found here.
Ryan: Because HF-ACTION failed to meet its primary endpoint, it can be regarded as a “negative” study. With this in mind, can you talk us through this approval process?
Piña: The Centers for Medicare & Medicaid Service (CMS) are most interested in improvements in the patient’s quality of life — which can be inferred from the significant increases in 6-minute walk distance and cardiopulmonary exercise time in HF-ACTION — and in safety, which was also demonstrated in the trial. Additionally, the analysis published in JACC showing the relationship between adherence and quantity of exercise with a positive relation to the primary endpoint probably sealed it for them. We had gone to CMS when we started the trial and kept them informed as we continued and completed it.
Ryan: With the increasing use of “wearables,” do you expect the compliance and monitoring of exercise in heart failure to change, and how will this affect the need for on-site cardiac rehab?
Piña: I don’t expect that wearables will really alter compliance rates significantly. You still need a “mother ship” to recommend their use and to give a prescription, and then there is no CMS coverage, that I know of, for heart failure rehabilitation at home.
Ryan: How do you discuss the risks of exercise with your heart failure patients?
Piña: The risks are small and the benefits are large. We discuss the importance of starting slow and building up; and the need for warm up,cool down, and lots of patience to see the results. I reassure patients about the safety of exercise and how much better overall they may feel with the increased energy and physical independence that result from it.
July 28th, 2014
No Reduction in Atherosclerosis Progression With Menopausal Hormone Therapy
Larry Husten, PHD
More than a decade ago the Women’s Health Study produced surprising and important results when it showed that broad use of hormone replacement therapy did not reduce cardiovascular risk in postmenopausal women. However, the study also led to speculation that hormone therapy might be beneficial when delivered closer to the time of menopause. Now a study published in Annals of Internal Medicine shows that menopausal hormone therapy (MHT) may have some favorable effects on some cardiovascular risk factors but it does not reduce the progression of atherosclerosis.
In the study, called KEEPS (Kronos Early Estrogen Prevention Study), 727 menopausal women were randomized to placebo or one of two forms of low-dose MHT (oral conjugated equine estrogens or transdermal 17β- estradiol). After four years there was no difference between the groups in the primary endpoint of the study, which was the progression of atherosclerosis as measured by carotid artery intima–media thickness (CIMT). There was also no difference in the coronary artery calcium scores. Women in the equine estrogen group had improvements in their lipid profiles (decrease in LDL and increase in HDL) while women in the transdermal group had improved insulin sensitivity. There was no difference in the incidence of serious adverse events.
The investigators offered several explanations for the findings, including a study population at low risk for athersosclerosis, a relatively short study duration, and the use of low-dose but not high-dose estrogen. “To the extent that these imaging methods predict CVD events, our findings suggest that MHT neither is a risk nor is protective in the population studied,” they wrote. The study was not powered to look at clinical events.
Andrew Kaunitz, a specialist in women’s health and menopause at the University of Florida, said that although it still remains unclear what the long-term effects of MHT will be on cardiovascular events, the study “does not support using hormone therapy to prevent CVD events.”
July 28th, 2014
Selections from Richard Lehman’s Literature Review: July 28th
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.
JAMA Intern Med July 2014
Comparative Outcomes of Catheter-Directed Thrombolysis Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-Extremity Proximal DVT: When I qualified in the 1970s, all the talk was about how the great days of medical progress had come to an end, that medicine was becoming unaffordable, that we needed to base practice on better evidence, that antibiotics would soon be useless, that doctors didn’t have enough personal contact with patients, that there was not enough emphasis on prevention, that hospitals were becoming outmoded and care should be transferred to the community, that we should look at the wider determinants of health, that America provided the worst model of healthcare in the world, that we should borrow more ideas from America, that the NHS was the ultimate moral standard of health provision/an outdated collectivist idea. Et cetera: dear children, there is nothing new under the sun. We spend our working lives fighting for what good there is until we tire and die. The immediate trigger for these thoughts is a paper about Comparative Outcomes of Catheter-Directed Thrombolysis (CDT) Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-Extremity Proximal Deep Vein Thrombosis. I hope this is self explanatory because I don’t intend to explain it. Looking at over 90 000 hospital admissions for DVT, the investigators find that the percentage treated with catheter delivered thrombolysis doubled from 2.3% in 2005 to 5.9% in 2010. There was no difference in mortality compared with simple anticoagulation, but longer hospital stays, increased costs, and increased adverse events. And 35% of the CDT patients also received vena cava filter placement, a procedure for which there is no evidence either. The authors call for a randomised trial. But how on earth do these procedures still get adopted without any RCT evidence to start with?
The BMJ 26 July 2014 Vol 349
The Epidemic of Pre-Diabetes: the Medicine and the Politics: Last week I was pressed for time and omitted to comment on John Yudkin and Victor Montori’s splendid demolition of “pre-diabetes.” When the full story is known, the dissemination of this bogus concept will be seen as a classic illustration of how the machinations of a lobby of vested interests can triumph over complete lack of evidence. “We need a shift in perspective. It is critically important to slow the epidemic of obesity and diabetes. Rather than turning healthy people into patients with pre-diabetes, we should use available resources to change the food, education, health, and economic policies that have driven this epidemic.” I am optimistic that—thanks in substantial part to the efforts of these two authors—we have reached a tipping point.
Dabigatran and Bleeding: This week’s exceptional issue of The BMJ is dominated by dabigatran and lipids. The blockbuster articles on dabigatran by Deborah Cohen, and Thomas J Moore and colleagues, are essential reading for industry followers, but the Editorial by Blake Carlton and Rita Redberg is the thing to read for everybody. The Food and Drug Administration thought the world needed new oral anticoagulants so desperately that it approved Boehringer Ingelheim’s Pradaxa on the basis of a single trial called RE-LY. “Dabigatran achieved blockbuster status, with sales of over $1bn (£580m; €740m) globally by April 2012 and $2bn in the US by 2014 despite increasing concerns about safety. By December 2011 adverse drug event databases in Europe, Japan, and the US showed thousands of serious and fatal haemorrhages in patients taking dabigatran, particularly older patients.” The selling point of Pradaxa was, of course, that you don’t need to do any blood monitoring, but in the unpublished parts of the RE-LY trial there was plenty of evidence that plasma level monitoring would improve dosing and help to avoid serious haemorrhage. “Society must consider the trade-offs of accelerated drug approval in terms of assurance of safety and effectiveness. A more transparent process of data collection and review would make important clinical data available without waiting for litigation and subpoenas, which is what it took to unearth some of Boehringer’s early concerns with dabigatran.” How many times do we have to say this?
Mass Treatment with Statins: For a variety of reasons, I spent weeks poring over the new NICE guidance on statins, summarized in The BMJ. It really came close to driving me mad, but nature came to the rescue by laying me low with a horrible complex migraine that lasted three days. Since then I have vowed to have no more to do with this document. To me, it’s the NICEst possible illustration of everything that is futile and outdated about guidelines. It barks endless orders (99 with subdivisions, and then some), which if taken seriously would leave no time for the rest of primary care, while providing nothing substantive to guide a genuine open dialogue with the individuals who are expected to take lifelong treatment. It covers its back by recommending dietary modification and activity before drugs, and exonerates itself by saying clinicians are free to do what they like after discussion with patients, but it provides nothing to aid such discussion except an endless list of study analyses. Which in turn brings us to the entirely inadequate state of the evidence for sharing decisions honestly with patients. I’m truly grateful to Ben Goldacre for summarizing this issue so brilliantly: “Mass prescription for modest individual benefit is new. Truly informed choice will require more than good intentions. We will need better data, from bigger trials, and better risk communication than for conventional medical treatment. Delivering this will require us to embed the gathering, communication, and implementation of evidence as seamlessly and cheaply as possible into the everyday routine of medicine. Without such innovation in the use of medical data, we can say only that statins are—broadly speaking—likely to do more good than harm. That is not good enough.”
(P.S. But mass prescription for modest individual benefit is not new. So-called “hypertension” needs to be the next field of battle.)
Non-cardiovascular Effects Associated with Statins: A few months ago, The BMJ came under attack from the high priests of the lipocentric religion for publishing a paper by Abramson and colleagues about the potential harmful effects of statins. Now The BMJ responds by publishing a far more detailed and scholarly traversal of the area by three authors from Johns Hopkins. The next step must be a massive prospective surveillance study—a useful job, perhaps, for the well-funded Clinical Trials Support Unit of Oxford.
Effect on CV Risk of High-Density Lipoprotein Targeted Drug Treatments Niacin, Fibrates, and CETP Inhibitors: Many years ago in these reviews, I called for a halt to trials of HDL-C raising drugs when I did a rough tally based on PubMed and found 200, without one of them showing substantive benefit. This meta-analysis finds 39 trials, which fulfilled stricter criteria, and comes to the same conclusion. Moreover it calls into question the whole lipocentric theory of statin action: “Notably, fine grained temporal analysis shows reduction in events from use of statins long before the plausible time at which lower lipid levels could mediate slower accumulation of atheroma and thereby could have had an effect. Whether the decrease in low density lipoprotein cholesterol level is the principal mechanism for the reduction of acute events by statins is, therefore, unknown.” This simple fact needs constant restating.
July 28th, 2014
Death by Running: It’s the Heat and Not the Heart
Larry Husten, PHD
The growing popularity of marathons and other extreme sports has sparked worries about the potential dangers of these activities. The press and medical research have both focused on the risk for arrhythmias. But that concern may be misdirected. A new study from Israel published in the Journal of the American College of Cardiology finds that a much more serious danger may be heat stroke, which is defined as a core body temperature above 104-105 degrees associated with multiorgan dysfunction.
Researchers retrospectively reviewed data from more than 137,000 runners who participated in endurance races in Tel Aviv. They found only two serious cardiac cases: one myocardial infarction and one hypotensive supraventricular tachycardia. Serious cases of heat stroke, however, occurred in 21 runners; two were fatal, and 12 were life threatening.
The Israeli researchers said that the diagnosis of heat stroke can be missed and mistaken for a cardiac disorder unless the core temperature — which can only be reliably obtained with a rectal measurement — is taken immediately. They raise the possibility that many cases that have been thought to be cardiac in nature may actually be caused by heat stroke:
…social-cultural conceptions and logistic issues may prevent the implementation of immediate rectal temperature assessment following collapse in a race, especially in urban areas. Unheralded collapse with documented ventricular fibrillation may be the mode of presentation of heat stroke. In this setting, the correct diagnosis will be missed if, as often happens, the rectal temperature is not measured promptly.
They further note that “the risk of heat stroke is not limited to endurance races,” and is “an important cause of death among high school and college football players, who train and compete wearing heavy protective equipment.”
The study may also have important implications for the ongoing debate over whether student athletes should be screened before participating in sports, the authors say. In an accompanying editorial, Brian Olshansky and David Cannom write that “heat stroke has no predictive clinical profile that a screening examination may uncover and can only be diagnosed at the onset of the episode.”
July 28th, 2014
Running: Any Amount Is Good and More May Not Be Better
Larry Husten, PHD
Although there is broad agreement that exercise is beneficial, there has been substantial uncertainty about how much exercise is good for you. Recently some studies have suggested that too much exercise may actually reduce the benefits of exercise. Now a study published in the Journal of the American College of Cardiology finds that even a small amount of exercise, even running for as little as 5 minutes a day, may be just as healthful as more exercise.
Analyzing data from more than 55,000 adults participating in the Aerobics Center Longitudinal Study, researchers found that, when compared with people who did not run, runners had a significantly reduced risk for both all-cause and cardiovascular mortality. There was no significant difference based on the distance run each week, or other measures of duration, speed, or frequency of running. The researchers report that runners at all levels had a 30% reduction in the risk for death and a 45% reduction in the risk for cardiovascular death, resulting in a 3-year increase in life expectancy.
The study “may motivate more people to start running,” say the authors.
In an accompanying editorial, Chi Pang Wen and colleagues write that despite the observational nature of the study, “the direct health benefits of exercise are irrefutable. The reality is that a virtuous cycle exists for an iterative process of incremental exercise promoting incremental health, and the healthier individuals in turn being more likely to exercise, blurring the simple cause-and-effect relationship.” They advise physicians to offer a simple exercise prescription to patients: “15 min of brisk walking or 5 min of running is all it takes for most clinic patients. Exercise is a miracle drug in many ways.”
July 23rd, 2014
More Questions Raised About Dabigatran
Larry Husten, PHD
Once again, dabigatran (Pradaxa) has raised the wrath of the critics. Several articles (see here, here, and here) and an editorial published today in The BMJ raise more questions and concerns about the drug, which is the first of the new oral anticoagulants. Relying on new evidence along with previously disclosed data, Deborah Cohen, the investigations editor for The BMJ, casts doubt on the reliability of the data supporting the drug as well as the behavior and decisions of regulatory authorities, trial investigators, and employees of Boehringer Ingelheim (BI), the drug’s manufacturer. Although the articles focus on dabigatran, it is entirely possible that similar questions may also be raised about other new oral anticoagulants, including rivaroxaban and apixaban.
All the new oral anticoagulants are trying to displace warfarin, the long-standing and much-maligned standard of therapy. Warfarin has been vulnerable because it requires constant monitoring of its anticoagulant effect and dose adjustments. A chief advantage of dabigatran is that it does not require monitoring, but critics have maintained that this advantage may be somewhat illusory, and they have raised repeated concerns that dabigatran may cause excessive bleeding complications. In her articles, Cohen maintains that BI failed to fully disclose findings that support these concerns and that regulatory authorities, perhaps in their eagerness to approve an alternative to warfarin, relaxed their standards of scrutiny in approving the drug.
The most important new accusation in The BMJ articles is that BI “failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible. The company also withheld analyses that calculated how many major bleeds dose adjustment could prevent.”
Analyses performed by the company, Cohen reports, found “that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30-40% compared with well controlled warfarin. The adjustment would have little or no effect on the risk of ischemic stroke.” The internal report concluded that “Optimally used (=titrated) dabigatran has the potential to provide patients an even better efficacy and safety profile than fixed dose dabigatran and also a better safety and efficacy profile than a matched warfarin group.”
BI responded to this allegation in a press release:
It is inappropriate to provide regulators simulations that are unreliable and have limitations. Post-hoc exploratory analyses are commonly performed to generate or test hypotheses and are not structured to direct patient management. Thus, they generally are not shared with regulators and first need to be tested in a clinical trial, as many hypotheses, such as the one discussed here, prove to be incorrect.
Regulators were aware of wide variations in the plasma levels of the drug. At the 2010 FDA advisory panel, one committee member, Darren McGuire, even commented:
“I’m struck by what my eyeball tells me about a five-fold variability [in plasma levels] within the 90% confidence [interval] of the 150-dose. That seems awfully big to me in a drug that we’re proposing to use without therapeutic monitoring.” But, notes Cohen, “McGuire’s concerns were not pursued by the agency.” Cohen cites internal BI documents in which Stuart Connolly, a principal investigator of the pivotal RE-LY trial, expresses similar concerns about this variability.
“Our scientists determined, and the FDA concurred, that the research does not support making dosage decisions based on plasma concentrations—a conclusion based solely on science and patient welfare,” the BI spokesperson told Cohen.
The BMJ articles also provide additional details about multiple efforts to re-examine the RE-LY data that uncovered additional events not originally reported.
In an accompanying editorial, Blake Charlton and Rita Redberg write that the articles raise “serious questions about” dabigatran.The material “illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration.” “Equally unsettling,” they write, “are data integrity issues.” The editorialists write that their “clinical concerns regarding dabigatran include potentially higher than reported bleeding risk; the possibility of undertreating or overtreating with fixed doses, especially in older patients and patients with changing renal function; the unknown value of monitoring dabigatran levels and adjusting the dose; and the lack of a specific reversal agent.”
It should be noted that similar charges against dabigatran have been brought previously. It is unclear whether the articles in The BMJ contain significant new information.
Stuart Connolly provided several comments in response to The BMJ articles:
1. To my knowledge there was never any withholding of information related to the concentration response relationship data. The concentration data was all filed with regulatory agencies who reviewed it independently. There was substantial discussion amongst the principal investigators and company representatives regarding many of our papers on the RELY data, with … disagreements from time to time and some vigorous discussions. The review of the concentration response data was no different. After much discussion we agreed that we were not in a position to recommend a fixed ‘therapeutic level’ for dabigatran. Indeed even if we had it would need to be prospectively verified with a new study. When some of us did actually try to target a therapeutic range for dabigatran in the subsequent valve study we found it difficult to do and the results were inconclusive.
2. In regards to the reviews of the RELY data, it is true that we did go back into the database to look for potentially unreported events and we did find some. However it is not surprising that we found events. In a trial of 18,000 patients with lots of co-morbid disease and multi-system failure from time to time, it is not surprising that if you look harder you will find more events even though the initial reporting of events was rigorous and met usual standards. The definition of bleeding used in these types of anticoagulation trials is quite comprehensive and all encompassing. In fact not only did we find very few ‘new’ events despite vigorous searching but the occurrence of these events was generally balanced across the three treatment groups suggesting an absence of any bias in reporting of events. The robustness of the main results of RELY is substantiated by the fact that adding these events had no impact whatsoever on the interpretation of the trial.
3. It is of note that the subsequent analyses by the FDA of their mini-sentinel and other databases showing the effects of dabigatran in clinical practice in the USA (mostly the higher dose) have strongly indicated that the effects in practice in tens of thousands of patients from a variety of types of practice are almost exactly what would be predicted by the RELY trial main results.
Therefore I remain entirely confident in the results of RELY and am confident that dabigatran performs in practice as predicted by RELY. There was no significant lack of transparency in the reporting of the RELY trial. I do not believe that we have sufficient evidence that adjusting the dose to achieve a specific therapeutic concentration would improve outcomes, although this would be an interesting hypothesis to test.
July 21st, 2014
Selections from Richard Lehman’s Literature Review: July 21st
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 17 July 2014 Vol 371
Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients (pg. 203): Niacin is an abundant natural B vitamin, which lowers bad cholesterol and raises good cholesterol. What’s not to like? Well, niacin, unfortunately. In doses that make any difference to lipid levels, it is very likely to make you feel sick, get flushes and/or rashes, and/or feel muscle pains. So Merck decided to market it in combination with laropripant, a prostaglandin antagonist that is meant to combat its unpleasant effects. Even so, a third of people who were recruited to the present trial could not continue past the run-in phase with the active combination. And now that the full results are out, we have confirmation that this dual agent definitely does not offer any cardioprotection despite its “favourable” effect on lipids. Worse still it causes bleeding, raises blood sugar, and shows a tendency to increase mortality in those who can tolerate taking it for three years. The Clinical Trials Support Unit (CTSU) at Oxford did a great job of running this trial with funding from Merck, following its usual rules of independence. In doing so, it provides a great illustration of the fact that lipid fractions are very unreliable surrogates for cardiovascular outcomes. But we knew that already, and it seems a great pity to me that many superb researchers were tied down for so long on a project that has made such a small contribution to clinical knowledge, whatever it may have contributed to the funds of CTSU.
Lancet 19 July 2014 Vol 384
Dual-Antiplatelet Treatment Beyond 1 Year After DES Implantation (ARCTIC-Interruption) (OL): The arrival of drug-eluting stents signalled a bonanza not just for device manufacturers, but for makers of anti-platelet drugs and platelet testing kits too. The small superiority of the new stents over the old bare metal ones depended on using clopidogrel or a similar agent in addition to aspirin for an initial period, now fixed by tradition at 12 months. An extension of the French ARCTIC-Monitoring trial sought to find out whether there might be additional benefit from continuing dual anti-platelet treatment for longer than a year. The answer is no: in fact this just increases the potential for harm from bleeding events.
NEJM Journal Watch — Recent Cardiology Articles- Estimating Heart Failure Risk in the U.S. Population with the PREVENT Calculator
- Atrial Fibrillation and Stable Coronary Artery Disease — What Is the Optimal Anticoagulation–Antiplatelet Regimen?
- β-Blockers After Myocardial Infarction
- Updated Guideline for Perioperative Cardiovascular Management of Patients Undergoing Noncardiac Surgery
- Strategies and Criteria for the Diagnosis and Management of Myocarditis