November 25th, 2013
A 2-Hour Diagnostic Protocol for Assessing Chest Pain in the ED
Martin Than, MBBS
CardioExchange’s John Ryan interviews Martin Than about a New Zealand study group’s randomized trial comparing a 2-hour diagnostic protocol with usual care for patients who report chest pain in the emergency department. The article is published in JAMA Internal Medicine.
THE STUDY
At a New Zealand hospital, researchers randomized 542 adults with acute chest pain consistent with ACS (all seen by an attending physician who planned further observation and troponin testing) to one of two diagnostic pathways:
- an accelerated (experimental) protocol using TIMI score, ECG findings, and 0- and 2-hour troponin results
- a standard (usual-care control) protocol of troponin testing on arrival, prolonged observation, and repeat troponin testing 6 to 12 hours after onset of pain
The rate of discharge within 6 hours after hospital arrival was significantly higher in the experimental group than in the control group (19.3% vs. 11.0%). An additional 12.9% of patients in the experimental group were classified as low-risk but were still admitted for cardiac investigation; none of the 35 received a diagnosis of ACS after inpatient evaluation.
THE INTERVIEW
Ryan: Your study was powered to detect a difference in the discharge rate, but another important issue is safety. Were you able to determine whether the accelerated pathway is safe?
Than: This is a key question. It is unusual for a new diagnostic test process to have its safety tested in an implementation study before being introduced into clinical practice. That is because the number of patients required to prove noninferiority for safety, compared with an existing diagnostic strategy, is very large, particularly (as in our case) when the expected false-negative rate is about 1%. Before introduction into clinical practice, it is common for new tests to first be evaluated in large observational cohorts. The previously published ADAPT trial used contemporary troponin I (TnI) assays in 1975 patients from Australia and New Zealand. It has been confirmed using high-sensitivity TnI in 909 patients from the APACE cohort in Germany and Switzerland. In ADAPT and APACE, the negative predictive values (NPVs) of the accelerated diagnostic pathway were 99.7% and 100%, respectively. In our trial, in the experimental arm, one patient had MACE out of 94 patients classified as low-risk, yielding a similar NPV of 98.9%.
We also believe that is worth highlighting the case of the single patient who had a MACE after early hospital discharge — the MACE occurred after a clinician’s error in interpreting a diagnostic test (which could have happened in either pathway). The second TnI test for that patient was performed 8.5 hours after symptom onset; therefore, it is likely that the same outcome would have occurred if the patient had been assigned to the control group. Local procedures were modified for both pathways so that senior clinicians now interpret stress tests. We also believe that after exclusion of myocardial infarction and despite the best efforts of clinicians, a very small number of patients will still have their underlying coronary artery disease missed and later detected, leading to a subsequent hospitalization. Trying to detect 100% of such patients would burden the healthcare system considerably.
In designing this study, we considered the possibility of assessing safety, but powering the study for safety would have required a sample size of at least 7500 patients (depending on what false-negative rate was expected). We believed that such a large trial was not economically justifiable with such a low expectation of detecting a difference. After completion of our trial, the accelerated pathway was implemented at three hospitals (in New Zealand; Queensland, Australia; and Hong Kong) and has now been running for almost a year without adverse events.
Ryan: How did you get the idea for the study?
Than: This study was a logical extension of 6 years of observational research by our group, in 10 countries of the Asia-Pacific region and Australasia (see ASPECT, Lancet 2011, 377:1077-84; ADAPT, JACC 2012, 59:2091-2098; and Cullen et al. JACC 2013, in press). These studies suggest that up to 20% of patients could be safely discharged following a troponin measurement taken 2 hours after hospital arrival. These results are promising, but data on the effectiveness and the cost of the accelerated approach required testing in a randomized controlled trial conducted under real-world conditions in terms that matter to the patient and the health institution. Although we provided pathways for the intervention and control arms, the final management decision, using the TIMI score and test results, was at the attending clinician’s discretion. Clinicians do not always follow protocols or act as we would expect on the basis of test results. A pragmatic design is also the reason for recruiting a broad spectrum of patients rather than just low-risk patients with an initially normal troponin level. A focused approach may achieve an impressive discharge rate but would be much less representative of real-world care and less likely to elucidate the real benefits. An impressive increase in the discharge rate will not benefit the system if it applies only to a tiny proportion of patients.
So our trial was designed to answer these two crucial questions: (a) Would the accelerated diagnostic protocol work in practice (i.e., would it actually reduce rate and duration of hospital admissions)? (b) Would early discharge (without subsequent harm) be achieved in a significant percentage of all patients who presented with chest pain (excluding ST-segment elevation MI)? Notably, a Journal Watch Emergency Medicine reviewer of the ADAPT study wrote, “This study begs for a randomized trial in which low-risk patients are actually sent home, but such a study is unlikely to ever be conducted.”
It may seem obvious that the experimental pathway would allow more patients to be discharged earlier, but this might not actually occur in real-world practice for several reasons:
First, clinicians do not always follow protocols or act as we would expect on the basis of test results. For example, a study of 117 emergency departments found that international guidelines for investigating pulmonary embolism were not followed for 47% of patients. Our report revealed this point in the high number of patients (13% of the experimental group) who were classified as low-risk but who were still hospitalized for further investigations for ACS. This affected the difference between primary outcomes in each group, although the difference still remained significant.
Second, for the experimental pathway to be easily and reproducibly adopted, no extra staff, bed, or capital resources were provided to the experimental group. Therefore, logistical constraints might have prevented timely discharge of low-risk patients. For example, the troponin results might not be checked in a timely manner or, in a busy ED, sufficient medical staff may not be available to review and discharge patients. In the trial, this actually occurred only twice.
We believed that it was important to determine effectiveness of the experimental pathway under typical real-world clinical conditions, so we selected a pragmatic trial design (as described by the CONSORT group). Demonstrating real-world effectiveness and estimating the size of that effectiveness will help clinicians and policymakers decide whether the experimental pathway is worth adopting. In addition, although results from existing observational studies are very promising, a change in practice is more likely to occur after a randomized controlled trial is published.
Ryan: Does New Zealand have unique characteristics that make a study like this less generalizable to other countries?
Than: Thank you for this very relevant question. Although similarities exist, each country’s health system has unique features that may affect reproducibility. New Zealand has a tax-funded national health system with universal coverage for all, as well as a very strong primary health care emphasis; therefore, many patients with low risk for ACS are seen by their primary care physicians and not sent to a hospital. In this study and our previous studies, the prevalence of major adverse cardiac event and ACS excluding STEMI has been relatively high, compared with that documented in other published studies. In systems that have a lower prevalence of ACS, we think the pathway is likely to be more effective because a greater number of low-risk patients may benefit from early discharge.
It is also possible that other healthcare systems will have significantly less availability — and use — of follow-up investigations. As such, adjustments may be needed to reproduce the accelerated diagnostic protocol in other healthcare settings. However, we believe that given that all the diagnostic parameters described are easily available, other overseas health institutions may be able to adapt their processes to effectively reproduce the accelerated protocol.
Finally, even within the context of similar healthcare settings, a single-center study is never as robust as a multicenter investigation. Unfortunately, funding for multicenter studies of diagnostic protocols is extremely difficult to obtain. Government-funded studies such as this one are extremely unusual in a multinational, multicenter context.
Ryan: Are you translating the results of your study into practice in New Zealand?
Than: In Christchurch, we have been running the pathway successfully for over a year, and no adverse events have occurred. The pathway has also been running without problems for a year at Nambour Hospital in Queensland and at Queen Elizabeth II Hospital in Hong Kong. We are currently working with the Ministry of Health in New Zealand and other key clinicians to introduce the pathway to other New Zealand hospitals.
JOIN THE DISCUSSION
Share your thoughts about the diagnostic protocol investigated by Dr. Than and his colleagues in New Zealand.
November 21st, 2013
Next Steps for the Randomized Registry Trial
Michael Solon Lauer, MD
CardioExchange’s John Ryan interviews Michael S. Lauer, coauthor of an NEJM Perspective article titled “The Randomized Registry Trial — The Next Disruptive Technology in Clinical Research?”
Ryan: What challenges do you anticipate in introducing randomized registries in the U.S., compared with those in Scandinavia?
Lauer: The biggest challenge will be cultural. We are so used to doing things a certain way, with clinical trial operations wholly divorced from clinical care, that people will skeptical — and some, I fear, even cynical. Moving to this kind of model for conducting trials may be analogous to the move from film to digital photography, which was perceived (rightly) as a threat to certain interests. When it first appeared, digital photography was criticized by people in the mainstream market as inferior and inadequate. We hear the same kind of critiques today when some folks in the “mainstream clinical trial market” talk about using registry data, claims data, or electronic medical records data as platforms for conducting trials.
Other important challenges do exist, of course, though in the long run they will be largely technical. These include the embedding of informed consent, identifying and managing missing values, ensuring confidentiality, and checking data quality.
Ryan: Are some populations more readily studied in this manner? The TASTE and the SAFE-PCI studies are both interventional studies — is that a more ideal population?
Lauer: One of the most difficult challenges in all clinical research is the ability to ensure reliable, accurate, and comprehensive follow-up. Short-term studies such as TASTE are attractive because follow-up is short. We also want to look for populations already included in registries (e.g., those automatically enrolled in the various NCDR registries) and those for whom follow-up is “built in.” These might include enrollees in integrated health care plans or people in fee-for-service Medicare.
Ryan: How substantial are the cost differences between running a randomized registry and conducting an RCT?
Lauer: The differences are potentially huge if trialists and sponsors leverage an existing resource to find patients, collect baseline data, and conduct follow-up. TASTE incurred only $300,000 in incremental costs (i.e., the cost that might have been borne by NHLBI, had we funded it). A traditional RCT would have easily cost tens of millions of dollars by current standard U.S. practices. I would also note that a randomized registry trial is a randomized trial — it’s a subtype of an RCT.
Ryan: Do you anticipate that registries will have more open access to data than RCTs?
Lauer: Yes, they should, but there is no automatic assurance. Investigators and sponsors will need to work on this.
JOIN THE DISCUSSION
Share your thoughts about the promise of randomized registry trials and Dr. Lauer’s take on them.
November 20th, 2013
Consumption of Nuts Linked to Mortality Benefit
Larry Husten, PHD
Nut consumption has long been linked to healthy lifestyles. Now, a study in the New England Journal of Medicine extends the finding and demonstrates a strong association with improved mortality.
Ying Bao and colleagues examined data from nearly 120,000 people enrolled in the Nurses’ Health Study and the Health Professionals Follow-up Study to assess the relationship of nut consumption and mortality. With over 3 million person-years of follow-up, the investigators found a strong inverse correlation between the frequency of nut consumption and mortality, after adjusting for other risk factors.
Here are the hazards ratio for death based on frequency of nut consumption (compared to no consumption):
- Less than once per week: 0.93 (CI 0.90-0.96)
- Once per week: 0.89 (CI 0.86-0.93)
- 2-4 times per week: 0.87 (CI 0.83-0.90)
- 5-6 times per week: 0.85 (CI 0.79-0.91)
- 7 or more times per week: 0.80 (CI 0.73-0.86)
Similar results were observed in both men and women separately. As well, there were significant reductions in deaths due to cancer and heart disease. The results were also similar when the investigators looked separately at the role of peanuts (a legume) and tree nuts.
Although nuts are often thought to cause weight gain, the investigators reported that increased nut consumption was associated with less weight gain in their study.
The authors acknowledged that as it was an observational study, they were not able to demonstrate a cause and effect relationship between nut consumption and mortality. However, they wrote, “our data are consistent with a wealth of existing observational and clinical-trial data in supporting the health benefits of nut consumption for many chronic diseases.” The ingredients in nuts “may confer cardioprotective, anti-carcinogenic, anti-inflammatory, and antioxidant properties.”
Recommended viewing: A NEJM animation, with narration by editor Jeffrey Drazen, explaining the study and its implications.
November 20th, 2013
AHA.13: Good until the End
Seth Shay Martin, MD
Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal Ramjee, Siqin Ye, Seth Martin, Reva Balakrishnan, and Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.
While the Exhibit Hall was closing down, the poster hall was still buzzing Tuesday afternoon at AHA.13. Here’s what it looked like:
Did anyone else stop by the side-by-side posters by Peter P. Toth on PCSK9 inhibition? The titles say it all:
- Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibody, Reduces Sterol Concentrations of All Serum Low-Density Lipoprotein Cholesterol Fractions
- Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibody, Reduces Triglycerides and Cholesterol Concentrations of Serum Remnant Lipoprotein Fractions and Very Low-Density Lipoproteins
Dr. Toth presented post-hoc analyses using samples from the three alirocumab phase 2 trials in heterozygous FH and non-FH patients. Lipoproteins were subfractionated by Vertical Auto Profile (VAP) testing.The reduction in remnants and VLDL-C by PCSK9 inhibition with alirocumab is both shocking and exciting. Given what we’ve known about the mechanism of action (increasing availability of LDL receptors), we all expected the robust LDL-C reductions, but not the remnant and VLDL-C reduction. How VLDL-C and RLP-C subfractions are been reduced is not yet known; these fascinating results deserve further research to better understand what is going on. To lipidologists, this seems to be a very sexy drug. I am very hopeful that these lipid changes will translate into improved clinical outcomes in the ODYSSEY phase 3 trial program of alirocumab!
Are you hopeful about this new approach?
November 19th, 2013
Big Impact from a Little-Publicized Session at AHA.13
Saurav Chatterjee, MD
Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal Ramjee, Siqin Ye, Seth Martin, Reva Balakrishnan, and Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.
Another power-packed day at the AHA annual Scientific Sessions in Dallas. I started the day trying to have a better understanding about how to interpret the literature as published in reputable journals, and the pitfalls thereof, and thus decided to attend the ‘ask the experts’ session held at 7:30 a.m., in a well-attended session in spite of the early hour.
The faculty was an all-star line-up. Sripal Bangalore of NYU presented common red flags and issues to look out for in meta-analyses, citing recent examples, like a Lancet paper which had found that trials that used acronyms of Greek philosophers for their names had ‘positive outcomes’ compared with names of trials that did not have acronyms of Greek philosophers! Sanjay Kaul of Cedars Sinai delved into the details of missing data and reporting biases with high-impact, published, randomized studies. Sharon-Lise Normand from the Harvard School of Public Health brought to the fore the many confounding issues with observational data, while Mark Hlatky unravelled the basics of cost effectiveness analyses.
A fabulous presentation overall in the Scientific Sessions, but again it defied logic — why did that need to be held at a relatively early hour and in one of the smaller meeting rooms? I gleaned a lot of valuable insights from this session and suspect sessions such these — primers on interpreting published data — may be of invaluable benefit to early-career individuals.
Which kind of presentation at the large cardiology conferences are the most useful to you?
November 19th, 2013
AHA 2013: Reflections on My Wish List
Vimal Ramjee, MD
Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal Ramjee, Siqin Ye, Seth Martin, Reva Balakrishnan, and Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.
At the airport, waiting for my flight back home. Like Reva, I reflect on what my time at AHA has meant to me and the prospects for future AHA meetings. At previous scientific meetings, I usually have only visited poster sessions, presented my poster, perhaps met with a few mentors or colleagues, and then headed back to my home program. There was never enough time to sit in on lectures, and I usually had to make a 1-day trip for my poster session. But what I have experienced these past 4 days – more time than I’ve ever had before – has been dramatically different in a positive way. I was able to sit in on dozens of lectures spanning from basic stem cell biology to the use of therapeutic hypothermia post-arrest.
While I enjoyed many aspects of the meeting, I have to agree with Reva that the attendance generally seemed less robust than prior meetings. It’s unclear to me why this is the case – it could be the time of year (senior residents just finished interviewing for fellowships around the country, likely leaving no time for this meeting, or funds, for that matter) or more expensive plane tickets and more conservative programmatic support (for expenses).
As for what I would absolutely love to see, the new things that would compel me to book my ticket to a given academic meeting include:
- Livelier expert panel discussions. After witnessing dozens of experts blaze through their findings in 15-minute clips, I wanted to hear more. Not just about their objective findings, but what they think about the field and where it is heading. Do they agree or disagree with their colleagues? What needs to be done next? Perhaps, the AHA could organize mini-panel debates in which an expert moderator asks controversial questions of a panel of 3-5 expert investigators. This would open the floor to lively, interactive discussions, a dynamic academic exchange, and a much more engaging experience than the series of 15-minute didactics for hours on end. Interesting things could be done to build on this model – perhaps FITs could be invited to comment or ask questions relevant to trainees.
- Better placement of poster sessions. I don’t understand why these are put into their own forum. Posters are the bulk of science at meetings but receive the least attention. A great and integrative approach would be to put small clusters of posters outside the mini-debate rooms (or the lectures, as they are now) to match the topic of discussion. This way, as people leave or enter the rooms, or mingle outside them, the posters create an environment for further discussions and scientific growth. This setup would also allow trainees to directly engage with the experts, something that does not happen often enough at these meetings.
- Pre-assigned mentorships. Fellows (including myself) often mention how amazing it is to walk the same halls with faculty whose work they find fascinating. A much stronger initiative that could help bolster trainee attendance would be to match trainees with experts. Perhaps when trainees register, they can select their clinical and research areas of interest. Matching these data to a meeting with 1-2 experts in that area per day would help trainees with their careers and incentivize them to stay at the meeting longer.
These considerations aside – I did have a great time at the AHA meeting and look forward to next year in Chicago.
November 19th, 2013
An ‘Iron-Triangle’ of Patients, Providers, and Payers?
Siqin Ye, MD
Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal Ramjee, Siqin Ye, Seth Martin, Reva Balakrishnan, and Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.
For those of us just beginning our careers, I think it’s safe to say that the dramatic changes now underway in the U.S. healthcare system are both exciting and anxiety-provoking.
It was with this in the back of my mind that I attended a talk by Karen Joynt on Sunday evening. Karen, who was my fellow when I was a CCU resident, offered a refreshing perspective on how to think about the ongoing transformations in how healthcare will be delivered.
She pointed out that as fee-for-service payment models are replaced by Accountable Care Organizations (ACOs), the alignment of incentives for insurers, providers, and patients also changes. ACOs’ missions are both to improve quality of care and to lower costs. However, since the payment structure for ACOs more explicitly aligns incentives for providers and insurers, we should also be vigilant for unintended consequences such as risk-aversion and new barriers to access. As an example, she points to her work on how public reporting may have affected the use of PCI in high-risk MI patients.
Her talk also reminded me of last week’s JAMA special article, “The Anatomy of Health Care in the United States,” by Hamilton Moses and colleagues. In the article, the authors discuss an “iron triangle” of priorities among payers (measured effectiveness, access, and cost), clinicians (professionalism, autonomy, science, and technology), and patients (prevention and care, information and unbiased guidance, perceived failure) that are sometimes mutually exclusive. How to negotiate among these priorities is one of the central challenges facing us today.
Although I strongly believe that it is our responsibility as physicians to improve the value of the services we deliver, I found these insights thought-provoking. What is your take on how we can harmonize the conflicting priorities among patients, providers, and payers?
November 19th, 2013
An Insider’s Look at TACT
Gervasio Antonio Lamas, MD
Changing minds is difficult. Unexpected results meet resistance. Out of the mainstream research is subject to heavy criticism. I guess I knew all these truisms when we embarked on the Trial to Assess Chelation Therapy (TACT). Still, I thought we were answering an important clinical question.
As a practicing cardiologist, patients still ask me whether they should undergo chelation therapy. A patient asked that question in 1999 and I said “No.” But I was in a scientific mood that week, and decided to look into the literature supporting my answer. There were reams of case reports and case literature, mostly in odd journals I did not read, supporting the practice. But there was no clear-cut randomized trial evidence that would allow me to make a recommendation to my patient. In fact, “no” should have been “I don’t know.” I then thought about the problem for a few weeks and decided that it should yield to a clinical trials approach.
The next step was to make sure that my friend and colleague, Kerry Lee, the senior biostatistician at Duke Clinical Research Institute with whom I have worked since 1995, was on board. In his usual understated way he assured me he was game. And so started a multi-hundred hour, 3-year quest that led to a National Center for Complementary and Alternative Medicine (NCCAM)-NHLBI RFA and an award of $30 million in 2002. An FDA investigational new drug application followed; then approval by multiple committees, the data and safety monitoring board (DSMB), and dozens of institutional review boards (IRBs). The first patient was enrolled a year later in 2003. TACT was underway, enrolling patients in an alliance of conventional cardiologists and chelation practitioners.
To say that this trial was controversial is an understatement. I had previously worked peacefully in other clinical trials, worrying about enrollment, about the DSMB, and about interpretation of data. Not so, here. In retrospect, I had always thought that the adversaries to this study would be the chelation practitioners. After all, they were using an unproven therapy. Why would they want us to show it did not work?
The opposite was true. The chelation practitioners and their main professional organization, the American College for Advancement in Medicine, helped us at every turn. They felt they were doing good, and that bringing chelation to the crucible of a clinical trial would lead to many more patients being helped.
In fact, the principal obstructionists were groups of self-appointed anti-chelation “experts”, who had never administered chelation, had never designed or run clinical trials, but who knew how to make noise and recruit media to their dubious cause – that scientific thought should not be brought to bear on the question of whether chelation was safe and effective. These groups used the Freedom of Information Act to get our protocols, spread hyperbole and twisted facts to recruit journalists, and even persuaded the Office for Human Research Protections (OHRP) to start an investigation.
But in our clinical research world, the truth usually wins. OHRP was thorough and professional. The investigation ended. The IRBs, with a few exceptions, acted ethically, and the acid journalists went on to hector other undeserving targets. We continued to enroll and infuse.
Finally, the study ended after enrolling 1708 patients and administering 55,222 infusions of chelation or placebo. After being blinded for a decade, we finally had the unblinding meeting at Duke in August 2012. By the way, Kerry Lee is like the sphinx. I never had any idea of the results.
We were astonished (our chelation colleagues were not). The study was positive. EDTA chelation reduced events by 18% in an optimally treated post-MI population, and we presented at the AHA Scientific Sessions in 2012.
Uh oh. More knives came out. No, I won’t name names here.
The gist of the objections to the trial, once legitimate methodological concerns were addressed, was an outcry that, because cardiologists believed that EDTA was quackery, the study had to be negative. Therefore we had done something wrong. Just imagine if this had been stem cells or a new anti-platelet: Kudos all the way, right? Humble chelation got heckles and hecklers. I told my dean at Columbia that people were very upset because they did not like the results. He said “That’s why you do research.”
But there are some great scientists and editors out there. The JAMA editors were superb. Their criticism was tough, but they believe in the scientific process. The NHLBI and NCCAM scientists, likewise – they are interested in the process leading to a valid answer, no matter what that is. The editor of Circulation: Cardiovascular Quality and Outcomes is also a scientist who is not afraid of unexpected results. So where are we today? What are the take-home points after this AHA 2013?
1. First of all, be happy that this is a non-guideline message.
2. In a population of well-treated post-MI patients, age 50 or older, treatment with an EDTA-based regimen is safe and leads to a modest reduction in combined cardiovascular endpoints.
3. The benefit of the EDTA-based regimen is made about 10% greater by the inclusion of very high-dose oral multivitamins and multiminerals.
4. Diabetic patients derive a greater benefit from EDTA chelation than do non-diabetics. They demonstrated a 41% reduction in combined cardiovascular events, including a 43% reduction in total mortality and a 50% reduction in recurrent MI. There is nothing like this in diabetes.
So now what? Do we recommend chelation? This is where the cautious scientist has to take control. We reported a subgroup, and we have been fooled by subgroups before, so more research has to take place before all of us can jump on this bandwagon.
There are scientific messages that have been ignored while the anti-chelation outcry was loudest, however.
1. There is sound epidemiologic evidence that metals are associated with cardiovascular disease.
2. Advanced glycation end products, mediators of complications of diabetes, almost all require auto-catalytic metal chemistry for their oxidation and cross-linking.
3. Metals also poison our intrinsic mechanisms to detoxify reactive oxygen species.
4. Therefore, anti-oxidant effect is our leading hypothesis.
So the findings have some mechanistic legs, but none that, at present, we can prove. My hopes are that we can pull together as a scientific community, and through the NIH, investigate these striking findings to get a new handle on treating the vascular complications of diabetes. As I said above, there is nothing else like this out there for our diabetic patients.
November 19th, 2013
Another New Anticoagulant Works Well in AF Patients
Larry Husten, PHD
Edoxaban, a direct oral factor Xa inhibitor, is the latest in the series of new oral anticoagulants seeking to take over the troubled role of warfarin in clinical practice. The results of ENGAGE-AF-TIMI 48 were presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicine.
In the trial, more than 21,000 patients with moderate-to-high-risk AF were randomized to one of two regimens of edoxaban or warfarin. Both high-dose and low-dose edoxaban were found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Here are the on-treatment annual rates of stroke or systemic embolism:
- 1.50% for warfarin
- 1.18% for high-dose edoxaban (HR 0.79, 97.5% CI 0.63-0.99, p <0.001 for noninferiority)
- 1.61% for low-dose edoxaban (HR 1.07, 97.5% CI 0.87-1.31, p=0.005 for noninferiority)
In the intention-to-treat analysis to assess superiority, when compared with warfarin, there were trends in favor of high-dose edoxaban (HR 0.87, 97.5% CI 0.73-1.04, p=0.08) and against low-dose edoxaban (HR 1.13, 97.5% CI 0.96-1.34, p=0.10).
Both edoxaban regimens also resulted in significant reductions in bleeding complications and cardiovascular death. High-dose edoxaban was more effective than low-dose edoxaban in reducing ischemic strokes, while low-dose edoxaban resulted in the fewest bleeding complications and hemorrhagic strokes.
High-dose edoxaban had a better effect than low-dose edoxaban on the primary endpoint, largely due to a 29% reduction in ischemic stroke compared with low-dose edoxaban (236 vs. 333 events), but there were fewer hemorrhagic strokes, which were more serious than the ischemic strokes, in the low-dose edoxaban group (49 vs. 30).
The annual rate of major bleeding was lower in both edoxaban groups:
- 3.43% for warfarin
- 2.75% for high-dose edoxaban (HR 0.80, 98% CI 0.71-0.91, p<0.001)
- 1.61% with low-dose edoxaban (HR 0.47, 95%CI 0.41-0.55, p<0.001)
The most feared bleeding complication, intracranial hemorrhage, was significantly reduced in both edoxaban groups:
- 0.85% annual rate for warfarin
- 0.39% for high-dose edoxaban (HR 0.47, CI 0.34-0.63, p<0.001)
- 0.26% for low-dose edoxaban (HR 0.30, CI 0.21-0.43, p<0.001)
The annual rate of cardiovascular death:
- 3.17% for warfarin
- 2.74% for high-dose edoxaban (HR 0.86, 95% CI 0.77-0.97, p=0.01)
- 2.71 for low-dose edoxaban (HR 0.85, 95% CI 0.76-0.96, p=0.008)
The rate of stroke, systemic embolism, or CV death:
- 4.43% for warfarin
- 3.85% for high-dose edoxaban (HR 0.87, 95% CI 0.78-0.96, p=0.005)
- 4.23% for low-dose edoxaban (HR 0.95, 95% CI 0.86-1.05, p=0.32)
Following discontinuation of the study drug, there were few rebound events, and they were equally distributed across the three groups. The investigators state that the findings were consistent with similar studies comparing previous new oral anticoagulants with warfarin in AF patients.
November 19th, 2013
TACT Substudy Suggests Possible Strong Benefit for Chelation in Diabetics
Larry Husten, PHD
One year ago the results of the TACT trial were published in JAMA, sparking an enormous controversy over the propriety of publishing a trial suggesting that chelation therapy might be beneficial in people with cardiovascular disease. Chelation therapy has long been a staple of alternative medicine, but until the publication of TACT it had received no credit whatsoever in mainstream medicine. TACT was supported by the NIH as part of an initiaitve to test the scientific basis of alternative medical therapies.
The JAMA paper reported positive results for the prespecified subgroup of patients who had diabetes at the start of the trial. Now a new paper, presented at the American Heart Association Scientific Sessions and published online in Circulation: Cardiovascular Quality and Outcomes, focuses on this important subgroup, and provides even stronger evidence for a possible benefit for chelation in patients with diabetes. The authors speculate that ethylene diamine tetra-acetic acid (EDTA) chelation might have an effect on metal-catalyzed oxidation reactions in the development of advanced glycation end-products, which appear to play a central role in diabetic complications.
The primary endpoint of the main trial – the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina – was significantly lowered from 30% in the placebo group to 26% in the chelation group (HR 0.82, 0.69-0.99, p=0.035). Patients with self-reported diabetes composed 31.5% of the study population, or 538 patients. In the new report, the definition of diabetes was changed to be more consistent with the latest guidelines and included patients with self-reported diabetes, taking oral or insulin treatment for diabetes, or with fasting blood glucose > 6.99 mmol/L at the start of the study. The study population thereby increased to 633 patients, or 37.1% of the entire population.
After 5 years of followup there was an absolute 15% difference between the groups in the primary endpoint (the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina), resulting in a highly significant 41% reduction in the chelation group (HR 0.59, CI 0.44-0.79, p<0.001). The finding remained highly significant after adjusting for multiple subgroups. The authors calculated that 6.5 patients would need to be treated for 5 years to prevent one event. There were no significant differences in the primary endpoint in the non-diabetes subgroup.
The investigators also observed reductions in the individual components of the endpoint, including recurrent MI, all-cause mortality, and coronary revascularizations, though these were no longer significant after adjusting for multiple subgroups.
During the course of the trial there were more patients who withdrew consent in the placebo arm. This was the subject of considerable criticism when the trial was first presented and published. However, sensitivity analyses performed by the investigators found that the results remained significant for all realistic scenarios. Furthermore, the findings were similar when the investigators defined diabetes using the trial’s original criteria.
In their discussion, the authors wrote:
“These findings, if replicable, would have an impact on the health of patients with diabetes. We emphasize, however, that these results are based on a subgroup of the overall trial, albeit prespecified, and therefore must be interpreted with caution.”
The findings, they wrote, may have “particular relevance when considering that patients were taking standard, evidence-based medications for post-MI patients, and patients with diabetes had a median LDL of 83 mg/dL.”
In addition, the authors write, the findings “support the initiation of clinical trials in patients with diabetes and vascular disease to replicate these findings, and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.”
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