April 7th, 2013
Researchers Find New Pathway Linking Heart Disease To Carnitine
Larry Husten, PHD
A new line of preliminary research has turned up a novel pathway linking atherosclerosis to red meat and a common supplement contained in energy drinks. If the research is upheld, the findings may have important implications for dietary recommendations and our understanding of atherosclerosis. The research also provides another quite surprising example of the previously unsuspected health effects of bacteria in the intestine.
Published online in Nature Medicine, the new studies suggest a possible major role in atherosclerosis for carnitine, which is commonly added to energy drinks and is found naturally in high concentrations in red meat. The new theory combines several lines of evidence from studies in both animals and humans.
Led by Stanley Hazen, researchers at the Cleveland Clinic and elsewhere found that digestive tract bacteria metabolize carnitine into trimethylamine-N-oxide (TMAO), which has previously been linked to atherosclerosis in mice, though the exact mechanism is still unknown. The researchers found that these bacteria were able to flourish and produce large amounts of TMAO, only in an environment of a carnitine-rich diet. For instance, after taking carnitine supplements or eating a steak rich in carnitine, vegetarians produced far less TMAO than omnivores.
In an additional line of evidence, based on an analysis of blood samples from a group of patients evaluated for cardiovascular risk, carnitine levels were significantly associated with the risk of cardiovascular disease, but the association was significant only in subjects who also had high TMAO levels.
Studies in mice suggest a possible direct connection between carnitine, bacteria, TMAO, and atherosclerosis. When mice were given carnitine supplements they had the expected increases in bacteria. This resulted in increased production of TMAO, and, eventually, atherosclerosis. However, the atherosclerosis was suppressed when the mice were given antibiotics to prevent bacterial growth in the gut.
“The bacteria living in our digestive tracts are dictated by our long-term dietary patterns,” said Hazen in a Cleveland Clinic press release. “A diet high in carnitine actually shifts our gut microbe composition to those that like carnitine, making meat eaters even more susceptible to forming TMAO and its artery-clogging effects. Meanwhile, vegans and vegetarians have a significantly reduced capacity to synthesize TMAO from carnitine, which may explain the cardiovascular health benefits of these diets.”
The authors noted that although the consumption of red meat has been linked to the risk of cardiovascular disease, previous targets of suspicion — dietary cholesterol and saturated fat — have not been able to fully explain the link. According to Hazen, the current research suggests a new possible candidate.
Hazen told the New York Times that although he is not a vegetarian and that he still likes red meat, he has dramatically reduced his own consumption of red meat as a result of his research.
“Carnitine is not an essential nutrient; our body naturally produces all we need,” said Hazen. “We need to examine the safety of chronically consuming carnitine supplements as we’ve shown that, under some conditions, it can foster the growth of bacteria that produce TMAO and potentially clog arteries.”
Hazen is particularly concerned about the potential effect of carnitine supplements. He told the Cleveland Plain Dealer that “the amount of carnitine in many energy drinks is equivalent to a porterhouse steak, or more. Especially if you’re talking about kids who are being targeted with all this advertising, drinking these drinks is like eating steaks every day and they’re getting it in a can and don’t even realize it.”
April 5th, 2013
Cardio-Oncology: Who Needs It?
John Ryan, MD
This post is the first in a series on Cardio-Oncology. Inspired largely by the recent publication of the study Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer in the New England Journal of Medicine, we invited study authors Candace Correa and Kazem Rahimi; author of an accompanying editorial, Javid J. Moslehi; and Jerry Walker, who has appointments in both the Division of Cardiology and the Department of Radiology at the University of Utah School of Medicine, to discuss this important topic. John Ryan moderated.
Which patients with cancer should a cardiologist evaluate? And how broad should the field of Cardio-Oncology be?
Dr. Walker: The field of Cardio-Oncology is a relatively new but rapidly expanding sub-specialty of Cardiology. Oncologists, Radiation Oncologists, and Surgeons already work in collaborative efforts to increase the cure rates of cancer patients. Cardiologists can provide additional support in this effort. Chemotherapy and radiation therapy, as indicated in the article of discussion, can increase risk of cardiovascular disease. If a patient survives the cancer due to these treatment protocols, there is a risk of the patient suffering or even dying prematurely from a completely unrelated cardiovascular disease process.
We should be screening and following all patients who might receive any treatments that could result in higher risk of cardiovascular disease. Some patients don’t even know they might have cardiomyopathy until it is discovered as an incidental finding on an echocardiogram after chemotherapy has been completed. Our involvement should not hinder these treatment protocols but should help our Oncology and Radiation Oncology colleagues best avoid the pitfalls of treatment. This will eventually help bring about the best long-term outcomes for these patients.
Dr. Correa: The field of Cardio-Oncology should be broad. We have a great opportunity for oncologists and cardiologists to work together to investigate the mechanisms, clinical outcomes, and treatment of cardiac disease in the unique oncology population. The cross-fertilization via collaborative basic science and clinical efforts by multispecialty teams would likely yield very useful information that could ultimately lead to improved survival and quality of life.
Dr. Rahimi: Oncologists can handle most of these issues. Specifically in terms of our study, I don’t think these findings suggest any change to current practice in terms of who evaluates the patients. In most circumstances, it is perfectly reasonable for the oncologist to evaluate these patients. If there is uncertainty about further management, advice can be sought from cardiologists.
Dr. Moslehi: Focusing just on breast cancer, the treatments have changed significantly over the past decade. Women who are being treated for breast cancer may receive multiple therapies, each of which may have cardiotoxic effects. For example, a woman who presents with HER2+ breast cancer would receive anthracyclines, cyclophosphamide, radiation, and any number of HER2 targeted therapies, each of which may have cardiac sequelae. Just within the HER2 targeted group, there are now different therapies including an antibody that targets the HER2 receptor (such as trastuzumab – Herceptin), an antibody that inhibits HER2 dimerization (pertuzumab), a tyrosine kinase inhibitor that antagonizes HER2 from inside the cell (such as lapatinib, neratinib) or a conjugate drug (TDM-1). The specific cardiac issues with these drugs are not well known because of the drugs’ novelty. This does call for a cardio-oncologist to be involved in patients’ care.
April 5th, 2013
Thrombi on Riata ICD Leads: Another Piece in the Puzzle of Riata Management
Sandeep K Goyal, MD
St. Jude Riata family ICD leads are subject to an FDA class I recall due to insulation failure, cable extrusions, and a high rate of electrical failures. Sometimes the extruded cables have been related to electrical malfunction but at other times no discernable abnormalities other than a “cosmetic” defect in lead appearance has been noted. Opinion on best management of Riata leads with extruded conductors and normal electrical function is divided, with arguments both in favor and against early lead extraction.
In the Journal of Cardiovascular Electropysiology, my colleagues and I report 5 cases of conductor-extrusion-associated thrombi on Riata leads in our cohort of 87 Riata patients (5.7%). Until now, the primary hazard associated with externalized conductor cables has been electrical failure, however, the significant number of patients that we found to have readily visualized thrombus suggests that externalized cables may result in a different sort of risk. Flow over externalized cables and exposed conductors may be associated with turbulence that predisposes to thrombus initiation.
Our data highlight several challenges when evaluating Riata ICD leads with conductor extrusions: Large thrombi carry a risk of pulmonary embolism, endocarditis, and tricuspid valve obstruction. The strategy of capping ICD leads with externalized conductors leaves the nidus for thrombus formation in the vascular system. Additionally, the thrombus may increase in size, complicating later efforts at extraction, and large thrombi adherent to externalized conductors may embolize. Conversely, this risk may increase with extraction. We also found that anticoagulation was not very effective except in one case with a small thrombus.
Based on these data, we recommend that evaluation for large thrombi be performed before transvenous lead removal of Riata leads and in all patients with visible externalized conductors. We are currently performing screening echocardiography for ICD-lead-associated thrombi for such patients. Screening guides consideration for hybrid surgical extraction when large or calcified thrombi are present, which poses increased procedural risk to a transvenous-only approach. Early extraction of Riata leads with externalized conductors may be considered in experienced centers to avoid the potential for large organized thrombus formation, regardless of electrical lead performance.
April 5th, 2013
Are Adults with Congenital Heart Disease Falling Off the Radar?
Michelle Gurvitz, MD MS and John Ryan, MD
John Ryan interviews Michelle Gurvitz, lead author of a new study published in JACC, that characterizes the gaps in care that patients with congenital heart disease experience as they move from adolescence to adulthood.
THE STUDY
A total of 922 adults (54% women) who presented for the first time to one of 12 adult congenital heart disease centers completed a survey about gaps in cardiology care. Of those patients, 42% reported a gap in cardiology care of more than 3 years, and 8% reported a gap of longer than a decade. The mean age at the first reported gap was 19.9 years. Gaps in care >3 years were reported by 59% of patients with mild disease, 42% of patients with moderate disease, and 26% of patients with severe disease. Clinic location significantly predicted gaps, but gender, race, and education level did not.
INTERVIEW WITH THE EXPERT
John Ryan: As patients with congenital heart disease survive longer, how would you ensure a smooth transition from adolescent to adulthood cardiology care, a particularly high-risk time for gaps in care, as your study identifies?
Michelle Gurvitz: There are many contributors to these gaps. One of the largest areas to address is educating patients, parents, and providers about lifelong care. Our study revealed that referral from a healthcare provider and encouragement from a family member are two of the most common reasons that adults with congenital heart disease return to cardiology care. Patients and their families need to hear the message of lifelong, age-appropriate care from their pediatricians and pediatric cardiologists. Just as all patients move from a pediatrician to an internist for primary care, a patient with congenital heart disease must learn at an early age that he or she must take responsibility for the lifelong care that the specific condition requires.
The transition from a pediatric cardiologist can be emotionally stressful for the patient, family, and even the physician. Providing a specific referral and helping the patient book an appointment can minimize logistics and ease stress. Similarly, healthcare providers to adults (e.g., general internists, obstetrician/gynecologists, general cardiologists) must be educated that patients with congenital heart disease need ongoing cardiology care, including referrals to adult congenital cardiology subspecialists. Educational efforts are already underway. The American College of Cardiology and the Adult Congenital Heart Association are piloting a program called PATCH that aims to educate general adult cardiologists about care and referrals for patients with congenital heart disease. Undoubtedly, insurance difficulties and geographical barriers will always create some gaps in care, but awareness at all levels among all parties will help to empower patients and to minimize the gaps that are avoidable.
Ryan: On a national level, are adults with congenital heart disease being cared for by PCPs, general cardiologists, or specialists in congenital heart disease?
Gurvitz: Unfortunately, we lack accurate national data. Estimates on birth and survival in patients with congenital heart disease lesions suggest that about 1 million people are living with congenital heart disease in the U.S. The Adult Congenital Heart Association website has a self-reported clinic directory listing <60,000 U.S. patients in specialty adult congenital heart disease clinics. We also know that some patients continue to receive care from pediatric cardiologists as adults, but this is probably not a majority. Many adult patients with congenital heart disease have PCPs and ob/gyns, and some have general adult cardiologists. As part of the Congenital Heart Futures Act, the CDC has funded a cooperative agreement with three sites to examine prevalence and surveillance of adults with congenital heart disease in the U.S., so more data should be forthcoming.
Ryan: When adults with congenital heart disease return to a provider after a gap in care, from whom do you recommend that they seek that care?
Gurvitz: Regarding where adult CHD patients should receive care, that depends on the anatomic and physiologic type of congenital condition and on the interventions a patient has had (and their sequelae). Other concomitant medical conditions, which of course increase as patients age, also matter. The 2008 ACC/AHA adult congenital heart disease guidelines include recommendations for follow-up for different types of congenital heart disease. In general, patients with moderate or complex conditions (e.g., more complex than an atrial or ventricular septal defect or single valve disease like aortic or pulmonary stenosis) should have regular follow-up with a specialty adult congenital heart disease physician. Patients with a simple congenital heart condition should have a single visit to a specialty care center during their adult years, to enhance education and awareness, as well as to develop a plan of care should urgent needs develop. In addition, if an adult with congenital heart disease returns to care after a gap, I believe that he or she should have at least one consultative visit with a congenital heart disease specialist to create a long-term plan and assess condition-specific issues. After this visit, patients with less complex conditions may not require regular, specialized congenital heart disease care.
If all adults with congenital heart disease were receiving recommended subspecialty care, the number of providers need to serve them would probably be insufficient. In November 2012, the American Board of Medical Specialties announced a new certification in adult congenital heart disease. The first exams should be offered in 2015, and estimates suggest that adult congenital heart disease subspecialists will continue to rise in number and availability.
Ryan: In your study, 42% of surveyed patients had more than a 3-year gap in cardiology care. “Changing or losing insurance” accounted for this gap in a significant proportion of patients with complex congenital heart disease. Do you anticipate that provisions of the Affordable Care Act will reduce such gaps in care?
Gurvitz: The Affordable Care Act shows promise for addressing the insurance problem in our patient population. The already-enacted provision that children can remain on their parents’ insurance until age 26 is helpful, as are the reductions in barriers for patients with preexisting conditions. However, having insurance is only part of the issue. Many patients need expensive tests (e.g., MRI, echocardiogram) and procedures (e.g., catheterization, surgery, pacemaker) that may require copayments or need to be performed at out-of-network specialty centers. With the concerted effort of providers and insurance companies, these barriers can sometimes be overcome, but they may remain for many patients.
How often have you encountered patients with congenital heart disease who experience gaps in care?
April 4th, 2013
Registry Study Offers Reassurance About Safety and Efficacy of Dabigatran
Larry Husten, PHD
As the first new oral anticoagulant since warfarin, dabigatran (Pradaxa, Boehringer-Ingelheim) has been subject to intense concerns over its safety and efficacy in a real-world population. Last November an FDA investigation found no indication that bleeding rates for dabigatran were any higher than bleeding rates for warfarin. A new study from Scandinavia, published in the Journal of the American College of Cardiology (see note at bottom of story), provides more real-world information that helps to confirm the safety and efficacy of the new drug.
Using data from the Danish Registry of Medicinal Product Statistics, researchers compared 4978 patients treated with dabigatran to 8936 matched patients who received warfarin. They found similar rates of stroke or systemic embolism and major bleeding with dabigatran and warfarin. In addition, mortality, intracranial bleeding, pulmonary embolism,and myocardial infarction were significantly lower in the dabigatran-treated group.
Here are the adjusted hazard ratios (and 95% confidence intervals) for dabigatran 110 mg and 150 mg, respectively, compared with warfarin:
- Stroke: 0.73 (0.53 -1.00), 1.18 (0.85 – 1.64)
- Systemic embolism: 0.60 (0.19 – 1.60), 1.00 (0.26 – 3.35)
- Death: 0.79 (0.65 – 0.95), 0.57 (0.40 – 0.80)
- MI: 0.30 (0.18 – 0.49), 0.40 (0.21 – 0.70)
- Pulmonary embolism: 0.33 (0.12 – 0.74), 0.24 (0.06 – 0.72)
- Intracranial bleeding: 0.24 (0.08 – 0.56), 0.08 (0.01 – 0.40)
- Major bleeding: 0.82 (0.59 -1.12), 0.77 (0.51 – 1.13)
The authors concluded that ”previous concerns about an excess of bleeding events or myocardial infarction amongst dabigatran treated patients were not evident in this propensity-matched comparison against warfarin in a large post-approval registry study.” However, they noted one limitation of their study: The Danish AF patients included in the study were at lower risk and had a lower event rate than the patients studied in the pivotal RE-LY randomized trial of dabigatran.
Note to readers: This study is now available on Science Direct and the manuscript has been posted on CardioSource. Due to technical problems the article will be published online in the Journal of the American College of Cardiology website on Wednesday, April 10.
April 3rd, 2013
International Cardiovascular Device Registries: The Next Big Thing
Larry Husten, PHD
A new initiative involving a wide variety of stakeholders — the FDA, the American College of Cardiology, the Society of Thoracic Surgeons, industry, medical journals, and others — could lead to an enormous international cooperative effort to make device registries a standard part of the practice of cardiology. This will be a “huge step,” said David Holmes, a former president of the ACC and one of the initiative’s leaders.
The initiative is a natural outgrowth and expansion of the STS/ACC TVT Registry, the registry for transcatheter valve therapies that includes every patient and every implanting center in the U.S. In the wake of the success of the TVT Registry, said Holmes, “we talked with different colleagues around the world and began to think about the possibility of global registries.” (See this for my earlier discussion about the importance of the TVT Registry.)
The initiative will be the subject of a meeting later this month at the FDA, entitled the “International Consortium of Cardiovascular Registries.”(News of the meeting was first reported by Alexander Gaffney in Regulatory Focus.) As described by the FDA, the purpose of the meeting “is to discuss the development of an international consortium of cardiovascular registries with a broad array of interested stakeholders. The initial pilot phase of this effort will be developing relationships and analysis strategies for transcatheter cardiac valve registries, with the understanding that these efforts would be expanded to additional cardiovascular devices in the future.”
Holmes said that the initial product of the meeting will be a white paper, which will then be used as a road map for future development of the registries. Data from the registries will allow for a more efficient approval process and should substantially improve post-approval monitoring of the safety and efficacy of cardiovascular devices, said Holmes. In recent years, the FDA and other regulatory agencies have received heavy criticism from all sides over the approval process and the subsequent monitoring of approved devices. The new registries, said Holmes, will allow regulators to avoid being either “too slow or too fast.”
The FDA announcement explains the limitations of the current system: “Information obtained from clinical trials is often limited due to small size, short followup, and lack of generalizability. Observational studies and registries… are often limited in scope and size to a specific country, region, or health care provider system.”
One important possible benefit of international registries will be the increased ability to discover and understand comparative differences between nations involving genomics or other factors that impact device safety and efficacy.
The resulting registries could be “a massive step up” from existing registries, notes Gaffney. The closest model for the new proposal is the International Consortium of Orthopedic Registries (ICOR).
April 2nd, 2013
Lifelong Statin Sentence Now Includes Furloughs
Larry Husten, PHD
Although the benefits of statins are among the best documented in all of medicine, continuous lifelong statin therapy is not always easy to achieve in clinical practice. Now a new retrospective study suggests that although clinical events causing temporary cessation of statin therapy occur often, most of these patients are later able to resume statin therapy.
In a paper published in Annals of Internal Medicine, researchers analyzed data from 107,835 patients with a statin prescription treated by physicians associated with Massachusetts General Hospital and Brigham and Women’s Hospital. Of these, 18,778 of these patients had documented statin-related events, resulting in 11,124 patients who stopped taking statins. Within a year more than half of these (6,579) were rechallenged with a statin, and most of these (92.2%) were taking a statin a year after the initial statin-related event.
Although, the authors acknowledged, it was impossible with their methods to fully understand how many patients really withdrew from statins and why, they concluded that many apparently statin-related events “may have other causes, are tolerable, or may be specific to individual statins rather than the entire drug class.” Because permanently stopping statins “could lead to many preventable cardiovascular events,” they write that “providers should consider rechallenging patients who report statin-related events to identify those who can continue taking them.”
In an accompanying editorial, Scott Grundy writes that lifelong treatment with statins “is a tall order for many persons.” Adherence to statins is further made difficult because of the clear presence of muscle weakness in some people taking statins, though the exact prevalence is not known and is disputed. Other possible adverse effects are liver injury, memory loss, and increased risk for diabetes, though Grundy wonders if these are true side effects.
Improved adherence is more likely in high-risk patients or in patients taking statins for secondary prevention, as “there is ample opportunity to monitor and promote adherence” in these patients when they see their physicians. For primary prevention, however, “adherence will probably emerge as a major issue.” Grundy observes that “the health care system is not fashioned to promote long-term drug adherence” in the United States.
April 2nd, 2013
Selections from Richard Lehman’s Literature Review: April 2nd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 27 Mar 2013 Vol 309
Effect of Disodium EDTA Chelation Regimen on CV Events in Patients With Previous MI (pg. 1241): Have you ever heard of someone who’s recently had a heart attack going off and having 40 infusions of disodium ethylenediaminetetraacetic acid, ascorbate, B vitamins, electrolytes, procaine and heparin? No, I hadn’t either, until I went to give a talk to some cardiac rehabilitation patients about 12 years ago.
I said my little piece about all the lovely medical progress being made, and then took questions. They were all about chelation therapy, and I was reduced to desperately scanning the large room for means of escape while saying that I looked forward to reading the results of large randomized trials of this improbable mumbo-jumbo – though I might not have used those precise words. And here, at last, it is! A large, well-conducted trial (TACT) of chelation versus intravenous placebo in 1708 survivors of myocardial infarction. The trend to benefit is consistent and adds up to a statistically significant reduction in adverse cardiovascular events, driven largely by a reduction in the perceived need for revascularization. But this cannot be true, argues Steve Nissen in a commentary. They must have cheated. Harlan Krumholz has fun taking the opposite view in a Forbes Weekly piece: “This study has opened my mind to the possibility that there may be something more to this therapy than I originally thought. And given what I thought about it before, I can hardly believe I am writing that.”
NEJM 28 Mar 2013 Vol 368
Effects of Off-Pump and On-Pump CABG at 1 Year (pg. 1179): Did I imagine it, or did I really see a tweet from a cardiac surgeon describing off-pump coronary bypass grafting as “like making love while standing up in a canoe: it can be done, but why would you want to?” Well, there’s the showing off of technical skill – no, wait, I am getting mixed up here – cardiac surgeons are not like that; it must be to achieve better neurocognitive outcomes for patients. Forget the canoe: let’s look at what happens when these surgeons stand on the terra firma of their operating rooms and perform CABG, using a cardiac bypass pump or not according to randomization schedule. The first large trial in this week’s NEJM randomized 4752 patients, and conclusion is “At 1 year after CABG, there was no significant difference between off-pump and on-pump CABG with respect to the primary composite outcome, the rate of repeat coronary revascularization, quality of life, or neurocognitive function.”
Off-Pump vs. On-Pump CABG in Elderly Patients (pg. 1189): The second trial looked at outcomes in 2539 Germans aged 75 or over, where cognitive effects might be expected to show up more clearly. But oddly enough, they were not looked for. The primary end-points that were measured showed “no significant difference between on-pump and off-pump CABG with regard to the composite outcome of death, stroke, myocardial infarction, repeat revascularization, or new renal-replacement therapy within 30 days and within 12 months after surgery.” So that’s it for off-pump CABG. It’s just showing off. Oops darling, splash!
Treatment of Anemia with Darbepoetin Alfa in Systolic HF (pg. 1210): Anaemia is a very common accompaniment to heart failure, and each decrement of haemoglobin is associated with worse survival, so it would seem logical to try and do something about it. But this randomized trial shows that using darpoetin alfa to achieve a haemoglobin of 13 in patients with systolic HF does not reduce death or hospitalization for HF. It does not even improve symptoms.
Lancet 30 Mar 2013 Vol 381
Use of Clopidogrel With or Without Aspirin in Patients Taking Oral Anticoagulant Therapy and Undergoing PCI (pg. 1107): Patients who are taking oral anticoagulants and who need to have percutaneous coronary intervention are, it seems, often loaded up with both aspirin and clopidogrel prior to the procedure, and not surprisingly they have a high incidence of bleeding. This trial from Belgium and the Netherlands tried the effect of omitting the aspirin and just using clopidogrel in a randomised comparison with standard triple therapy. “Use of clopiogrel (sic) without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.”
April 2nd, 2013
Intensive Glucose Control and ESRD – Strongest Evidence?
Kasia Lipska, MD, MHS
Multiple randomized clinical trials conducted in patients with type 2 diabetes showed that intensive glucose control reduces composite endpoints of microvascular disease, primarily driven by reductions in albuminuria. None, so far, has established the effect of intensive glucose control on macrovascular clinical outcomes, such as end-stage renal disease (ESRD) or death from renal disease. Even when trial data were aggregated in a meta-analysis of over 28,000 patients, the evidence for a significant effect on renal outcomes was lacking.
Perkovic and colleagues now report “the strongest evidence yet that intensive glucose-lowering regimens may protect against the development of ESRD.” The investigators analyzed data from the ADVANCE trial to determine the effect of an intensive glucose control strategy (target HbA1c, ≤6.5%; achieved HbA1c, 6.5%) compared with standard care (defined by local guidelines; achieved HbA1c, 7.3%) on multiple renal outcomes, including ESRD (defined as need for dialysis or renal transplantation), renal death, renal death or ESRD, sustained or any doubling of creatinine to >200 mmol/L, new micro- or macroalbuminuria, and progression or regression of albuminuria. They found modest but significant reductions in new micro- and macroalbuminuria, but no effect on doubling of creatinine. However, they did find a significant reduction in ESRD, with an associated hazard ratio of 0.35 (95% CI, 0.15–0.83).
Are we convinced that intensive glucose lowering strategies will reduce the need for dialysis or transplantation?
Here are a few things to consider:
- Only 27 ESRD events occurred, so the absolute risk for ESRD was extremely low. Among 11,140 participants with type 2 diabetes followed over 5 years, the annual event rates of ESRD were 0.075% in the standard group versus 0.026% in the intensively treated group. This means that 410 persons would need to be intensively treated over 5 years to prevent 1 ESRD event.
- Multiple renal endpoints were tested in this post-hoc analysis — without adjustment for multiple comparisons. In this context, it is tough to consider the results more than simply hypothesis-generating. Furthermore, as noted above, when evidence from ADVANCE and other randomized controlled trials was considered together in a meta-analysis, the results were not significant for ESRD.
- Even if we accept that out of 410 intensively treated patients, 1 ESRD event will be prevented, does this benefit outweigh the risks? Intensive glucose strategies increase the risk for severe hypoglycemia requiring external assistance. Although the incidence of hypoglycemia varied considerably across trials, a conservative estimate would place a number needed to be harmed at about 50 (and this number may underestimate hypoglycemia that may occur in community settings). In addition, the ACCORD study was terminated early because of an increased rate of mortality in intensively treated patients, with 1 extra death per 95 patients treated for 3.5 years.
The analysis conducted by Perkovic et al. may be the strongest evidence yet, but it doesn’t provide compelling reasons to recommend intensive glucose control for prevention of ESRD in type 2 diabetes patients like those enrolled in ADVANCE.
April 2nd, 2013
Perspective On The Controversy About The TACT Trial
Sanjay Kaul, MD
Let me begin with a disclaimer that I do not endorse chelation therapy, and do not view the results of the TACT trial as providing ‘actionable’ evidence for regulatory decision making or for guiding clinical practice. However, notwithstanding the flaws in trial design and conduct, I would like to make the following observations that address some of the key criticisms launched against the TACT trial. (The following has been adapted from earlier comments I made in response to a blog post on Respectful Insolence.)
1. Missing data, the elephant in the room
The amount of missing data, while vexing, is not unexpected given the onerous treatment protocol involving multiple infusions over a prolonged period of time. The missing data can challenge the interpretation of trial results, but the claim that it invalidates the results is not supported by careful examination of the supplementary information provided in the eAppendix. There do not appear to be major imbalances in either the key prognostic covariates or in the reasons for ‘missingness’ amongst the dropouts in the 2 randomized groups. Thus, careful scrutiny of the data doesn’t necessarily lead to the conclusion that ‘informative censoring’ did indeed occur in favor of chelation treatment. Moreover, the results of the sensitivity analyses, which I find quite reasonable, do not support the assertion that differential missing data bias the results in favor of the chelation treatment. I acknowledge that missing data are problematic in general as they challenge the interpretation of the overall results, but the onus is on those who claim that it invalidates the results to prove so! By the way, the problem of missing data (and sloppy trial conduct) is quite common even in clinical trials run by academic research organizations of the highest repute!
2. Potential investigator or patient unmasking
Impugning the integrity of the trial investigators, especially at CAM sites, requires a higher burden of proof than simply innuendo. These sites were audited and after implementation of remedial measures, they passed the scrutiny of NIH, FDA, and OHRP.
One would have expected a greater treatment effect as a result of potential trial misconduct at these sites, but the data do not suggest a differential treatment effect at CAM (HR 0.89) vs non-CAM sites (HR 0.72), interaction p = 0.28.
3. Subjective endpoints
It has been stated that the treatment effect was driven by the soft and somewhat subjective endpoints of CV hospitalizations and revascularization. For a variety of reasons, I am not a big fan of the type of composite endpoint used in TACT. However, the inclusion of these soft endpoints is driven primarily by trial feasibility considerations as these components are more prevalent. In fairness, the trial was not powered for ‘hard’ endpoints of mortality, MI or stroke. It is somewhat reassuring to note that the HR for the composite of cardiovascular death, nonfatal MI, or nonfatal stroke (stringent MACE), a prespecified secondary endpoint, was 0.84 (p=0.22), similar to the HR of 0.82 (p=0.035) for the primary quintuple composite endpoint (MACE plus). Finally, there doesn’t appear to be heterogeneity of treatment effect across the components of the composite endpoint, thus strengthening the observations.
It is important to understand that the inclusion of subjective endpoints like CV hospitalization and revascularization increases the potential for ascertainment error and misclassification that typically biases the results towards the null. So, if the objective of the trial is to prove superiority, as was the case in TACT, the bias would operate against it (conservative). Conversely, if the objective of the trial is to prove noninferiority, i.e., rule out unacceptable risk, the bias would operate towards it (anti-conservative).
4. Implausibility of treatment effect and Bayesian analysis
It has been argued that “there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and we know that chelation therapy can cause harm; so the risk was not minimal.” “A Bayesian analysis would not look kindly on the results due to the low prior probability of treatment effect.”
First, let me state there are several examples in medicine that have shone the spotlight on the slippery slope argument of plausibility (antioxidant vitamins, hormone replacement therapy, magnesium for MI, anti-reperfusion injury therapy come to mind). Thomas Huxley said it best, “the tragedy of science, the slaying of a beautiful (plausible) hypothesis by ugly facts!”
Second, the reason for the low prior probability of benefit assertion is not clear to me. The available evidence for treatment effects of chelation therapy in patients with coronary heart disease or peripheral arterial disease is mixed, and limited to case series and three small trials evaluating surrogate endpoints. No outcome data derived from properly designed clinical trials existed to support or refute treatment effect! Despite the lack of supportive evidence, the number of patients undergoing chelation therapy increased by >50% between 2002 and 2007. Thus, it was important to clarify the benefits and harms of chelation therapy in a controlled outcome trial. Accordingly, the argument that the trial was unethical, as has been suggested by some, doesn’t hold water!
Third, the principle of equipoise, an ethical prerequisite for patient randomization and enrollment, would require suspension of one’s belief in treatment effect as reflected in a pretrial null hypothesis probability of 50%. The p value of 0.03 translates into a minimum Bayes’ factor of 0.09, which reduces the null probability from 50% pretrial to about 9% post-trial. While this does not represent strong evidence against the null, it does reduce the level of skepticism surrounding chelation therapy.
Here is a formal Bayesian analysis of TACT that might be instructive:
Evidence (likelihood) = 0.82 (0.69, 0.99)
Prior (skeptical) = 1.0 (0.75, 1.33)
The mean is centered on null, and there is only 5% probability of an extreme treatment effect, i.e., >25% risk reduction or >33% risk increase. Many would argue that this is a reasonably skeptical prior distribution.
Posterior = 0.87 (0.75, 1.02)
The posterior probability of a >13% risk reduction is 50%, and the probability of a >10% risk reduction is 66%.
So if we start from a position of skepticism, integrating the results of the TACT trial reduces the degree of skepticism. This is exactly how Bayesian analysis helps upgrade knowledge and information. One would require a prior probability of 2-fold increase in CV risk with chelation (not supported by evidence to my knowledge) to completely nullify the results of the TACT trial, an arguably IMPLAUSIBLE conjecture!
5. Implications for clinical practice
Given the significant treatment by diabetes interaction, some have argued ‘tongue-in-cheek’ that “the recommendation from this trial should be that no non-diabetic with cardiovascular disease should be treated with chelation therapy because it definitely does not work for them.”
The presumption that the TACT trial provides actionable evidence for clinical practice is not endorsed by anyone including the TACT investigators. The best case interpretation of the data is that the evidence is inconclusive. Ideally, under such circumstances, the only worthwhile recommendation should be ‘additional studies are warranted to adjudicate the uncertainties’. That is how science and knowledge should progress.
6. Double standard for acceptance of convenient versus inconvenient evidence
I agree with the notion that there is clearly a double standard when it comes to accepting the results of trials evaluating so-called dubious quack cures such as chelation versus trials assessing promising de rigueur cures such as gene transfer or stem cell therapy.
Bottom line, in my opinion, the arguments that the TACT results are dubious or not valid are overstated. While the debate surrounding TACT is clearly warranted and welcome, I hope it generates more light than heat.
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