December 10th, 2014
Focus on Getting Rid of Sugar, Not Salt, Say Authors
Larry Husten, PHD
Too much negative attention has been focused on salt and not enough on sugar, write two authors in Open Heart. Reviewing the extensive literature on salt and sugar, they write that the adverse effects of salt are less than the adverse effects of sugar. The evidence supporting efforts to reduce salt in the diet is not convincing and we would be far better off reducing sugar instead of salt in the modern diet.
“Future dietary guidelines should advocate substituting highly refined processed foods (ie, those coming from industrial manufacturing plants) for natural whole foods (ie, those coming from living botanical plants) and be more explicitly restrictive in their allowances for added sugars,” write James DiNicolantonio and Sean Lucan. “The evidence is clear that even moderate doses of added sugar for short durations may cause substantial harm.”
Salt prevention is often the cornerstone of dietary therapy for people with hypertension or at risk for developing hypertension. Less appreciated is that sugar can raise blood pressure in addition to its other well known adverse metabolic effects. Hypertensives are also much more likely than nonhypertensives to have insulin resistance — and it is well established that high sugar in the diet can exacerbate this problem and lead to diabetes.
“Sugar may be much more meaningfully related to blood pressure than sodium, as suggested by a greater magnitude of effect with dietary manipulation,” they state.
Lowering salt in processed foods may cause people to compensate and ultimately consume more processed food, the authors write. The end result is consumption of the same amount of salt but even more sugar, since these foods also often contain high amounts of added sugars.
The authors cite a wide variety of studies showing the ill effects of sugar. For instance, people who get a quarter or more of their calories from added sugar have a nearly threefold increased risk of cardiovascular death.
One particular villain is high fructose corn syrup, which is most often used in sugar sweetened beverages. “Worldwide, sugar sweetened beverage consumption has been implicated in 180,000 deaths a year,” they write.
One piece of good news: sugars, including fructose, are not harmful and may be even beneficial when they are consumed “in their naturally occurring biological contexts”– in other words, as whole fruits.
December 8th, 2014
Selections from Richard Lehman’s Literature Review: December 8th
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 4 December 2014 Vol 371
Surgical Treatment of Moderate Ischemic Mitral Regurgitation (pg. 2178): When I first read about “functional” mitral regurgitation in echo reports of my heart failure patients in the 1990s, I wondered if anybody had done a trial to see if mitral valve repair might help this. Well, it’s now been done and the answer is no, probably. The trial randomly assigned 301 patients with moderate ischaemic mitral regurgitation to coronary artery bypass alone or CABG plus mitral-valve repair. The mean age of the patients was 64-5, and most of them had New York Heart Association (NYHA) grade 3-4 heart failure, although those in the group randomised to valve surgery were slightly younger and fitter. Despite that, they showed no benefit at one year judged by left ventricular end-systolic volume index (a surrogate for adverse remodelling), and inevitably had longer hospital stays and more neurological complications.
JAMA 3 December 2014 Vol 312
Effect of Screening for CAD Using CT Angiography on Mortality and Cardiac Events in High-Risk Patients With Diabetes (pg. 2234): Find and cure: identify those at greatest peril and save their lives by early intervention. That’s the great sales pitch for screening but it’s seldom true. To be sure, lots of people with type 1 or 2 diabetes have silent coronary artery disease and many of them will die from it, but it does not follow that picking it up early with CT angiography will work better than giving preventive drugs to everybody. The FACTOR-64 trial shows that “among asymptomatic patients with type 1 or type 2 diabetes, use of CCTA to screen for CAD did not reduce the composite rate of all cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. These findings do not support CCTA screening in this population.”
The BMJ 6 December 2014 Vol 349
Mediterranean Diet and Telomere Length in Nurses’ Health Study: Telomeres tell us how long we’ve got left, right? And they can be shortened by bad behaviour but never lengthened by good? I hope I understand the telomere, since it is the latest vehicle for trying to prove that the Mediterranean diet is a good thing. As I have told you almost every week, the Nurses’ Health Study enrolled 121 700 American nurses in 1976, and not one was male. Many of them kept food diaries and most had lots of blood tests. From these we can assess the “Mediterraneity” of their diets, and also measure how their telomeres changed over time, as the Fates snipped at them with their abhorred shears until the day of their personal doom. It seems that if you eat the necessary amount of whatever diet dweebs deem to be Mediterranean, the Fates will do less snipping. I tell you this because it is in The BMJ.
December 8th, 2014
New Anticoagulant Spotlights Major Role for the Intrinsic Pathway
Sanjay Kaul, MD and Ethan J Weiss, M.D.
An entirely new approach to anticoagulation will likely change our understanding of coagulation and thrombosis but the clinical implications may be less clear. FXI-ASO, under development by Isis Pharmaceuticals, is an antisense oligonucleotide that reduces the level of factor XI, a key component of the intrinsic (contact) coagulation pathway. All the currently available anticoagulants target the extrinsic (tissue factor) coagulation pathway.
In a phase 2 trial, 300 patients undergoing total knee arthroplasty were randomized to either enoxaparin or one of two doses of FXI-ASO. The incidence of venous thromboembolism, as assessed by venography, was 30% with enoxparin, 27% with the low (200 mg) dose of FXI-ASO, and 4% with the high (300 mg) dose of FXI-ASO. The low-dose FXI-ASO group was noninferior to enoxparin while the high-dose group was superior (p<0.0001). Bleeding occurred in 3% of each of the FXI-ASO groups and in 8% of the enoxaparin group, though this difference did not achieve statistical significance.
The investigators wrote in the New England Journal of Medicine that their “study showed that factor XI contributes to postoperative venous thromboembolism and that lowering factor XI levels was an effective method for its prevention and appeared to be safe.” The finding “challenges the concept that tissue factor is the main driver of thrombosis among patients undergoing surgery” and “raises the possibility that factor XI may be involved not only in the propagation of thrombosis, but also in its initiation.”
In an accompanying editorial, Robert Flaumenhaft agrees that the study “challenges the current paradigm” and offers “the best clinical evidence to date” for an important role for the intrinsic pathway in thrombus formation. But, he writes, the “results do not make a compelling case for the clinical use of the factor XI antisense oligonucleotide over anticoagulants that are currently used.” Among other limitations, he notes that the reduction in venous thromboembolism as detected by venography may not be clinically significant. The utility of FXI-ASO is also questionable given that it was initiated 36 days prior to surgery.
Sanjay Kaul:
Overall, this is an interesting finding that provides support for the role of the intrinsic coagulation pathway in venous thrombosis post orthopedic surgery. The profound reduction in thrombotic events without adverse hemostatic events appears to be “too good to be true.”
The promising results of this open-label phase 2 trial need to be replicated in a large, adequately powered trial using clinically relevant endpoints. Eighty percent power for a noninferiority trial might be acceptable for a phase 2 trial, but not for a phase 3 trial. The noninferiority margin appears to be liberal. And the choice of the comparator (subcutaneously injected enoxaparin) when oral alternatives are available could be questioned. The risk reduction in this trial was primarily driven by asymptomatic distal thrombosis diagnosed on venography which is rarely used in clinical practice, thereby raising questions about its clinical relevance.
Other issues that might limit the clinical utility of this drug include the need to give it via weekly subcutaneous injections for 4-5 weeks prior to the procedure, and the prolonged pharmacodynamic effect with potential impact on reversibility. Bottom line: promising proof of principle results, but larger studies required to clarify the benefit-risk profile of this novel agent.
Ethan Weiss:
Going back 20 years the dogma has been that in developing systemic anticoagulants, there is a see-saw model with bleeding on one side and thrombosis on the other. That is, the more you inhibit thrombosis, the more you bleed, whether with increased doses of an existing drug or with drugs with increased potency. As stated in many places, it has been the holy grail of hemostasis and thrombosis research to dissociate the two and to uncover an agent that might protect against pathological thrombosis while not increasing the risk of bleeding.
Historically, almost all agents developed in this field were designed to inhibit thrombosis without much concern for what was considered to be a necessary evil — bleeding. As a result, all the agents on the market today primarily inhibit the extrinsic or tissue factor pathway. Preclinical experience in animals and our vast clinical experience tells us that this strategy will indeed result in a see-saw of safety and efficacy and that as we learn more about the real clinical cost of bleeding, we may have reached the ceiling in terms of clinical utility.
The contact pathway is relatively new in evolution. Contact pathway proteases are absent in fish and begin to show up in lower amphibians such as frogs. Since its discovery, there has been great debate about its necessity, as people born without contact pathway proteases have little or no bleeding. Of course, this exposes the bias that if there is no effect on bleeding, there is no effect. While it remains unknown why it developed, it is very clear that the contact pathway does play a role in thrombosis. Many recent and elegant animal studies have suggested that inhibition of contact pathway proteases might just offer a means toward breaking the see-saw. Perhaps activation of the contact pathway is a key driver of pathological thrombosis in surgery, acute illness, or other conditions with increases in systemic inflammation.
Investigators at ISIS pharmaceuticals developed a strategy to inhibit translation of factor XI protein by administration of an antisense oligonucleotide. The study they have published is the first significant clinical experience with this drug. The study itself is small and has many flaws, including that it was unblinded and that the protocol was changed mid-study. The drug is difficult to take, has to be administered long in advance of the “event”, and has a enormous rate of discontinuation due to injection-site issues. There is a very steep dose-response curve which is going to have to be explored more fully. However, with all these necessary caveats aside, this study represents a very exciting demonstration of how inhibition (reduction) of a contact pathway protease (factor XI) can reduce pathological thrombi after knee replacement at least as well as the standard inhibitor of the extrinsic pathway, enoxaparin. There was a tantalizing suggestion that this efficacy might come without the previously believed to be increase in bleeding. However, we have been led astray in small studies like this in the past; for right now, the best we can do is to say that this very interesting small study absolutely provides strong rationale for larger studies by ISIS and other companies developing small molecule or antibody-directed inhibitors of factor XI and perhaps factor XII.
It speaks volumes that a small study with its many warts appears in the New England Journal of Medicine. Expect lots more from this area and expect some disappointments along the way. But for now, there is great excitement about the contact pathway and the hope that we might have finally found a way to target pathological thrombosis without impacting blood clotting associated with wound healing (hemostasis).
December 4th, 2014
No Evidence to Support Routine Use of Aspirin in Women for Primary Prevention
Larry Husten, PHD
Although once widely recommended, aspirin for primary prevention has lost favor in recent years, as the large number of bleeding complications appeared to offset the reduction in cardiovascular events. But at the same time evidence has emerged demonstrating the long-term effect of aspirin in preventing colorectal cancer, leading some to think that the risk-to-benefit equation for aspirin should be reconsidered.
Investigators in the Women’s Health Study therefore analyzed long-term followup data from 27,939 women who were randomized to placebo or 100 mg aspirin every other day. They then calculated the 15-year risk for cardiovascular disease and colorectal cancer for the women in the study. In the overall study population aspirin use led to very small reductions in absolute risk for cardiovascular disease and colorectal cancer, resulting in NNTs (number need to treat) of 371 and 709. This tiny benefit occurred at the expense of the increase in gastrointestinal bleeding, reflected in the NNH (number needed to harm) of 133.
However, in women who were 65 or older the cardiovascular benefits of aspirin were more pronounced, with a 3.11% reduction in absolute risk at 15 years yielding a NNT of 29. GI bleeding was also increased in this older group,”but this increase was relatively smaller than the decrease in CVD, especially if bleeding is given less weight than CVD and cancer,” wrote the authors.
In their paper published in Heart, the authors conclude that aspirin for primary prevention “is ineffective or harmful in the majority of women with regard to the combined risk of CVD, cancer and major gastrointestinal bleeding.” However, they state that “selective treatment” in women 65 and older may be reasonable.
December 2nd, 2014
Adherence to Mediterranean Diet Linked to Marker of Healthy Aging
Larry Husten, PHD
Following a string of recent successes and favorable publicity for the Mediterranean Diet, a a new study published in The BMJ finds that women who more closely followed a Mediterranean diet had longer telomeres, a key measure of healthy aging.
The new report is based on data from 4676 women in the Nurses’ Health Study who completed food-frequency questionnaires and who also had their telomere length measured. In line with much previous research, the researchers found longer telomeres in younger women and nonsmoking women. Women with high scores indicating close adherence to the Mediterranean Diet had longer telomeres after adjustment for age. The association remained significant after adjustment for other characteristics likely to influence telomere length, including body mass index, smoking history, exercise, postmenopausal hormone therapy, and hypertension.
There was no significant link between telomere length and individual components of the Mediterranean diet, which included above-average consumption of vegetables (but not potatoes), fruits, nuts, whole grains, legumes, fish, and monounsaturated fats like olive oil; moderate alcohol intake; and below-average consumption of red and processed meats. The authors write that this finding emphasizes “the importance of examining the relation between dietary patterns, in addition to separate dietary factors, and health.”
The researchers found no significant association between telomere length and other dietary patterns, including the prudent and Western dietary patterns. There was weak positive association with a generic healthy eating pattern.
The authors calculated that the difference in telomere length among women who were more adherent to the Mediterranean Diet could translate into an average gain of about 4.5 years of life, roughly comparable to the difference between nonsmokers and smokers or being highly active and less active.
“To our knowledge, this is the largest population-based study specifically addressing the association between Mediterranean diet adherence and telomere length in healthy, middle-aged women,” the authors write. “Our results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity.”
The study “adds to the evidence” that longer telomeres are linked to healthy lifestyles, writes Peter Nilsson, in an accompanying editorial. “A Mediterranean diet is the cornerstone of dietary advice in cardiovascular disease prevention, and the fact that it also links with a biomarker of slower ageing is reassuring.” But he also points out the limitations of cross-sectional studies and calls for studies that measure “the attrition or shortening of telomeres over time.” He notes that genetic factors might explain “some of the variation in the association between dietary patterns and telomere length.”
December 1st, 2014
Selections from Richard Lehman’s Literature Review: December 1st
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 27 November 2014 Vol 371
Atenolol vs. Losartan in Children and Young Adults with Marfan’s Syndrome (pg. 2061): Antoine Bernard-Jean Marfan (1858-1942) was a French paediatrician who lived in the happy era of medicine when you could affix your name to new signs, symptoms, laws, and syndromes, and Marfan bagged at least one of each for himself. But, ironically, his name is immortalised by a syndrome distinctly different from the one he described—a fate which has also overtaken Drs Alzheimer and Asperger. Marfan (pronounced to rhyme with enfant) presented a girl with arachnodactyly and digital contractures, whereas Marfan (to rhyme with bar-fan) describes a hereditary disorder of connective tissue without contractures. In the full blown form of this autosomally dominant condition, the leading cause of death is cardiovascular disease, mainly progressive aortic root dilatation and dissection. To prevent this, beta-blockers have been generally used since an open label trial showed survival benefit in 1994. But theoretical reasons have been put forward that angiotensin receptor blockers might work better, and this trial pitted atenolol against losartan. At the end of three years, in 608 subjects aged 6 months to 25 years, there was no detectable difference between the agents. The primary outcome was a surrogate—the aortic root z score. And the trial was not adequately blinded. Be that as it may, it is good to note that in both groups the aortic root actually decreased in diameter as the study progressed.
JAMA 26 November 2014 Vol 312
Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients (pg. 2135): Back in those heroic days of medicine I alluded to above, a second year medical student at Johns Hopkins called Jay McClean isolated an anticoagulant from dog’s liver and called it heparin. This was in 1916, and had he called it McCleanin we might still remember him. It took another 20 years for a sufficiently pure and non-immunogenic liver extract to be produced for use as a human anticoagulant, and a further 50 years for low molecular weight heparins to be manufactured. However, although new is always more expensive, it is not necessarily better. A distinguished international line-up of authors use data from 2344 patients in the Prophylaxis for Thromboembolism in Critical Care Randomized Trial to determine whether LMWH dalteparin is worth the extra asking price compared with unfractionated heparin in ICU inmates. They conclude that it is. In fact, there is a cost saving driven by lower rates of pulmonary embolism and heparin induced thrombocytopenia, and corresponding lower overall use of resources with LMWH. Incidentally, old fashioned heparin is now made largely from pig intestine and bovine lung, which you’d think might preclude its use among hundreds of millions of religionists.
Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors (OL): By far the most dangerous ingredient in the proposed polypills is aspirin, and the evidence that it prevents cardiovascular disease in the general population is very slender. But populations vary, and so do risk scores in those populations. Officially, 98.5% of people living on the islands of Japan are “ethnically Japanese,” but according to Wikipedia this has no established veracity, or indeed meaning. However, we can take it that they are ethnically largely similar, and may have subtly different physiological traits from Europeans or North Americans. The Japanese Primary Prevention Project (JPPP) was designed to determine whether once daily, low dose, enteric coated aspirin reduces the total number of atherosclerotic events (ischaemic heart disease and stroke) compared with no aspirin in Japanese people 60 years or older with hypertension, dyslipidemia, or diabetes mellitus. Nearly 15 000 people were randomised. Result: “Once daily, low dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors.”
JAMA Intern Med November 2014 Vol 174
Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs. Advanced Life Support (OL): Probably the aspect of clinical medicine I will miss least is the requirement to waste three hours annually undergoing “life support training.” I can now confess that for several years I managed to go under the radar and skip these sessions. And I have been a doctor for 40 years without ever encountering an out of hospital cardiac arrest. If I do, I shall pump the chest as hard and frequently as I can and hope that someone has called an ambulance. Even this may be too much—nobody knows, because this is an evidence free area. This Less is More paper reports on outcomes following out of hospital cardiac arrest, according to whether basic or advanced life support was employed. There was a considerable difference. Those given advanced life support were less likely to survive and significantly more likely to suffer neurological damage.
Lancet 29 November 2014 Vol 384
Mechanical vs. Manual Chest Compression for Out-of-Hospital Cardiac Arrest (OL): While the basic concept of performing chest compressions for out of hospital cardiac arrest has never been subjected to a randomised trial, mechanical chest compressors have been compared with humans. By mechanical criteria, they perform better. But in trial after trial, PARAMEDIC being the latest, they make no difference to mortality. Which really makes you want to do that trial with no compressions as the control; but nobody would let you. A huge, earnest industry of well meant meddling stands to suffer. If you so much as lift an eyebrow during a CPR training lecture, you are made to feel at best like an incompetent, at worst like a murderer.
Relation Between D2B Times and Mortality After Primary PCI Over Time (OL): The leading figures in US cardiac outcomes research combine to examine trends in door to balloon (D2B) time and mortality after ST elevation myocardial infarction in 423 American hospitals, between January 2005 and December 2011. Their findings are paradoxical. Shorter patient specific door to balloon times were consistently associated at the individual level with lower in-hospital mortality and six month mortality. And during those six years, the median D2B fell from 86 minutes to 63. “By contrast, risk adjusted in-hospital and six month mortality at the population level, independent of patient specific D2B times, rose in the growing and changing population of patients undergoing pPCI during the study period.” So the investigators are explaining a paradox of worsening overall outcomes by a change in the population over that period. But if that is true, don’t we have to repeat all the trials comparing pPCI with thrombolysis, for example? I’m not entirely sure what is going on here. I leave these things to Harlan Krumholz, who is final author on this paper.
December 1st, 2014
Study Suggests Epinephrine for Cardiac Arrest May Be Harmful
Larry Husten, PHD
Epinephrine has been a cornerstone of therapy during cardiac resuscitation after cardiac arrest because of its well-established ability to stimulate the heart and increase the probability of a return of spontaneous circulation (ROSC). In recent years, however, concerns have been raised that people treated with epinephrine may have worse neurological outcomes following their resuscitation.
In a study published in the Journal of the American College of Cardiology, French researchers analyzed data from more than 1,500 patients who were successfully resuscitated after an out-of-hospital cardiac arrest and were subsequently treated at a large hospital in Paris. A total of 73% received epinephrine during resuscitation. The two groups were different in a number of respects: patients who received epinephrine were older, had a longer resuscitation, were less likely to have had a witnessed event, and were less likely to have had a shockable rhythm.
In the entire study group 31% survived to hospital discharge and 29% survived with a good neurological outcome. However, patients in the epinephrine group were less likely to have survival with a good neurological outcome (17% of patients in the epinephrine group versus 60% in the no epinephrine group).
This difference remained significant after adjusting for known differences between the groups. The researchers also reported that in a subset of the study population involving 228 matched pairs, epinephrine-treated patients were again less likely to have a good outcome. The authors acknowledged the criticism that epinephrine could be “considered a surrogate marker of severity rather than an independent predictive factor” but said that their “multiple methodological efforts” to remove bias led to their robust findings.
Early use of epinephrine within the first nine minutes of treatment was associated with a better outcome than later use of epinephrine. The authors suggested that epinephrine may not be helpful in the very early “electrical” phase of cardiac arrest and that the vasopressor effect of the drug may be harmful in the late “metabolic” stage. But epinephrine may still be helpful in the middle “circulatory” phase, they speculate.
“The role of epinephrine is more and more questionable in cardiac arrest,” said the first author of the study, Florence Dumas, of the Parisian Cardiovascular Research Center in France.
“It’s very difficult, because epinephrine at a low dose seems to have a good impact in the first few minutes, but appears more harmful if used later,” said Dumas. “It would be dangerous to completely incriminate this drug, because it may well be helpful for certain patients under certain circumstances. This is one more study that points strongly to the need to study epinephrine further in animals and in randomized trials.”
In an accompanying editorial, Gordon Ewy writes that the study “adds to the concern that epinephrine is not the ideal vasopressor during resuscitation of patients.”
November 28th, 2014
FDA Approves New Noninvasive FFR Technology
Larry Husten, PHD
The FDA said Wednesday that it had granted approval to a novel technology that noninvasively measures fractional flow reserve (FFR) using data obtained from a CT scan of the heart. In recent years a catheter-based form of FFR has been used by interventional cardiologists during catheterization procedures to measure the pressure gradient in partially blocked coronary arteries in order to identify lesions that are suitable candidates for a stent.
The HeartFlow FFR-CT, manufactured by HeartFlow Inc., “is a computer modeling program that provides a functional assessment of blood flow in the coronary arteries from detailed anatomical data,” said William Maisel, the deputy director for science and chief scientist in the FDA’s Center for Devices and Radiological Health. The HeartFlow FFR-CT was approved through a de novo premarket review pathway, which is available for some low- and moderate-risk devices.
Data from a CT scan of the heart is uploaded to the company headquarters in California where it is analyzed by the HeartFlow FFR-CT software. According to the FDA, “a case analyst creates 3D computer models of different sections of the patient’s heart and runs a blood flow simulator program on the models. After analyzing the data and the models, the case analyst electronically sends a report with the estimated FFR values (called FFR-CT values) displayed as color images of the patient’s heart.”
The FDA said that in clinical studies FFR-CT correctly identified 84% of lesions identified by traditional catheter-based FFR that required intervention and 86% of lesions that did not require intervention.
NEJM Journal Watch — Recent Cardiology Articles- To Lower Stroke Risk in Patients Undergoing Atrial Fibrillation Ablation, Is a Device or a Medication Better?
- Intensive vs. Standard Blood Pressure Lowering in Patients with Diabetes
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- Spironolactone Use After Percutaneous Intervention for Acute Myocardial Infarction
- CRISPR/Cas9 Gene Editing for Transthyretin Cardiomyopathy