May 9th, 2013
Another Disappointing Study for Fish Oil Supplements
Larry Husten, PHD
Another large study has failed to find any benefits for fish oil supplements. The Italian Risk and Prevention Study, published in the New England Journal of Medicine, enrolled 12,513 people who had not had a myocardial infarction but had evidence of atherosclerosis or had multiple cardiovascular risk factors. The patients were randomized to either a fish oil supplement (1 g daily of omega-3 fatty acids) or placebo.
After 5 years’ follow-up, the primary endpoint — the time to death from cardiovascular causes or admission to the hospital for cardiovascular causes — had occurred in 11.7% of the fish oil group versus 11.9% of the placebo group (adjusted hazard ratio 0.97, CI 0.88-1.08, p=0.58). There were no significant differences in any of the prespecified secondary endpoints.
With one exception, there were no significant differences in outcomes in the prespecfied subgroups. Women who received fish oil supplements had a significant reduction in the primary endpoint (HR 0.82, CI 0.67-0.99, p=0.04). The study investigators also report that although there was no difference in the rate of hospital admissions for cardiovascular causes, there was a significant reduction in hospital admissions for heart failure in the fish oil group (1.5% vs. 2.3%, p=0.002).
Due to a lower-than-expected rate of events, after the first year the investigators modified the primary endpoint, which originally had been the cumulative rate of death, MI, and nonfatal stroke.
The investigators write that “the consistently null effect across the various end points and subgroups does not suggest alternative interpretations.” The observed benefits in women and in reducing hospital admissions for heart failure “must be considered conservatively,” they add.
The trial investigators discussed two previous Italian trials, the GISSI-Prevenzione trial, in MI patients, and the GISSI-HF trial, in heart failure patients, which found benefits for fish oil supplements in their respective populations. In both trials, they say, the benefit may be attributed to a reduction in sudden deaths from cardiac causes. “It is conceivable that the effects of n-3 fatty acids become manifest primarily in patients who are particularly prone to ventricular arrhythmic events,” they write. The population in the current trial, by contrast, was much less prone to arrhythmias.
One expert on cardiovascular prevention, James Stein, said that “the results are disappointing, but consistent with recent studies showing no significant effect of fish oil supplements.” He said that fish oil supplements “are not a panacea” and that it would be most accurate to say that “some studies suggest a benefit.”
Dariush Mozaffarian, a leading researcher in the field, sent the following comment:
Heart disease death (rather than nonfatal heart disease or total cardiovascular disease) is the main outcome likely influenced by fish oil, at least at relatively low doses such as used in this trial. Thus, this is an important study, because among the more recent trials of fish oil and heart disease, it is the only one that has larger numbers of heart disease deaths (158 total).
The lack of any discernable effect on heart disease death (“coronary death”) raises concerns about the real benefits of fish oil supplements in patients at high risk for cardiovascular disease. Recommendations to eat fish, in the context of an overall healthy diet, increasing activity, and stopping smoking, should remain the priority for reducing risk. Still, there was no evidence that fish oil supplements cause any harm or risk, so for patients who won’t eat fish or wish to be sure they are getting their omega-3’s, there is no reason to stop taking fish oil supplements if they are already on them.
May 9th, 2013
Blogging from HRS 2013: VT/VF Summit, and Bill Clinton Too!
Luis Garcia, MD
Several Cardiology Fellows who are attending the Heart Rhythm Society meeting in Denver this week are blogging for CardioExchange. The Fellows include Luis Garcia, Sandeep Goyal, and Amit Mehrotra. You can view the next post here.
Yesterday was the 1st day of the HRS 2013 sessions. I had the pleasure of attending the VT/VF Summit and President Clinton’s address.
As an incoming ep fellow attempting to absorb as much as mentally possible, the VT/VF Summit served as a fantastic start! It was a tremendous, day-long event that began with Dr. Josephson’s early work on VT mapping and ended with Dr. Dixit’s presentation on surgical therapies for VT. Notable presentations by Dr. Zipes on autonomic modulation, Dr. Hutchinson on imaging utilization for characterization of VT, and Dr. Asirvatham’s presentation on novel therapeutic approaches highlighted the event. The summit offered a wonderful framework of the state of ventricular tachyarrhythmias.
President Clinton’s plenary address filled the entire theater at the Denver Convention Center! His usual gravitas certainly captured the attention of all. He focused on the features of equality, instability, and consumption of care as important features of the current healthcare system. He highlighted the phenomena of the positive interdependence we have in our world today (i.e., technology, resource utilization), his own experience with cardiovascular disease, and the need for novel solutions to the changing global health care milieu.
Overall, a great start, and I’m looking forward to some late breakers and electrograms!!
May 9th, 2013
Journal X: Not so Subtle Marketing Messages
Eric Lindley, MD
I was the rare resident who thought that conflict of interest issues in medicine were a bit overblown. I did not find (or ignored) the evidence that pharma played a role in prescribing habits very persuasive, at least not when it came to my personal prescribing habits. I was not alone among the house staff, however, in appreciating an occasional “free” lunch, and the much rarer sponsored dinners at places I couldn’t afford as a physician-in-training.
Now I’m a fellow, and my attitudes about the pervasiveness of pharma influence have changed. Am I older and wiser? I’d like to think so. But I owe most of my conversion to the fresh perspective of my three-year-old daughter. She refers to most things by their color, including a majority of my medical journals. For instance, my JACC journals: blue for the mother journal, red for heart failure, green for interventions, etc. But then she started calling the original JACC the “X” journal. When I asked her why, she pointed to the “X” in Xarelto (rivaroxaban). I realized that every issue of JACC is covered front to back with the “X”. The message was subliminal to me, but quite obvious to her.
How do you think all of our pharma marketing looks with naive eyes?
May 7th, 2013
Longer Detection Time Helps Prevent Unnecessary ICD Shocks
Larry Husten, PHD
Increasing the detection intervals in ICD programming can reduce the number of unnecessary or inappropriate shocks, according to results of the ADVANCE III study published in JAMA.
A group of Italian investigators randomized 1,902 patients receiving an ICD to programming with either long- or standard-detection intervals. After 12 months of followup, patients in the long-detection group had a significant reduction in the primary endpoint, which was the total number of antitachycardia pacing (ATP) episodes and shocks:
- 346 events versus 557 events, for an incident rate ratio of 0.63 (CI 0.51-0.78; p<0.001)
- ATP: 308 versus 142, IRR 0.58 (CI 0.47-0.72)
- Shock: 249 versus 154, IRR 0.77 (CI 0.59-1.01)
Although there was a significant reduction in the incidence of inappropriate shocks (IRR 0.55, CI 0.36-0.850), there was no difference in appropriate shocks (IRR 0.95, CI 0.67-1.37). There were no significant differences in mortality or episodes of syncope. Patients in the long-detection group were hospitalized less frequently.
The authors wrote that “ADVANCE III demonstrated that the use of a long detection setting… significantly reduced the rate of ventricular therapies delivered and inappropriate shocks compared with the standard detection setting.” They concluded that “this programming strategy may be a useful approach for ICD recipients.”
In an accompanying editorial, Merritt Raitt writes about the striking finding in previous trials in which ICD shocks have been associated with an increased risk of death. Although ADVANCE III was not designed to assess mortality, the benefits of long-detection programming are evident:
Regardless of whether these programming interventions lead to reduced mortality, the unequivocal reduction in ICD shocks and the reduction in hospitalization without an increase in adverse events such as syncope suggests that this programming approach should be considered for adoption in the care of patients with ICDs and clinical characteristics similar to those enrolled in these studies.”
May 7th, 2013
Burton Sobel, Towering Cardiologist, Dead at 75
Larry Husten, PHD
Burton Sobel, a towering scientist and cardiologist, died at home on May 3 at the age of 75. Sobel had been treated in the past for prostate cancer and had suffered a recurrence, but it is not known if this was the immediate cause of his death.
Sobel was among the most powerful and influential cardiologists in the 1980s when he played a key early role in the development of fibrinolysis and the first major biotechnology product, TPA. From his perch as the chief of cardiology at Washington University in Saint Louis and as the editor of Circulation, Sobel was a member of a small group of cardiologists who set the agenda for cardiology and moved the field forward. The group, which also included James Willerson, Myron Weisfeldt, and Eugene Braunwald, was “innovative” and “visionary,” said Allan Jaffe, who worked closely with Sobel at Washington University for many years. “It was a very exciting time in cardiology,” he said.
Sobel’s research exploring the biochemistry of fibrinolytic agents, fatty acids, diabetes, and insulin resistance “was way ahead of his time” and “seminal,” said Jaffe. Sobel was also “tremendously innovative” as the editor of Circulation, helping propel it into the modern era of rapid review and publication.
One highlight of this period was Sobel’s partnership with Désiré Collen, a Belgian scientist. After Collen purified TPA and accumulated enough of the protein for research purposes, it was Sobel who then worked out how best to test the protein, at first in animals and then in humans.
Sobel was an undergraduate at Cornell University and completed medical school at Harvard. Following an internship and residency at the Peter Bent Brigham Hospital, he did his cardiology fellowship at the NHLBI.
In the mid-1990s, following a congressional investigation which revealed that Sobel had received options in Genentech stock, Sobel’s visibility and influence waned, though he remained active as a researcher and educator. He left St. Louis and in 1994 became the chairman of the department of medicine at the University of Vermont. He created the Cardiovascular Research Institute at the University of Vermont.
Sobel served on the board of directors of Arca Biopharma. Said Michael Bristow, president and CEO of the company:
“Burt was recognized as one of the great academic physicians of our time. He did groundbreaking work in several fields of cardiovascular medicine including blood coagulation, which led to major advances in the treatment of heart attacks and other thromboembolic diseases, as well as seminal work on myocardial function and biochemistry in response to hemodynamic stress. Burt will be deeply missed by his family, friends, colleagues, and the many patients whose lives were greatly improved by his contributions to cardiovascular medicine.”
Sobel is survived by his wife Susan, to whom he was married for 55 years, his children Jonathan and Elizabeth, and his granddaughter Skye.
May 7th, 2013
Selections from Richard Lehman’s Literature Review: May 7th
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.
BMJ 4 May 2013 Vol 346
When to Remeasure CV Risk in Untreated People at Low and Intermediate Risk: This study was carried out in Australia using data from Massachusetts and Tokyo, and it shows that you don’t need to go remeasuring cardiovascular risk more than about every 10 years in low-risk groups. This is a really useful analysis. In higher-risk groups, measure more often if you have decided not to treat: above all, involve the patient in making any decisions, and help all smokers to stop.
May 6th, 2013
Meta-analysis Finds Same-Day Discharge for Low-Risk PCI May Be Feasible
Larry Husten, PHD
Although elective PCI for most low-risk patients is extremely safe, overnight observation is still standard practice in the U.S., largely due to the lack of evidence demonstrating that same-day discharge is safe. Now a new meta-analysis, published online in the Journal of the American College of Cardiology, provides support for same-day discharge in carefully selected low-risk patients.
Kimberly Brayton and colleagues analyzed data from 37 studies, 7 of which were randomized trials and 30 of which were observational studies. Among the 2,738 patients who were randomized to either same-day discharge or overnight observation, there was no difference in the primary composite endpoint of death, MI, and target lesion revascularization or in the rate of major bleeding and vascular complications. Among 10,065 patients who were included in observational studies, the pooled rate of the primary composite endpoint and the rate of major bleeding and vascular complications occurred at the very low rates of 1% and 0.68%.
In their discussion, the authors write that it was “important to note that patients with significant comorbidities were excluded from most of these studies.” Patients with low LVEFs or with chronic kidney disease “are unlikely to be ideal candidates for same-day discharge even when PCI is elective.” Hospitals seeking to develop a same-day discharge program “should develop formal criteria for identification of appropriate patients as well as a system for close follow-up.” Currently, they point out, PCI guidelines do not incorporate recommendations for same-day discharge. They conclude:
Although larger studies are needed to provide definitive comparisons of same-day discharge vs. overnight observation, in aggregate the data… support consideration of programs for same-day discharge in carefully selected patients.”
I asked Brayton to comment on whether same-day discharge is likely to become common practice in the near future:
It appears that there are two separate issues to consider for routine implementation of same-day discharge – safety and cost. Our study indicates that same-day discharge is safe for a large number of relatively low-risk patients undergoing PCI (mostly elective), and that it would be reasonable for most programs to consider instituting a protocol allowing same-day discharge of appropriate patients. However, cost considerations are considerably more complex. In general, the potential cost-savings of same-day discharge depend on two factors – a program having sufficient volume of low risk patients to justify the up-front costs of implementing a change in protocol, and the ability of a program to successfully recapture the resources liberated by same-day discharge, either through a decrease in staffing or through reallocation of the freed resources for use for another patient. Programs are heterogeneous enough, and the reimbursement structure fluid enough, that it is hard to predict how common the practice will become, even if data supporting the safety of same-day discharge continue to accrue.
May 3rd, 2013
FDA Approves Combination of Ezetimibe and Atorvastatin
Larry Husten, PHD
The FDA has approved a new combination drug from Merck for lowering cholesterol. The drug, which will carry the brand name of Liptruzet, is a combination of two previously approved cholesterol-lowering drugs, ezetimibe and atorvastatin.
Merck said the new drug (pronounced “LIP-true-zett”) would be commercially available starting next week. Liptruzet will be available as a once-daily tablet combining 10 mg of ezetimibe with either 10, 20, 40, or 80 mg of atorvastatin. In clinical trials Liptruzet lowered LDL cholesterol by 53% to 61%, depending on dosage.
Merck said the drug had been approved for the treatment of elevated LDL cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. It is also indicated in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Prior to going off patent in 2011, atorvastatin (Lipitor, Pfizer) had been the best-selling drug in the world for many years. Ezetimibe, marketed as Zetia, and, in combination with simvastatin, as Vytorin, was also a blockbuster, though in recent years its popularity has diminished as a result of controversy over the drug’s research program and the lack of evidence demonstrating clinical benefits beyond lowering the surrogate endpoint of LDL cholesterol. The Merck press release acknowledges this:
No incremental benefit of LIPTRUZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.”
Click here to read Merck’s press release.
Click here for a PDF of the Liptruzet label.
Click here for a PDF of the patient information sheet.
May 2nd, 2013
Danish Study Finds No Increased CV Risk with Azithromycin in General Population
Larry Husten, PHD
A large observational study found no increased risk for cardiovascular events associated with azithromycin (Zithromax, Pfizer) in a general population of young and middle-age adults. In a paper published in the New England Journal of Medicine, Danish investigators report the results of a large national observational study comparing people who took azithromycin with matched controls who took no antibiotics and with controls who took penicillin V for similar indications.
Although there was a significant increase in the risk for death from cardiovascular causes in people taking azithromycin compared with people taking no antibiotics (RR 2.85, CI 1.13 – 7.24), there was no increase in risk when compared with people taking penicillin V (RR 0.93, CI 0.56 to 1.55). The findings, write the authors, indicate “that the increased risk that was observed in the comparison with no antibiotic use was entirely attributable to the risk of death associated with acute infection (or some other adverse health characteristic in persons receiving antibiotic treatment, as compared with those not treated with antibiotics) rather than with its treatment.”
The current study appears to contrast with an earlier study by Ray et al. which found a small increase in risk with azithromycin in people at high initial risk for cardiovascular disease. This was followed in March of this year by an FDA statement warning that QT prolongation associated with azithromycin can result in a potentially fatal arrhythmia. But, the Danish investigators write, their study provides “a clinically relevant complement to, rather than a contrast with, the findings of Ray et al.” They propose that azithromycin may increase risk in a population already at high cardiovascular risk but “this effect is not present in the general population.” They conclude:
The implications of these findings for clinical decision making are reassuring; they indicate that for the general population of patients seen in office practice, azithromycin can be prescribed without concern about an increased risk of death from cardiovascular causes, whereas the benefits of therapy need to be weighed against the risk of death from cardiovascular causes among patients with a high baseline risk of cardiovascular disease.
In an accompanying perspective, FDA officials review the currently available evidence regarding the cardiovascular risk of azithromycin and other antibiotics. They recommend that “clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.”
May 1st, 2013
FDA Warns That Tolvaptan Can Lead to Serious Liver Injury
Larry Husten, PHD
The FDA has issued a drug safety communication concerning tolvaptan (Samsca, Otsuka), a selective vasopression V2-receptor antagonist used in heart failure patients to treat clinically significant hypervolemic and euvolemic hyponatremia. The FDA said tolvaptan “should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death. ”
The liver injury risk was discovered in clinical trials testing tolvaptan in patients with autosomal dominant polycystic kidney disease. The drug label has been updated and now states that use of the drug should be limited to 30 days and that it is no longer indicated in patients with cirrhosis. The FDA recommended that tolvaptan should be discontinued in patients with liver disease who are currently taking the drug.
NEJM Journal Watch — Recent Cardiology Articles- Reevaluating Genetic Associations in Hypertrophic Cardiomyopathy
- Does Use of Drug-Coated Devices Improve Outcomes in Chronic Limb-Threatening Ischemia?
- New Recommendations for Lipid Management in Patients with Acute Coronary Syndromes
- Postpartum Blood Pressure Control in Hypertensive Disorders of Pregnancy: Is Lower Better?
- Beta-Blocker Use After Takotsubo Syndrome