November 15th, 2010
Omega-3s Fail to Show Benefits in Atrial Fibrillation
Larry Husten, PHD
In sharp contrast to earlier studies suggesting a positive effect, a large study of high-dose prescription omega-3 fatty acids found no evidence of benefit in treating atrial fibrillation. The trial, called the Efficacy and Safety of Prescription Omega-3 Acid Ethyl Esters (P-OM3) for the Prevention of Recurrent Symptomatic Atrial Fibrillation, included 663 patients with AF (542 with paroxysmal and 121 with persistent AF). Patients were randomized to take, for 24 weeks, either placebo or a prescription formulation of high-dose omega-3 fatty acids (8 g/day for the first week, 4 g/day thereafter).
There were no differences between the treatment and placebo groups in the primary endpoint, which was the time to the first recurrence of paroxysmal AF symptoms. Overall, in the placebo group there were 147 (46%) documented AF events compared to 167 (52%) in the omega-3 group. The omega-3s were well tolerated, the investigators reported.
“This was an attempt to do a definitive study to find out if manufactured omega-3 is beneficial in patients with atrial fibrillation,” said Peter Kowey, the lead author of the study, in an AHA press release. “The major finding was that fish oil did not work.”
November 15th, 2010
ROCKET AF Hits Chicago
Larry Husten, PHD
ROCKET AF hit the AHA on Monday morning. Results of ROCKET AF (Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation) had been the topic of intense speculation and interest.
The trial showed that the experimental factor Xa inhibitor rivaroxaban was as effective as warfarin in preventing stroke in 14,264 AF patients and did not increase their risk of bleeding. In the per-protocol analysis, the rate of stroke and embolism was lower in the rivaroxaban group than in the warfarin group (P<0.001 for noninferiority, P=0.018 for superiority). Major bleeding complications occurred at a similar rate in the two groups (P=0.576).
Rate of stroke and embolism:
- Rivaroxaban: 1.71 events per 100 patient-years
- Warfarin: 2.16 events per 100 patient-years
Major bleeding complications:
- Rivaroxaban: 3.60 events per 100 patient-years
- Warfarin: 3.45 events per 100 patient-years
However, in the full intention-to-treat analysis, the superiority of rivaroxaban over warfarin did not achieve statistical significance (P=0.177). Intracerebral hemorrhage occurred in 55 patients on rivaroxaban and 84 on warfarin (P=0.019).
“The main implication is that we have an alternative to warfarin,” said Robert Califf, M.D., co-principal investigator of the study, in an AHA press release. “Equally important, there was no increase in bleeding, so we have a drug you can take once a day, without monitoring, that is at least as good as warfarin and carries no additional risk.”
Note: The AHA 2010 presentation slides for ROCKET-AF can be found on the Duke Clinical Research Institute website.
November 15th, 2010
Networking at AHA
John Ryan, MD
Several Cardiology Fellows who are attending this week’s AHA meeting are blogging together on CardioExchange. The Fellows include Susan Cheng, Madhavi Reddy, John Ryan, and Amit Shah. Check back often to learn about the biggest buzz in Chicago this week — whether it’s a poster, a presentation, or the word in the hallways. You can read the preceding post here.
Chicago may have failed to become host city for the Olympic games, but it is still largely regarded as one of the best conference cities in the U.S. When the cardiology world started to descend upon us on Friday and Saturday, I found myself driving out to O’Hare Airport several times to pick up friends and colleagues. “This is something that you should never offer to do,” one of my colleagues said. “Because there is nothing fun about driving to and from airports.” Although he was probably right, there was something nice about having one-on-one meetings with old friends and getting to talk about career plans and personal lives before going into the sessions with the however many thousands of card-carrying cardiologists in attendance.
AHA can be depressing at times because you arrive pretty upbeat, doing well in your program and having gotten some papers out — and then you see the leadership giving talks and presenting their research, and you feel like a nobody. I was mentioning this to a guy who I did residency with, and he corrected me. He said, “John, when I was a senior in college, I felt that the freshmen owned the campus more than we did, because they had four more years there and were the future of the college. Similarly, we are the college freshmen of AHA.” He was not alone in his thinking, as the Council for Clinical Cardiology sponsored over two hundred fellows to attend the scientific session this year and organized an early career program.
Everyone always mentions that the AHA is a great opportunity to network. That is true to a certain extent, but in the past I have found that a lot of the networking was with one’s peers. However, the session with the mentors that Madhavi talked about was very well organized and gave us all one-on-one time with many leaders in cardiology, including a session where we met in small groups and had lunch with folks such as Drs Elliott Antman, Roberto Bolli, and Clyde Yancy.
Last night, the clinical cardiology council arranged a dinner that again was well organized and more fun than I anticipated. Again there were hundreds of fellows at the dinner, many of whom I had met before either in training in Boston or at prior meetings. The good thing about these meetings is that you can pretend to remember everyone’s name by subtly looking at the oversized name tags hanging around his or her neck (“Great to see you again…Robert”).
At the end of the dinner and the subsequent socializing, I offered, as a representative of the host city, to drive a few colleagues to their hotels. Now, I rarely go to downtown Chicago, and when I am downtown, I use Lake Michigan as my compass (“am I going towards the lake or away from the lake?”; “should I keep the lake on my right or on my left?”). Being downtown at night becomes somewhat more of a challenge because I cannot see the lake. But after a few wrong turns, I successfully dropped off a council chair, two co-fellows and a faculty member from Europe at their hotels. The AHA had successfully brought three generations of cardiologists together into my Toyota Forerunner, and that is the unique and uplifting aspect of this meeting.
November 14th, 2010
Blast off to AHA: A Call for Solutions to the Obesity Epidemic in America
Amit Shah, MD, MSCR
Several Cardiology Fellows who are attending this week’s AHA meeting are blogging together on CardioExchange. The Fellows include Susan Cheng, Madhavi Reddy, John Ryan, and Amit Shah. Check back often to learn about the biggest buzz in Chicago this week — whether it’s a poster, a presentation, or the word in the hallways. You can read the preceding post here.
“Ladies and gentlemen, I am sorry to announce a delay in our flight because…for the first time…our plane is overweight, and we need to let people off the plane.”
I could not believe my ears. I was on my way to AHA, quietly sandwiched on the plane between the window and a 300+ pound man who was periodically dozing off onto my shoulder, crashing into me with what felt like 100 pounds of force with each dip into dreamland.
I tried to remain focused on the conference ahead, browsing the itinerary and the myriad of great sessions that all seemed to be taking place at the same time. I began, however, to get restless, as we were waiting over 30 minutes for them to unload the plane. Only in America do we have situations where, even if the plane is not full, it is still overweight! I wondered, would this happen in other countries where obesity is not such an issue? I was face to face with the issue….
It was an uncomfortable moment at the time, but looking back, I found it motivating. Of course, we all tackle obesity in the clinic with patients. Additionally, however, we have the challenge and responsibility to tackle the problem on a broader level through research and advocacy, whether we assess mechanisms of obesity, promote public health initiatives, or do other similar work.
My plane had not even lifted off for Chicago, and I felt as if the didactic experience was already beginning. I was grateful for the conference ahead; only by putting our minds together can we start to understand and address one of the most challenging and weighted issues in America.
November 14th, 2010
New LVAD Shows Promise as Bridge-to-Transplant
Larry Husten, PHD
ADVANCE (Evaluation of the HeartWare HVAD Left Ventricular Assist Device System for the Treatment of Advanced Heart Failure) evaluated the clinical efficacy of a novel small centrifugal flow pump as a bridge-to-transplant. In the trial, 140 patients who received the device were compared to a contemporaneous control group of 499 similar patients who had received a commercially available LVAD as a bridge-to-transplant. Results of ADVANCE were presented on Sunday at the AHA meeting in Chicago.
At 180 days, 92% of HVAD patients were alive, had received a transplant, or had recovered and no longer needed the device, compared to 90% of controls. This result met the predefined test for noninferiority (P<0.001). The 1-year survival rate was 91% in the HVAD group compared to 86% in the controls.
Compared to baseline, HVAD-treated patients were able to walk farther (113 meters) and had significant improvements in several quality-of-life measures. The investigators reported that the HVAD had a favorable adverse event profile when used as a bridge-to-transplant and that “large quality of life and functional capacity improvements are similar to those obtained with cardiac transplantation.”
November 14th, 2010
A Life-RAFT for Patients with HF?
Arthur J. Moss, MD
CardioExchange welcomes Arthur Moss, Professor of Medicine at the University of Rochester School of Medicine and lead investigator of the MADIT-CRT trial, to discuss his New England Journal of Medicine editorial on the RAFT trial, in which patients with mild-to-moderate HF were randomized to receive either an ICD alone or ICD plus CRT.
It seems notable that the vast majority of patients in the RAFT and MADIT-CRT trials had left bundle branch block (LBBB). To what extent do you think the results of both trials are actually driven by patients with LBBB?
The results in MADIT-CRT were driven by LBBB, and that is why the FDA approved the CRT-D indication for the MADIT-CRT enrollment criteria, which includes LBBB. In the RAFT trial, patients with LBBB had a better result than patients with each of the other QRS morphologies. Thus, I think that LBBB is the prime indication for CRT-D therapy in patients who qualified for MADIT-CRT or RAFT.
RAFT included individuals with a QRS duration >=120 msec, compared to the MADIT-CRT cut-point of >=130 msec. However, the mean QRS of all enrolled patients was still close to 160 msec. Do you think this fact should influence the way we consider patients who have QRS durations on the narrower end of the spectrum?
Yes. Patients with LBBB get the best results. However, in MADIT-CRT, women with QRS >130 msec obtained a favorable result even without LBBB. Thus, there are some subsets of patients who obtain benefit with QRS durations in the narrower end of the spectrum, but that may be too much “subsetting”. Thus, I favor the presence of LBBB as the primary indication for CRT-D therapy.
In MADIT-CRT, women seemed to respond better to CRT than men. In RAFT, the sex interaction is not quite significant, although the overall proportion of women in the trial was smaller than in MADIT-CRT. Do you think there is likely a real difference in the treatment effect between women and men? If so, are there any thoughts on what might account for this difference?
Women obtained a dramatically better result than men with CRT-D vs. ICD therapy in MADIT-CRT, but this finding was borderline in RAFT. I interpreted the less significant findings in RAFT as being due to a power issue because the percentage of women in their CRT-D arm was only 15% (compared to 25% in MADIT-CRT). There may be other factors operating (LBBB, ischemic vs. non-ischemic cardiomyopathy, age, etc.), so I look forward to the gender-related substudies from RAFT. Our gender-related substudy in MADIT-CRT has been accepted for publication in the Journal of the American College of Cardiology with anticipated publication in December 2010. In MADIT-CRT, the female benefit from CRT-D persisted even after adjusting for all relevant co-variates, including LBBB.
Do you think that results from MADIT-CRT and, now, RAFT are ready for incorporation into clinical guidelines? If so, how do you think these results should be best incorporated?
With these two major studies showing very similar results and the findings from the REVERSE trial consistent with these two larger studies, I do believe that clinical guideline recommendations should be developed by the AHA, ACC, and HRS. I would keep it simple by following the recommendations of the FDA, with criteria including EF<30%, NYHA class I/II symptoms, QRS >130 msec, and LBBB on ECG. Unfortunately, no U.S. patients were enrolled in the RAFT study.
Note: For more information on RAFT, see our news story .
November 14th, 2010
AHA: A Global View
Paul Armstrong, MD
Several Cardiology Fellows who are attending this week’s AHA meeting are blogging together on CardioExchange. The Fellows include Susan Cheng, Madhavi Reddy, John Ryan, and Amit Shah. Check back often to learn about the biggest buzz in Chicago this week — whether it’s a poster, a presentation, or the word in the hallways. You can read the first post here.
The very first thing I noticed while boarding the massive buses to the AHA this morning was the advertisements by Takeda. While somewhat intrusive, the ad itself was rather clever. It did not mention a particular drug but just showed the company name alongside a giant aortic arch shaped as an iceberg and the words “Hypertension, a global warning.” The ads were everywhere — on the side of the bus, on the backs of every seat on the bus, and in the giant arrival hall at McCormick Place.
I was there early to attend the Early Career and Fellows-in-Training Program on Saturday, one day before the main conference. The vast behemoth of a hall was eerily empty. In the exhibits hall, steel boxes were being unloaded in preparation for the main events. After some help from some friendly security staff, I located room N427 for the opening session. One of the first speakers was Bob Bonow from Northwestern who delivered a rather sobering speech on the current state of clinical research in the U.S. He discussed how NIH funding for scientific research was decreasing and ended by saying that “the clinical investigator is an endangered species.” This left me rather reflective for the rest of the morning.
Luckily the afternoon session was more cheerful. There were several simultaneous small groups each on a specific topic, and I chose to attend the session on “Global Cardiovascular Research Training; Opportunities and Experiences.” I have been interested in global cardiovascular research since attending a World Heart Federation Conference on global cardiovascular epidemiology in 2006. I didn’t really know how to incorporate this interest into my clinical training as a cardiology fellow and this was a very practical presentation on exactly how to do so. All of the speakers were either cardiology fellows or recent graduates who had spent a significant portion of fellowship doing research abroad in countries ranging from India to Kenya and South Africa. The speakers talked about the challenges in setting up these projects, including finance and being far from family, but underlined how rewarding it had been. Most useful to me were some of the resources they used to finance their endeavors. Those interested in learning more might want to look at a short article in Circulation written by two of the speakers earlier this year.
In summary, the first day was everything we would expect from a scientific meeting — exciting, thought-provoking, and breathtakingly dull, all at the same time. Just kidding — the meeting is terrific, and I’m happy to have the opportunity to be here.
November 14th, 2010
ASCEND-HF: Nesiritide Is Safe But Not Effective
Larry Husten, PHD
ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial) was started in response to the enormous controversy over the safety and efficacy of nesiritide, which was being used in growing numbers of heart failure patients. The trial randomized 7141 patients with acute, decompensated HF to receive standard therapy and either continuous intravenous nesiritide or placebo.
Results of ASCEND-HF, presented as a late-breaking clinical trial at the AHA meeting, showed that there were no significant differences in the pre-specified endpoint of dyspnea. Shortness of breath improved in 15.0% of nesiritide patients and 13.4% of placebo patients. At 24 hours, the pattern was similar: 30.4% of nesiritide patients and 27.5% of placebo patients had improved breathing function. At 1 month, the rate of all-cause mortality and hospital readmission for HF did not differ statistically between the groups (9.4% with nesiritide and 10.1% with placebo).
Although the early controversy over nesiritide was fueled by concerns that the drug might cause an increase in mortality or renal damage, the ASCEND-HF investigators found no evidence to support these concerns.
In an AHA press release, study chair Robert Califf said:
“Nesiritide was marketed and widely used in the U.S. because of a perception that it had a major effect on dyspnea and then largely abandoned in clinical use because of concerns that it might increase rates of death and renal failure. Now that we finally have a proper clinical trial we know that both perceptions were incorrect; nesiritide is safe but has only a modest effect on dyspnea. This is a major signal that we must do a better job defining the biological effects of drugs early in development and conduct adequately powered outcomes trials much earlier to give doctors and patients the necessary information to enable appropriate use of the treatment in practice.”
Said trial investigator Adrian Hernandez: “I think the main message is that we need to do adequately powered studies to really understand the balance of safety and effectiveness. Now that we’ve done an adequate trial, we know that nesiritide can be used safely, but there is no mandate to use it because of its modest effects.”
One investigator, Randall Starling, did not rule out the use of nesiritide in some patients: “Given the complexities of heart failure, there is a significant need for better medications for use in treatment. With the safety questions related to nesiritide having now been addressed, it could be an option for physicians depending on their interpretation of clinical benefit.
Note: The AHA 2010 presentation slides for ASCEND-HF can be found on the Duke Clinical Research Institute website.
November 14th, 2010
Emphatic Support for Eplerenone in NYHA Class II Heart Failure
Larry Husten, PHD
Aldosterone antagonists have proven beneficial in heart failure patients with moderate-to-severe symptoms and in MI patients with LV dysfunction and heart failure. Now EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) has extended these benefits to patients with systolic HF and mild symptoms.
EMPHASIS HF randomized 2737 patients with NYHA class II HF and an ejection fraction not over 35% to receive eplerenone or placebo in addition to standard therapy. The trial, which was presented at the AHA meeting in Chicago and published simultaneously in the New England Journal of Medicine, was stopped early after 21 months. The rate of cardiovascular death or HF hospitalization was reduced from 25.9% in the placebo group to 18.3% in the eplerenone group (P<0.001). Total mortality was reduced from 15.5% to 12.5% (P<0.001). Hyperkalemia occurred significantly more often in the eplerenone group.
In an accompanying editorial, Paul Armstrong writes that the effect reported in EMPHASIS HF “seems surprisingly large for a trial of mildly symptomatic patients.” He points out that most of the trial participants were “heart disease veterans” at high risk and that few patients received implantable defibrillators or cardiac resynchronization therapy. Nevertheless, he states that with a number needed to treat of 19 to prevent one cardiovascular death or hospitalization and an NNT of 51 to prevent one death, the trial places “this therapy in the front rank of therapeutic choices.”
November 14th, 2010
ICD-CRT Found Beneficial in RAFT
Larry Husten, PHD
RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial) randomized 1798 patients with NYHA class II or III heart failure, LVEF < 30%, and a wide QRS complex to either an ICD alone or an ICD-CRT. After a mean followup of 40 months, the rate of death or heart failure hospitalization was 40.3% in the ICD group compared to 33.2% in the ICD-CRT group (p<0.001) and overall mortality rates were 26.1% and 20.8%, respectively (p<0.003). There were more adverse events in the ICD-CRT group, however (124 versus 58 in the placebo group at 30 days). As in the MADIT-CRT trial, an increased benefit was observed in patients with QRS durations of 150 msec or more.
RAFT was presented at the AHA meeting in Chicago and published online simultaneously in the New England Journal of Medicine. Speculating about why RAFT, unlike MADIT-CRT, was able to show a survival benefit, the RAFT investigators pointed out that RAFT patients were sicker than their MADIT-CRT counterparts and underwent a longer and more complete followup.
In an accompanying editorial, Arthur Moss writes that three trials (MADIT-CRT, RAFT, and REVERSE) now provide “convincing evidence of the therapeutic prowess of CRT in appropriately selected patients with ischemic or nonischemic cardiomyopathy.”
Note: In an accompanying post on CardioExchange, Moss sheds additional light on the role of LBBB, QRS duration, and women in RAFT.