September 3rd, 2013
For CRT, Let ECG — Not Echo — Be Your Guide
Clyde Yancy, MD and John Ryan, MD
CardioExchange’s John Ryan interviews Clyde Yancy, who co-wrote the NEJM editorial about the EchoCRT Study Group’s randomized trial of echocardiography-guided CRT for patients with NYHA class III–IV heart failure and a narrow QRS complex. The trial was presented at the European Society of Cardiology conference in Amsterdam.
THE STUDY
Ruschitzka and colleagues evaluated the effect of cardiac resynchronization therapy (CRT) in patients with NYHA class III or IV heart failure, an LV ejection fraction ≤35%, a QRS duration <130 msec, and echocardiographic evidence of LV dyssynchrony. Participants from 115 centers underwent device implantation and were randomly assigned to have CRT capability turned on or off. In March 2013, with 809 patients randomized (mean follow-up, 19.4 months), the study was stopped. Incidence of the primary endpoint — a composite of death from any cause or first hospitalization for worsening heart failure — was 28.7% in the CRT group and 25.2% in the control group, a nonsignificant difference. The mortality rate was significantly greater in the CRT group (11.1% vs. 6.4% in the control group).
INTERVIEW WITH THE EDITORIALIST
Ryan: What should a busy practitioner take from this study? Is this just reinforcing existing guidelines, or is anything new?
Yancy: The findings offer several takeaways for the practitioner:
1. We need to focus on the sweet spot of efficacy for CRT, making every effort to optimize device therapy in those with the strongest indications — i.e., wide QRS, LBBB pattern already on optimal guideline directed care.
2. As with so many other proven therapies in heart failure, we remain uncertain about the true markers of benefit for CRT. Arguably, it isn’t truly necessary to discover mechanical dyssynchrony, whereas it is imperative to identify a wide QRS.
3. We are once again reminded of the perils of “indication creep.” Pushing indications for proven therapies into categories that are heuristically reasonable but substantively unproven might be a major therapeutic misstep.
4. Most important, our guidelines and the process used to generate them really work. As we enter an increasingly transparent era of clinical practice with greater practitioner accountability and much more financial risk, having trusted practice templates will serve our community well.
Ryan: Was there anything less than straightforward about the trial — something fellows should notice about how it was done?
Yancy: Clinical trials remain challenging. Those of us who define our skill set as that of “clinical trialists” should beware. An excellent investigatory group conducted this study, yet a substantial number of patients withdrew, were lost to follow-up, or couldn’t be contacted. That’s not sloppy—it’s the reality of the process. All readers, especially fellows, need to appreciate the incredible number of potential permutations and perturbations that can surface when designing and implementing a clinical trial. This isn’t an easy business.
JOIN THE DISCUSSION
What lessons do you take away from the EchoCRT trial? Do you agree with Dr. Yancy?
September 3rd, 2013
Study Fails to Support Broader Patient Population for Cardiac-Resynchronization Therapy
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Cardiac-resynchronization therapy (CRT) has been shown to be beneficial in heart failure (HF) patients with a wide QRS interval. These benefits have not been reproduced so far in patients with narrow QRS intervals, though many such patients have ventricular dyssynchrony. Now a new study, presented at the European Society of Cardiology in Amsterdam and published simultaneously in the New England Journal of Medicine, once again has failed to find benefits for CRT in a broader patient population.
The EchoCRT Study Group randomized HF patients with a QRS duration < 130 msec and left ventricular dyssnchrony upon echocardiography. All patients received a CRT-D device; half the patients were randomized to have the CRT feature activated.
The study was stopped prematurely after 809 patients had been randomized and followed for nearly 20 months.
- The primary endpoint (composite of death from any cause or first hospitalization for worsening HF) occurred in 28.7% of the CRT group versus 25.2% of the controls (HR 1.20, CI 0.92-1.57, p=0.15)
- There was a significant increase in mortality in the CRT group :11.1% versus 6.4%, CI 1.11-2.93, p=0.02)
There were also more inappropriate shocks in the CRT group and more adverse events — largely driven by lead-related complications — in the CRT group.
“Our results reinforce the notion that, at least until new methods of assessment are developed, QRS width with or without mechanical dyssynchrony) remains the primary determinant of response to CRT,” the authors write.
Definitive Results
In an accompanying editorial, Clyde Yancy and John McMurray say the results of the trial “were definitive: CRT is not beneficial in patients with HF and a narrow QRS complex and may be harmful.” They also sought to emphasize that “…CRT itself is not without risk, including periprocedural complications, lead-related issues, and inadvertent right ventricular pacing that aggravates left ventricular dysfunction.”
CRT is unwarranted in patients with a QRS duration < 120 msec, while for patients between 120 and 130 msec, current guidelines should be followed, though echo should not be used to identify patients who may benefit from CRT.
“Today, in addition to measurement of left ventricular ejection fraction, the simple 12-lead surface ECG remains the only evidence-based means of identifying patients who may obtain the substantial benefits of CRT.”
See also Edward J. Schloss’s perspective on EchoCRT.
September 2nd, 2013
Living History and a Glimpse into the Future
M. Louis Handoko, MD PhD
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
My Monday morning started with an historic overview on the milestones in cardiovascular medicine. Who better to give this lecture than Dr. Eugene Braunwald himself, whom I consider the Godfather of Cardiology. Of course I know his legacy, but I have never seen him in person. Despite his fragile appearance (84-years old!), his presentation was energetic and very inspirational. It made me feel proud to be a member of the cardiovascular community that has accomplished such major achievements in just a few decades.
Braunwald’s talk made me think about my (near) future as cardiologist. Although I just started my training in cardiology, I’ve already developed something of a preference for electrophysiology. By mere luck, I came across a live demonstration of the human cardiac anatomy by Dr. Ho, with specific emphasis on anatomical structures relevant to electrophysiology.
This is better than any atlas on clinical anatomy! I got even more enthusiastic after following a session about the emerging role of catheter ablation in paroxysmal atrial fibrillation. I think today I had a glimpse of my future.
September 2nd, 2013
Losartan Reduces Aortic Enlargement in Marfan Syndrome
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
A small study from the Netherlands provides the first confirmation that the angiotensin receptor blocker losartan can help prevent the aortic enlargement that may presage the catastrophic aortic dissection often associated with Marfan syndrome. Many Marfan patients have been taking losartan following the publication of a groundbreaking mouse study in 2006.
“Our study is the first large, prospective randomized study to assess the effects of losartan on aortic enlargement in adults with Marfan syndrome, and confirms previous findings in a mouse model,” said lead investigator of the COMPARE study, Maarten Groenink, in an ESC press release. COMPARE was presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the European Heart Journal.
A total of 233 Marfan patients were randomized to losartan or placebo in addition to standard therapy with beta blockers. Groenink reported that the rate of aortic dilatation over 3 years was significantly lower in the losartan group than in the placebo group (0.77 mm vs. 1.35 mm, p=0.014). One-half of the patients in the losartan group had no growth of the aortic root compared with 31% of controls (p=0.022).
The effect was consistent across all subgroups examined. There were no significant differences in the aortic dilatation rate beyond the aortic root, except in the aortic arch for the group of patients who had had aortic root replacement. There were few clinical events in both groups. Eight patients in the control group and 10 patients in the losartan group underwent aortic root surgery. One control patient had distal aortic surgery and 2 control patients had a type B aortic dissection.
“We’re very excited to see that such a commonly used drug that is not expensive and has a familiar side-effect profile could have a significant effect on this very serious and frightening risk factor for these patients,” said Groenink. “These findings may change standard clinical management.”
For Fellow Paddy Barrett’s take on COMPARE, read his blog
September 2nd, 2013
What You See Is Not Always What You Get
Paddy Barrett, MB BCh BAO MRCPI MCTI
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Today’s late-breaking sessions included the much-anticipated COMPARE trial assessing the efficacy of losartan in reducing aortic root dilatation rates in patients with Marfan syndrome. Although losartan is already a recommended therapy in the guidelines on Marfan disease, the recommendation was based solely on promising pediatric and mouse-model data.
In COMPARE, losartan therapy resulted in significant reductions in aortic root dilatation in both native and post-surgically corrected Marfan patients. This study is truly a welcome addition to the management options for an often fatal condition in the young.
However, this trial raises two very important issues. First, surgical correction is one of the only therapies available that reduce mortality from aortic dissection or rupture, but losartan therapy continues to demonstrate benefit post-surgery. Why is this worrisome? We still have progression of the underlying disease even after our most effective therapy; we are treating a symptom and not the actual disease pathology. This is where losartan is different — it targets the very core of the disease.
Second, this study raises an even broader scientific question about how we characterize, classify, and target diseases. Marfan syndrome is characterized by over 30 signs and symptoms, and its diagnosis is based on fulfilling a set of — often contentiously — agreed-upon criteria. Almost all of these criteria qualify the phenotypic manifestations of the disease rather than the molecular or genetic features of the condition. This is not to say that a single genetic mutation equals the diagnosis of a disease, but I believe in the era of molecular medicine, we need to reassess classifying disease primarily based on clinical signs and symptoms and consider doing so by precise molecular pathophysiological hallmarks.
Such an approach has profound consequences for how we target the disease itself. The COMPARE trial included patients with Marfan syndrome who fulfilled the prespecified diagnostic criteria but may or may not have been carriers of the fibrillin-1 gene mutation. It is this gene mutation that results in abnormal TGF-B function and is probably the reason why losartan therapy in Marfan syndrome reduces aortic root dilatation, even post-surgical correction. By including Marfan patients without FBN-1 gene mutations, one runs the very real risk of diluting the beneficial effect of losartan in those who carry the gene mutation.
Furthermore, Marfan syndrome presents as a continuum of disease states and severity. This range of presentation is likely to result from the almost 700 different gene mutations that have been identified and their varied expression in Marfan syndrome. Even in patients with the FBN-1 gene mutation, there may be a variety of different pathophysiological processes at play, which may or may not be likely to respond to therapies that influence TGF-B function.
In other words, not all Marfan patients are FBN-1 gene mutation carriers, and not all FBN-1 gene mutations in Marfan patients result in the same pathophysiological consequences.
The COMPARE data add substantially more weight to the use of losartan in Marfan syndrome patients. However, maybe it is time we design and conduct more trials based on the molecular features of the disease rather than the clinical features. Such an approach may substantially amplify the beneficial effect of therapies we test and in such a fashion that matches the likely molecular mechanism of the disease to the molecular mechanism of the therapy.
To read CardioExchange’s news story on COMPARE, click
September 2nd, 2013
Sharper Focus Needs a Wider View
Paddy Barrett, MB BCh BAO MRCPI MCTI
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
An Internal Medicine Attending I had the opportunity to work with during my residency training would routinely regale the team with tales of when he first took up his position and was only one of two physicians covering the entire hospital. Ward rounds were not on your patients alone but were on all of those under the medical service, both adult and pediatric. He did, indeed, wear many hats and, more importantly, had to be comfortable doing so. As the field of medicine evolved, so did the volume and complexity of its content, and thus the subspecialist was born.
From the range of niche topics being presented here at the Congress it is clear that no one physician can be entirely au fait with the all details of all specialties or pathologies. And that’s okay; being all things to all people will surely leave a knowledge gap somewhere; subspecialization, whether you like it or not, is here to stay.
However, it is becoming more apparent that to achieve greater degrees of specialization, one must learn to appreciate not just the minute details of one’s own specialty but also the inner workings of others also.
At the EACVI Club 35 presentation this morning, Dr Emer Joyce of Leiden University Medical Center gave a tour de force overview of the role of multimodality imaging in complex interventional procedures such as TAVI and LAA closure. What was most striking was the illustration of the necessity for both imaging and interventional specialists to have an incredibly robust understanding of the inner workings of each others’ speciality. Our degree of subspecialization has reached a point where we can no longer act in isolation — indeed, we cannot function without expanding our knowledge base outside of our subspeciality field of interest.
Subspecialties are here to stay, but we who work within them will have to broaden our view to achieve even sharper focus.
September 2nd, 2013
Automatic Wireless Monitoring Shows Benefits in Chronic Heart Failure
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Following in the wake of studies that failed to find benefits associated with remote wireless monitoring of heart failure (HF) patients, the In-Time trial, presented at the European Society of Cardiology meeting in Amsterdam, is the first trial to show that home monitoring of HF patients may be beneficial.
Gerhard Hindricks, the coordinating investigator of the trial, said that In-Time was designed to test whether automatic remote home monitoring can detect events that precede clinical events and thereby spark interventions to help reduce hospitalizations for HF. In the trial, 664 chronic HF patients with an indication for an ICD were randomized to home monitoring plus standard care or standard care alone.
The primary endpoint was a modified Packer Score by which each patient was classified at the end of the study as worsened, unchanged, or improved based on the following factors: death; overnight hospitalization for worsening heart failure; favorable, unfavorable, or no change in NYHA class; and improvement, deterioration, or no change in the patient’s global self-assessment score.
- After 12 months, 18.9% of patients in the home-monitoring arm had worsened, compared to 27.5% in the control arm (p<0.05).
- There were 10 deaths in the home-monitoring arm versus 27 deaths in the control arm (p=0.004).
- Cardiovascular mortality was reduced from 21 deaths in the control arm to 8 deaths in the home-monitoring arm (p=0.012)
- Home monitoring was a significant prognostic factor for death in both a univariate and a multivariate analysis
The investigators have not fully analyzed the events detected by the home monitors, but an initial examination showed that most of the clinical events were related to atrial fibrillation, CRT performance, lead parameters, VT/VF shock, and premature ventricular contractions. As a result of home monitoring, there were 696 patient contacts, which worked out to 2.27 per patient per year. Of these contacts, 13% revealed drug incompliance; 16% triggered a visit to the physician.
At an ESC news conference, Hindrick speculated that the trial may have succeeded because it did not rely on patient activity. Data from the device was automatically sent to a central monitoring unit where alerts were monitored by a team of trained nurses who contacted patients and intervened as necessary.
Hindrick concluded that “In-Time is the first implant-based remote monitoring randomized controlled trial demonstrating significant benefits of implant-based home monitoring for patients with advanced heart failure…. Home-monitoring-based detection of changes in clinical status or technical events can trigger medical action that prevents worsening of heart failure.”
In-Time was sponsored by Biotronik.
September 2nd, 2013
Cardiovascular Outcome Studies in Diabetes Drugs Finally Arrive
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
For many years critics have bemoaned the absence of outcome studies for the many diabetes drugs used to lower blood glucose levels. Now, finally, two large trials with different drugs have been presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in The New England Journal of Medicine. The good news is that the drugs appear safe. Both trials turned up no evidence for the adverse cardiovascular events that some had feared. The bad news is that neither drug appeared to improve cardiovascular outcomes, though cardiovascular disease is the cause of death in most people with diabetes.
SAVOR-TIMI 53
A total of 16,492 people with type 2 diabetes at high risk for a cardiovascular event were studied in SAVOR-TIMI 53. Participants were randomized to the DPP-4 inhibitor saxagliptin (Onglyza, Bristol-Myers Squibb and AstraZeneca) or placebo.
- The primary endpoint (composite of CV death, MI, or ischemic stroke) occurred in 7.3% of the saxagliptin group and 7.2% in the placebo group (hazard ratio 1.0, CI 0.89-1.12, p=0.99 for superiority, p<0.001 for noninferiority).
- An important secondary endpoint, the composite of CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 12.8% of the treatment group versus 12.4% of the placebo group (HR 1.02, CI 0.94-1.11, p=0.66).
- There was an excess of hospitalization in the saxagliptin group compared with the placebo group: 3.5% versus 2.8% (HR1.27, CI 1.07-1.51, p=0.007).
“Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes,” the investigators wrote.
Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE)
In the EXAMINE trial, 5,380 people with a recent acute coronary syndrome (ACS) were randomized to alogliptin (Nesina, Takeda Pharmaceuticals) or placebo.
- The primary endpoint (a composite of death from CV causes, nonfatal MI, or nonfatal stroke) occurred in 11.3% of the alogliptin group versus 11.8% of the placebo group (HR 0.96, p<0.001 for noninferiority)
- As expected, alogliptin therapy resulted in a significant reduction in glycated hemoglobin levels, but there were no significant differences in hypoglycemia, cancer, pancreatitis, or initiation of dialysis.
The authors of both studies said that the relatively short duration of their studies meant that they were unable to rule out possible benefits associated with longer-term usage of the study drugs.
These trials represent the first round of FDA-mandated cardiovascular outcomes trials for diabetes drugs, a major result of the rosiglitazone controversy. In an accompanying perspective in NEJM, William Hiatt, Sanjay Kaul, and Robert Smith, all members of the FDA advisory committees that debated the fate of rosiglitazone, discuss the complicated recent history of diabetes drugs at the FDA. After all the serious concerns raised about the cardiovascular safety of rosiglitazone, they write that it now appears that rosiglitazone, along, now, with saxagliptin and alogliptin, “appear to be relatively safe” from a cardiovascular standpoint.
“It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.”
They suggest that the FDA might reconsider its requirement that all diabetes drugs be forced to demonstrate their cardiovascular safety. These trials might only be necessary when warranted by clinical or preclinical problems. “The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.”
September 1st, 2013
Thank You, Dr. Messika-Zeitoun!
M. Louis Handoko, MD PhD
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
For my training, I recently started seeing out-clinic patients. One of the challenges I am struggling with is the management of patients with apparently asymptomatic aortic stenosis. This morning, there happened to be a session about this specific topic, so I was very eager to attend.
I was especially pleased with the third speaker. David Messika-Zeitoun offered some very simple solutions for cases where guidelines fail to guide clinical decision-making. Sometimes, echocardiographic data is ambiguous (low aortic valve area with a paradoxical low pressure gradient over the valve) and exercise testing is not possible or inconclusive. He proposed to use quantification of aortic valve calcification, easily determined by non-contrast CT scanning. I will definitely study his paper! Thank you, Dr. Messika-Zeitoun, and thank you, ESC.
September 1st, 2013
A TASTE of Today and Tomorrow
Paddy Barrett, MB BCh BAO MRCPI MCTI
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Last night, I had a disbelieving discussion with a more senior colleague about how he went about undertaking a literature search in years gone by without the aid of electronic assistance. Thumbing through index cards, sifting through mountains of paper and struggling to find the papers most pertinent to your research question. Today, we communicate and explore data at the speed of light, refining our exact questions with ever more precise filters. Information has never before been as accessible and in a more digestible format.
In somewhat of a parallel theme, those who conducted large scale clinical trials in the past appeared remote and inaccessible, and I must applaud the ESC for the “meet the trialist” sessions. Watching an almost fireside discussion on the TASTE trial with the lead investigators very much brought home the degree of access we now have to those who conduct these influential trials and how much things have evolved over the years. I wonder in years to come will I be in awe at a junior colleague’s access to information, or to those who are conducting trials, and what indeed that will look like?
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