October 16th, 2013
Redefining MI After Revascularization
Beth Waldron, MA
James de Lemos reflects on a new definition of “clinically relevant myocardial infarction after coronary revascularization” from the Society for Cardiovascular Angiography and Interventions (SCAI). The SCAI proposal is published in JACC.
KEY FEATURES of the NEW DEFINITION
The new SCAI definition of MI after revascularization differs in several ways from the 2012 Universal Definition of procedural MI, which was authored by a joint task force representing the ESC, ACC, AHA, and World Heart Federation. Among the key differences are these:
1. The SCAI proposal recommends creatine kinase-MB, rather than troponin, elevation to define procedural MI.
2. The SCAI proposal requires a much larger amount of procedural injury to meet the definition of “clinically relevant MI”: 10x the upper limit of normal for CK-MB (or if CK-MB is not available, a 70-fold elevation in troponin) versus 5x ULN for troponin in the universal definition.
3. The SCAI proposal does not require associated evidence of ischemia, whereas the universal definition requires “ischemic context” (i.e., chest pain, ECG changes, angiographic evidence of a procedural complication or a new wall-motion abnormality) to meet the MI definition.
COMMENTARY from JAMES de LEMOS
Virtually all of the pivotal modern trials leading to new drug approvals for antiplatelet and anticoagulant drugs have included procedural “myocardial infarctions” in the endpoint definition. In fact, the procedural MIs (the type 4a MIs that are the focus of a new SCAI consensus document and a related editorial by Harvey White) outnumber spontaneous MIs in most trials. If these procedural MIs had not been included, studies of GP IIb/IIIa inhibitors and prasugrel, for example, would be considered only marginally positive or null, and very different risk/cost/benefit interpretations for those drugs might have been made.
Before 2012, definitions of procedural MI had been based purely on modest elevation of biomarkers, typically creatine kinase-MB. In most cases, these are simply lab abnormalities, completely unrecognized by the patient and the treating physician. Moreover, those small periprocedural enzyme elevations are weighted in clinical trials (and by the FDA) as more important even than significant bleeding events. Most clinicians would agree that even a TIMI minor bleed is a much bigger deal to a patient than is an asymptomatic 3-fold biomarker elevation after PCI.
Although even modest CK-MB elevations have met criteria for procedural MI, it is clear that for all except the very large procedural MIs, the prognosis is not equivalent to a spontaneous MI. There is also a huge debate about whether these are true “events” that contribute directly to long-term outcomes or, rather, markers of sicker patients with worse atherosclerotic (or LV muscle) disease, in which case preventing the enzyme elevation would not improve long-term outcomes. The aggregate data suggest that except for very large procedural MIs, no causal association with poor long-term outcomes exists.
Both the universal definition and the SCAI recommendations improve on the earlier definitions, which were just way too wimpy. The addition of “clinical context” in the most recent universal definition attempts to raise the bar by requiring some mechanism for ischemia. This is a welcome change and at least elevates the diagnosis beyond a simple, minor lab abnormality. The problem is that tiny amounts of myocardial necrosis can meet the universal definition of MI. Because the reference range for troponin is so low, a 5-fold elevation is still a trivial amount of necrosis: 5 times nothing is still nothing! I think CK-MB is clearly preferable to troponin for definitions of procedural MI, particularly for drug-approval trials. Much more work is needed to define troponin thresholds that might be comparable with CK-MB, but a 5x ULN elevation in troponin is likely to be far too low a bar for procedural MI.
In my opinion, the use of troponin and the low threshold of elevation for procedural MIs was a mistake in the universal definition. The SCAI authors propose a more rigorous definition (CK-MB >10x ULN) and also allow the possibility of characterizing somewhat smaller MIs (CK-MB >5x ULN) if there is an ischemic mechanism. This is a sensible middle ground. They also provide a tentative troponin threshold for situations where CK-MB is not available, with the caveat that the evidence base to support these troponin thresholds is tenuous.
It would be interesting to reevaluate trials of GP IIb/IIIa inhibitors, cangrelor, and prasugrel using this more rigorous definition of procedural MI. It would not be surprising for the “benefit” of the antiplatelet therapies to be attenuated and for the trials to look quite different if a more clinically relevant definition of procedural MI were used.
JOIN THE DISCUSSION
Share your view of the SCAI’s new definition of MI after revascularization and of Dr. de Lemos’ assessment of it.
October 15th, 2013
First Leadless Pacemaker Gains Approval in Europe
Larry Husten, PHD
St. Jude Medical announced on Monday that the world’s first leadless pacemaker has gained CE Mark approval in Europe. The company also announced that it was buying Nanostim, the company that developed the innovative device. The FDA recently granted conditional approval for an Investigational Device Exemption (IDE) application and a pivotal clinical trial, St. Jude also reported.
The new leadless pacemaker is implanted directly inside the heart through a catheter. The single-chamber VVIR device has an expected battery life of about 8-10 years.
Initial results from the first-in-man LEADLESS study were presented in May at the Heart Rhythm Society meeting. The device was successfully implanted in 32 out of 33 patients. The mean procedure time was 28 minutes, and the performance of the device was said to be comparable to that of a conventional pacemaker. The great advantage of the device is that it may not cause the complications associated with pacemaker leads. However, as reported by Wells Fargo analyst Larry Biegelsen, one patient in the trial had a cardiac perforation and tamponade, which resulted in the patient’s death.
October 15th, 2013
Former ACC CEO Takes Reins of Cardiovascular Research Foundation
Larry Husten, PHD
The Cardiovascular Research Foundation (CRF) announced today that it has appointed Jack Lewin as its next President and Chief Executive Officer.
Lewin is the former CEO of the American College of Cardiology. In April 2012, the ACC announced his abrupt departure from the college. No explanation was ever given for the sudden change.
The CRF said that Lewin will also serve on the CRF’s Board of Directors.
October 15th, 2013
Questions Remain About George W Bush’s Stent
L. David Hillis, MD
The National Journal reported yesterday that “George W. Bush’s recent heart problems were far more dangerous than generally believed — potentially life-threatening, in fact.” The Journal cited “an authoritative source”:
“He was more than 95% occluded. With a blockage like that in a main artery you’re supposed to die. He was pretty lucky they caught it.”
On the Nightly News” broadcast Brian Williams said that NBC news had “confirmed” the report.
But it is impossible to know for certain precisely what Bush had. I am assuming that he was discovered to have a positive exercise test at the Cooper Clinic in Dallas. First, what are the details of the supposedly “worrisome changes” on the electrocardiogram? Was the test, in fact, markedly positive, or just positive? Positive at a low workload or at a high workload? Symptomatic during the test or not?
Second, what coronary artery had the 95% stenosis? They imply that it was his left anterior descending, but I can’t be certain. Was it his left main (in which case PCI or CABG would be appropriate even in the absence of symptoms)?
I don’t think news organizations should report “new” information like this that doesn’t really help us better understand the indication for the procedure. What do other CardioExchange members think about this issue?
October 14th, 2013
Selections from Richard Lehman’s Literature Review: October 14th
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 10 Oct 2013 Vol 369
Cardiac-Resynchronization Therapy in HF with a Narrow QRS Complex (pg. 1395): It’s been known for at least four thousand years that the heart has two ventricles, but what they actually did was a source of confusion until William Harvey began to sort things out in the seventeenth century. In the twenty-first century, cardiologists remain obsessed with the left ventricle and usually define “heart failure” by the proportion of its contents expelled in each contraction—the left systolic ejection fraction. In this trial, participants were selected for having an EF of 35% or less, normal QRS duration on ECG, and some echographic evidence that their right ventricle did not beat in exact synchrony with the left. These people were also considered suitable for an implantable cardioverter-defibrillator, so they were fitted with one of these plus a biventricular pacemaker, but in half the subjects, this was switched off. By the time the trial was stopped for futility, 809 patients had been recruited and followed up for a mean of 19.4 months. “In patients with systolic heart failure and a QRS duration of less than 130 msec, cardiac resynchronization therapy does not reduce the rate of death or hospitalisation for heart failure and may increase mortality.” So for selecting patients to have CRT, measuring the QRS interval on the ECG beats echocardiograpy.
Edoxaban vs. Warfarin for the Treatment of Symptomatic VTE (pg. 1406): A trial of edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. OK, children, what is the first question we must ask? Yes, time within the INR target range for the warfarin group. Here it was 63.5%. Is that good or bad? It’s probably the current UK average, as far as I can discover. The authors describe this as “high-quality standard therapy:” compare it with your own figures, if you have them, before considering whether to use this latest fixed-dose factor Xa inhibitor. The new drug was as good for VTE as this degree of warfarin control, and caused less bleeding in this trial. For cognoscenti of natriuretic hormones, it’s also interesting that the Japanese investigators used NT-pro-BNP as a measure of right ventricular strain in pulmonary embolism. Nice to see this, 20 years after it was first proposed.
JAMA 9 Oct 2013 Vol 310
Risk of Major Adverse Cardiac Events Following Noncardiac Surgery in Patients With Coronary Stents (pg. 1462): Simple retrospective cohort studies often make nice easy reading, but I’m not sure if there is a great deal for generalists to take away from this one, which describes the risk of major adverse cardiac events following noncardiac surgery in patients with recently placed coronary stents. If this is a subject that interests you, you can read the full article for free. People who have non-cardiac surgery within two years of stent placement have a greater surgical risk in the first six months, and it is higher with emergency than with elective surgery, and relates to the degree of coronary disease and not significantly to the type of stent. Which all makes sense, but apparently contradicts current guidelines.
BMJ 12 Oct 2013 Vol 347
Aircraft noise and CVD near Heathrow airport in London: I am a cause of cardiovascular morbidity across the Northern hemisphere. Last week I caused atheroma in the citizens of inner London and outer Dresden, and this week I am doing the same for those of Slough, Boston (Mass), and Toronto. The noisy aeroplanes which have conveyed me to and from these destinations howl every few minutes over the tops of numerous homes of brick, concrete, or white clapboard, and the unfortunates who inhabit them are a teeny weeny bit more likely to end up in hospital with a cardiovascular diagnosis: “Averaged across all airports and using the 90th centile noise exposure metric, a zip code with 10 dB higher noise exposure had a 3.5% higher (95% confidence interval 0.2% to 7.0%) cardiovascular hospital admission rate, after controlling for covariates.” So scarcely worth making a big noise about, really.
October 14th, 2013
The Benefits of Switching From Hydrochlorothiazide to Chlorthalidone: What’s Stopping Us?
Nicholas Bergfeld, BS, BA
As a medical student, I’m currently on a nephrology service and hypertension, cardiovascular (CV) events, and diuretics have been on my mind a lot, particularly the issue of chlorthalidone (CTDN). Released at about the same time as hydrochlorothiazide (HCTZ) — 1959 and 1960, respectively — there is great evidence of CTDN’s non-inferiority, and with the exception of a study published a few months ago in the Annals of Internal Medicine that garnered some strong critiques of its validity, CTDN has consistently shown to be superior to HCTZ for the prevention of CV events in every analysis short of a head-to-head randomized, controlled trial. Additionally, the medication benefit cannot entirely be explained by the difference in systolic office blood pressure, which points to some other beneficial mechanisms.
Researchers at St. Vincent’s Medical Center in Bridgeport, CT, have published a nice analysis using data collected on over 50,000 patients from various trials that shows the calculated percentage risk reduction of CV events in patients with congestive heart failure who were prescribed CTDN vs. HCTZ was 23% (95% CI, 2-39; P=0.032), and in all CV events was 21% (95% CI, 12–28; P<0.0001). Relative to HCTZ, the number needed to treat with CTDN to prevent one CV event over five years was 27.
What other medication class could have a drug that is 23% more effective than standard practice with an equivalent side effect profile and the result not be considered a major breakthrough? If there are over 134 million prescriptions of HCTZ (48 million as the sole blood pressure medication), that’s 4.96 million fewer CV events in five years. This benefit could be gained simply by switching from one monetarily equivalent, generic, pharmacologically similar medication to another.
The part that bothers me is that this is something the more academically inclined clinicians are aware of and occasionally write about, lamenting how this is an unfortunate issue. It wasn’t hard to find articles on the data and information I listed above. If our ultimate goals are to be patient advocates and promoters of health, isn’t this something we should be actively trying to change? When I ask doctors about why they don’t prescribe it, I usually get:
1. I haven’t heard of that medication.
2. I didn’t know there was anything better.
3. It is only offered in combination with three other blood pressure meds.
4. It only comes in a dose that’s twice the actual recommended starting amount.
The first two reasons are a failure of dissemination and implementation of ideas, which to me are issues that should be soon resolved now that we live in a connected world that is transitioning care to EMR-based systems. It would be easy to have a clinical decision tool to search every patient on HCTZ and ask if you’d like to switch them to CTDN. To think that the flow of ideas still operates in Balas and Boren’s “17 years, 13% translation” is frustrating, and I think the CDC or the AHA could do more to promote these changes. Is a campaign to prevent almost 5 million CV events in five years unappealing? Can some monetary incentive (reward or punishment) be incorporated as part of the new focus on pay-for-performance?
The second two reasons are flaws in U.S. health policy. The fact that the only way drug regulatory changes occur is when a company stands to benefit monetarily is fully exposed in this setting. If Medicare is one of the major purchasers of these medications, as well as the sufferer of poor outcomes that can occur with CV events, the federal government would benefit monetarily from this change, as well. Is there a reason why it could not act like a commercial entity to apply to the FDA to allow for CTDN to be combined with the same medications as HCTZ? Or that it should be able to be dispensed at 12.5 mg a tablet rather than 25 mg?
Irrespective of the benefit the government would receive, how is it that this profession and organizations like the Patient-Centered Outcomes Research Institute don’t put forth a more concerted effort to tackle such an issue? No new incredible drugs need to be made. No fantastic leaps in science or efficiency. What stands in the way is simply a bureaucratic issue that’s non-ideological, and the overwhelming majority agree that these changes will lead to better health outcomes. What are the actual steps that would be necessary for regulatory approval for combination medications for something that has been reliably used with other hypertension medications for close to half a century?
It frustrates me because of how frequently physicians claim that the problems with healthcare in the U.S. are beyond our control. In recent surveys we place more blame on insurance companies, hospital management, etc., than we do ourselves. But when we have the opportunity to truly be an advocate for something that could have a tangible and meaningful impact far beyond an HCAHPS survey or proton accelerators for prostate therapy, we don’t go beyond decrying the reality of what is, and proceed to do nothing to change the problem.
October 10th, 2013
CardioMEMS Heart Failure Device Gets Mixed Reception From FDA Advisory Panel
Larry Husten, PHD
The FDA’s Circulatory System Devices Panel sent a mixed message to the FDA today about the CardioMEMS Champion HF Pressure Measurement System. The small implantable device provides daily pulmonary artery pressure measurements to guide physicians in their treatment of patients with congestive heart failure.
In December 2011 the same panel voted 9-1 that the device was safe, 7-3 that the device had not been shown to be effective, and 6-4 that the benefits did not outweigh the risks. Now, two years later, the vote wasn’t much different: the panel agreed unanimously (11-0) that the device was safe; 7-4 that it had not been shown to be effective, and 6-4-1 that the benefits outweighed the risks.
Panel member Rick Lange said that the panel today tried to look beyond the pivotal Champion clinical trial, which was the subject of considerable controversy at the earlier meeting. Instead, the panel today wrestled with the followup study, but found it difficult to draw conclusions based on unrandomized and unblinded followup data of a segment of the original trial population. The problem, according to Lange, is that although the patients seemed to have less heart failure, it was impossible for the panel members to tie the daily measurements of the pulmonary artery to a decrease in hospitalizations or other important clinical outcomes. “We couldn’t connect the dots,” said Lange.
Another major dilemma faced by the panel was the complete lack of evidence showing efficacy in women. “You can’t assume in today’s world that what’s effective in males is effective in females,” said Lange.
October 10th, 2013
Prevalence of Cardiovascular Disease Likely to Increase Despite Gains in Treatment
Larry Husten, PHD
It is the best of times and the worst of times in the battle against cardiovascular disease. On the one hand, mortality rates from cardiovascular disease in the U.S. have dropped by more than half in the last 30 years, likely due in large part to improvements in treatment for elevated blood pressure and cholesterol levels and big declines in smoking. On the other hand, it is uncertain whether these gains will continue, and many experts think that cardiovascular disease may well be on the rise once again, largely due to the aging of the population and to increases in obesity and diabetes.
In an article in Health Affairs, Ankur Pandya and colleagues (including cardiologist Thomas Gaziano of Brigham and Women’s Hospital in Boston) forecast cardiovascular disease trends through the year 2030 using data from the National Health and Nutrition Examination Survey. They project that although the age-adjusted risk for cardiovascular disease is likely to continue to decline through 2030, the overall incidence of cardiovascular disease will increase because of an aging population and the increase in obesity.
The authors considered various scenarios relating to control of obesity, high blood pressure, and cholesterol. One important unknown factor is whether the recent stabilization in obesity will continue. If the trend holds, they write, 1.6 million fewer people will develop cardiovascular disease in 2030.
The authors warn that “the United States should expect to see a sharp rise in the health care costs, disability, and reductions in quality of life due to increases in the prevalence of cardiovascular disease.”
The study may also have an impact on the often controversial question of whether resources are better devoted to treatment or prevention: “our findings suggest that substantial reductions in incidence are crucial: Otherwise, improvements in mortality from cardiovascular disease (along with aging and obesity trends) will lead to a troubling increase in prevalence.”
They recommend the adoption of policies to reduce obesity and improve treatments of high blood pressure and cholesterol “to curb the imminent spike in prevalence of cardiovascular disease.”
October 10th, 2013
How Well Do Standard ECG Criteria Detect RV Hypertrophy?
Isaac Russell Whitman, MD
CardioExchange’s John Ryan interviews Isaac Whitman and Steven Kawut about their study of the sensitivity and specificity of electrocardiographic criteria in screening for MRI-detected right ventricular hypertrophy in patients without clinical cardiovascular disease. The study is published in JACC.
THE STUDY
Researchers studied data from 4062 Multi-Ethnic Study of Atherosclerosis participants without clinical cardiovascular disease who had cardiac MRIs that were interpretable for right ventricular morphology. Electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) came from ECG recommendations published by the AHA in 2009. Of the 3719 participants with normal LV function, 6% had RVH, most often mild.
Traditional ECG criteria had high specificity (often >95%) but low sensitivity (often <10%) for identifying MRI-detected RVH. Positive predictive values (similar to the underlying prevalence of RVH) and negative predictive values (equal to the prevalence of RVH-free subjects) were not high enough to be clinically useful. Findings were consistent across demographic subgroups and whether participants with abnormal LV mass or function were included. No combination of ECG variables, nor changing cutoff points, improved how well the ECG criteria predicted RVH.
THE INTERVIEW
Ryan: Most patients in this study had mild RVH. How clinically relevant is it to detect mild RVH?
Whitman and Kawut: RVH reflects an increase in afterload (e.g., from diseases affecting the left side of the heart, lungs, and breathing during sleep). Even mild RVH is an independent predictor of clinical heart failure and cardiovascular death. It is possible that identifying RVH at a subclinical state could provide an opportunity for earlier treatment and a reduction in the untoward sequelae of RVH. However, this approach is untested and, for now, unproven.
Ryan: As you know, most of our patients with pulmonary arterial hypertension have moderate-to-severe RVH. Are the ECG criteria valid for detecting moderate-to-severe RVH?
Whitman and Kawut: The ECG criteria for RVH were first developed from very small cadaveric dissection studies in patients with known advanced cyanotic congenital heart disease, cor pulmonale, or mitral stenosis; the applicability to modern-day adults without symptoms or a known cardiopulmonary diagnosis is unclear. We therefore do not recommend basing clinical decisions solely on the presence or absence of these findings in adults who do not have clinical cardiovascular disease. The availability and acceptability of transthoracic echocardiography make this the preferred approach to initial testing if pulmonary hypertension or RV abnormalities are suspected on the basis of clinical risk factors, other testing, or physical examination findings.
Ryan: Your study did not identify a superior method of characterizing RVH on ECG. What do you now tell your house staff and trainees when they say, “no RVH on ECG”?
Whitman and Kawut: Given our results, we believe that in adults without known clinical cardiovascular disease, the absence (or presence) of the AHA’s ECG criteria for RVH may not be helpful in ruling out (or suggesting) RVH. We do not know the implications of the presence or absence of these criteria, whether diagnostic or prognostic, in a patient with known or suspected clinical cardiopulmonary disease.
JOIN THE DISCUSSION
Will this study change your approach to patients without clinical cardiovascular disease for whom an ECG does not detect RVH?
October 9th, 2013
New Drug for Pulmonary Hypertension Approved by FDA
Larry Husten, PHD
The FDA approved on Tuesday a new drug for pulmonary hypertension. Bayer HealthCare’s riociguat (brand name Adempas) was approved for two indications:
- the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class
- the treatment of adults with pulmonary arterial hypertension (PAH) to improve exercise capacity, improve WHO functional class and delay clinical worsening
In an FDA press release, Norman Stockbridge, director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research, said that “Adempas is the first in its drug class approved to treat pulmonary hypertension and the first drug of any class to be shown to be effective for patients with CTEPH.” The drug was reviewed as part of the FDA’s priority review program, which provides for an expedited 6-month review of drugs that may offer major advances in treatment.
The drug will carry a Boxed Warning alerting patients and healthcare professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Women will be able to receive the drug only through the Adempas REMS program, which will require them to comply with pregnancy testing requirements and be counseled regarding the need for contraception.
Riociguat is a soluble guanylate cyclase stimulator and is thought to have vasodilating, antiproliferative, and antifibrotic effects. The results of two phase 3 studies supporting the new indications were published in July in the New England Journal of Medicine. In August an FDA advisory panel unanimously recommended approval of the drug for the two indications. Last month the FDA granted an orphan drug designation for the indications.
Both forms of pulmonary hypertension are characterized by blockage of the pulmonary vasculature. Patients with pulmonary hypertension are at high risk for right ventricular failure and death. Even though there already were several approved therapies for pulmonary arterial hypertension, the yearly mortality rate remained high, at about 15%. No drugs were previously approved for chronic thromboembolic pulmonary hypertension, though a surgical procedure, pulmonary endarterectomy, could cure the disease when it was successful. However, pulmonary endarterectomy is a difficult procedure that should only be performed at a very few centers with experience performing the procedure.
CardioExchange’s John Ryan, a pulmonary hypertension researcher at the University of Utah, offered the following comment:
“It will be interesting to see where this fits in our treatment options of PAH. Prostacyclin therapy is used for patients with severe right heart failure and is first line in these patients. PDE5i and ERAs have been the oral treatment options for a lot of PAH providers in patients without overt right heart failure. Then if symptoms persist or if right heart failure develops, despite dual oral therapy, providers have been upescalating patients to prostacyclins. It is unclear if, now that riociguat is available, this agent will be introduced before opting for prostacylins. Currently, there is a delay in referral of PAH patients to specialist centers of about 14 months. If providers opt for ERA plus PDE5i plus riociguat before the introduction of prostacyclins, or referral to PH centers, this has the potential to postpone the introduction of prostacyclins in these sick patients. Therefore, the outcomes in these patients will need to be followed closely to see if such delays have an impact in morbidity and mortality in this population.”
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