March 3rd, 2014
Case: Palpitations in a Young Runner with Lamin A/C Deficiency
Anna Catino, MD and James Fang, MD
A previously healthy 26-year-old man is seen for evaluation of palpitations. He reports “skipped beats” since age 18, with occasional short runs of fast, strong beats that are precipitated by alcohol use and marked exertion. He denies associated symptoms such as syncope, chest pain, and shortness of breath.
His medical history is unremarkable, and he takes no medications. He is currently a graduate student and an avid long-distance runner, having run several marathons. He denies tobacco and illicit drug use and drinks alcohol socially.
The young man has an extensive family history of cardiac disease related to lamin A/C deficiency. His father was the index patient, diagnosed as heterozygous for the mutation at age 54, following cardiac resynchronization therapy (CRT) upgrade of an implantable cardioverter-defibrillator (ICD). The father had been diagnosed with atrial fibrillation and high-degree atrioventricular block at age 46, requiring pacemaker placement. He experienced ventricular tachycardia (VT) at age 50, requiring ICD placement with the subsequent CRT upgrade at 54. Four of the father’s six siblings carry the lamin A/C deficiency: One suffered a sudden cardiac death, one had a heart transplant, two received ICDs, two received pacemakers, and three have undergone catheter ablation for atrial fibrillation. Average onset for cardiac involvement has been age 40.
The young patient’s baseline ECG shows sinus arrhythmia, a PR interval of 204 msec, low-voltage P waves, and right-axis deviation. An ambulatory ECG monitor showed multiple episodes of nonsustained VT.
Genetic analysis reveals lamin A/C deficiency.
A transthoracic echocardiogram shows low-normal systolic function (LV ejection fraction, 53%) and high-normal LV size. Cardiac MRI shows significantly delayed enhancement in the mid myocardium of the basal to mid septum, and in the basal inferior and inferolateral walls.
Questions:
1. How would you manage this patient?
2. What are your considerations for device therapy (permanent pacemaker, ICD)?
3. Would you initiate pharmacologic therapy? If so, what drugs?
4. How would you advise the patient about participating in competitive sports, specifically long-distance running?
Response:
March 10, 2014
1. How would you manage this patient?
Patients with laminopathies (Disease Models & Mechanisms 2011; 4:562) are generally at risk for very rapidly progressive heart failure and premature sudden death (Circulation 2000; 101:473; J Am Coll Cardiol 2002; 39:981). There is often associated conduction-system disease and skeletal-muscle involvement (e.g., Emery-Dreifuss). Inheritance is usually autosomal dominant. Although this patient’s LVEF remains above 50%, his risk for arrhythmia is high (N Engl J Med 2006; 354:209).
2. What are your considerations for device therapy (permanent pacemaker, ICD)?
I would consider ICD therapy for primary prophylaxis despite the preserved LVEF because of the underlying disease, myocardial scarring, family history, and symptomatic nonsustained ventricular tachycardia (N Engl J Med 2006; 354:209).
3. Would you initiate pharmacologic therapy? If so, what drugs?
I would consider beta-blockers, although the recommendation is not based upon a substantial evidence base.
4. How would you advise the patient about participating in competitive sports, specifically long-distance running?
I would recommend against long distance running in general.
Follow-Up:
March 18, 2014
Thank you for the insightful responses. The patient underwent successful ICD implantation for primary prevention, given his MRI findings and NSVT on Holter monitor. Follow-up interrogation of the device has revealed short bursts of NSVT and atrial tachycardia, but the patient has not had any sustained arrhythmias. As you all note, it is unclear whether prophylactic use of ACE inhibitors or beta-blockers is beneficial prior to LV dysfunction, although some animal data suggest that carvedilol may delay LV dilation and dysfunction when introduced prophylactically (Circ Res 2010; 106:573). At this time, the patient has not started either therapy because he is concerned about side effects at his young age. He has been advised to limit participation in competitive sports but to continue moderate-intensity exercise.
March 3rd, 2014
New Guidelines Issued for Valvular Heart Disease
Larry Husten, PHD
The American Heart Association and the American College of Cardiology today released new practice guidelines for the management of patients with valvular heart disease (VHD). Among its most notable features, the new document provides a new system of classification for VHD and lowers the threshold for interventions, including, for the first time, transcatheter as well as surgical interventions.
The new guidelines includes a new system of classification, similar to the one used in the ACC/AHA heart failure guidelines. The four stages of progression are:
- Stage A, for people with risk factors that place them at risk for VHD.
- Stage B, for people with asymptomatic but progressive, mild-to-moderate VHD.
- Stage C, for people with asymptomatic but severe VHD. C1 is for people in whom the left or right ventricle remains compensated. C2 is for people with a decompensated ventricle.
- Stage D, for people with severe VHD who have developed symptoms.
The guideline endorses the movement in recent years towards the use of a multidisciplinary Heart Valve Team. “Patients with severe VHD should be evaluated by a multidisciplinary Heart Valve Team when intervention is considered,” the document states.
The Heart Valve Team also plays a central role in the decision to choose surgical aortic valve replacement (AVR) or the newer transcatheter AVR (TAVR). In general, surgery is recommended for patients who require AVR who are at low or intermediate surgical risk. TAVR is recommended for patients with an appropriate indication for AVR but who have a prohibitive surgical risk. TAVR is “a reasonable alternative” to surgery in some patients with a high surgical risk.
The document also includes a new and more comprehensive method of risk assessment of patients for whom intervention is being considered.
“Due to more knowledge regarding the natural history of untreated patients with severe VHD and better outcomes from surgery, we’ve lowered the threshold for operation to include more patients with asymptomatic severe valve disease,” said the Mayo Clinic’s Rick Nishimura, co-chair of the writing committee, in a press release. “Now, select patients with severe asymptomatic aortic stenosis and severe asymptomatic mitral regurgitation can be considered for intervention, depending on certain other factors, such as operative mortality and in the case of mitral regurgitation, the ability to achieve a durable valve repair.”
March 3rd, 2014
Pfizer Starts Testing for Over-the-Counter Atorvastatin
Larry Husten, PHD
Looking backward to improve its future, Pfizer will once again try to gain FDA approval to market its blockbuster drug, atorvastatin (Lipitor), over-the-counter (OTC). Peter Loftus reports in the Wall Street Journal that the company has started a clinical study to support the application for low-dose atorvastatin (10 mg).
Over-the-counter statins have been unsuccessfully proposed in the past. Merck tried several times to gain approval for lovastatin (Mevacor). In 2007 an FDA advisory panel recommended against approval. And in 2011, prior to the expiration of Pfizer’s patent on Lipitor, the company said that it would pursue OTC approval.
The new study, which has been registered on ClinicalTrials.Gov, will enroll 1200 people at pharmacies in the U.S. The main outcome of the study will be to determine the percentage of patients who comply with directions on the box to check their LDL levels and who take appropriate actions based on the test result. “It’s our responsibility to demonstrate patients can safely and effectively use these products,” a Pfizer executive told the WSJ.
But the study may provide an answer to a question that is no longer being asked. New lipid guidelines released last year are based on an overall assessment of risk and do not hinge on lipid measurements. The article quotes guideline co-author Neil Stone: “The new guidelines insist on a patient-clinician discussion before a statin prescription is written.”
But, Loftus writes, “other doctors say the removal of specific cholesterol targets could make it easier for patients to take an OTC statin. Once patients know they are in a risk group identified by the new guidelines—for which the low-dose level in over-the-counter Lipitor is appropriate—they could buy the product off the shelf and not worry about treating to a specific target.”
The WSJ reports that after peaking at nearly $13 billion in 2006, Lipitor sales for Pfizer last year were $2.3 billion. An OTC version could bring in an addition $1 billion in sales each year, Goldman Sachs estimates.
February 27th, 2014
Tooth Extraction Prior to Cardiac Surgery May Not Be a Good Idea
Larry Husten, PHD
People with an infected or abscessed tooth are at elevated risk for cardiovascular disease. They are at particular risk for developing a serious infection during surgery, including endocarditis. Because of this risk, in order to reduce the risk of infection many patients undergo dental extraction prior to having a planned cardiac surgery. Now, however, a new paper published in The Annals of Thoracic Surgery raises the possibility that prophylactic dental extraction may be far more risky than previously thought.
Physicians from the Mayo Clinic retrospectively reviewed data from 205 patients who underwent dental extraction prior to a planned cardiac operation. They found a higher than expected (8%) rate of adverse outcomes, defined as death, acute coronary syndrome, stroke, renal failure requiring dialysis, and postoperative mechanical ventilation. A total of 3% of the subjects died after the dental extraction and before the cardiac surgery.
It seems possible, they wrote, that “preoperative dental surgical procedures may increase risk in these patients.” But they were “unable to conclude the adverse outcomes were due to dental extraction. However, the cumulative insults endured by these patients during dental extraction (additional anesthetic and surgical stresses), along with delay in definitive cardiovascular operation, may have contributed to the outcome.”
“Guidelines from the American College of Cardiology and American Heart Association label dental extraction as a minor procedure, with the risk of death or non-fatal heart attack estimated to be less than 1%,” said the first author, Mark Smith, in a press release. “Our results, however, documented a higher rate of major adverse outcomes, suggesting physicians should evaluate individualized risk of anesthesia and surgery in this patient population.”
The paper represents “a significant departure from current thinking,” writes Michael Jonathan Unsworth-White in an invited commentary. It “raises the question whether we should in fact get on with our cardiac operations and deal with the dental work at some other time, if at all, or risk killing our patients with good intent!”
February 27th, 2014
Steve Jobs Rejected the First Medical App in 1977
Larry Husten, PHD
There’s been a lot of speculation that future Apple products will include health-related apps and biometric sensors. Here’s the story of what might have been the first Apple medical app, except for the fact that in 1977 Steve Jobs had absolutely no interest in going in that direction.
George Diamond is now retired after a long and very distinguished career as a cardiologist at Cedars-Sinai Medical Center in Los Angeles. But in 1977 he was just starting his career at Cedars, where he was working on cutting-edge devices and statistical methods to improve the diagnosis of heart disease (a major problem that even today is far from being solved).
George Diamond today
Diamond’s work involved one of the first attempts to use Bayes’ theorem — a sophisticated and complex tool for analyzing probability — and it involved a lot of computation. In 1977 there weren’t a lot of choices. Here’s his (lightly edited) story:
“I bought one of the very first programmable hand calculators — the TI 59. It had magnetic cards that stored 1k of memory, and I was able to write a program that used Bayes’ theorem to calculate the probability of disease based on the test results. It worked wonderfully, except that I immediately exhausted the 1k of memory because there were so much data.
Just about that time the Apple II was introduced. There was a computer store in Santa Monica — one of the very first computer stores — called ‘The Computer Store.’ So I went there to see an Apple II in action. I fell in love with it immediately and purchased it with my own money. (And by the way, you know what it cost? Forty-eight k of memory and 2 floppy disk drives and a 9″ monochrome monitor: I shelled out $2700.)
With the Apple II I wrote a reasonably sophisticated program that analyzed multiple diagnostic tests using Bayes’ theorem for the diagnosis of coronary disease. Now I thought it was really great and should be marketed, but it needed to be expanded with people who really knew something more about programming than I did. So I picked up the telephone and called Apple in Cupertino. I told the secretary that I wanted to speak with somebody about a medical application for the Apple II computer. The secretary connected me directly to Steve Jobs. (Of course I didn’t know who he was. I didn’t even recognize the name as being one of the people who had actually invented the thing.)
He listened to me for a couple of minutes on the phone. I said I’d love to come up and talk with him about my idea. He said sure, any time, just pick a date. and so I did, and I got on a flight to Cupertino. When I got to his office he looked exactly like he always looked in the future — he was wearing jeans, a black t-shirt, and sandals. His desk was absolutely cluttered with all kinds of stuff on it, including, of course, an Apple II.
I described to him what I had been doing, and how impressed I was with his device. Other people thought it was a toy but I saw something serious in it and thought that eventually a computer like this should be on the desk of every doctor in the world. I told him that I thought my program could be a means toward that end, and I would love to get his thoughts about it, and if would he be willing to do something to help us advance that idea.
He said he was very impressed with what I had done, and that he agreed about the potential for the future, but also said, ‘frankly I’m not interested in working with you on this.’ I asked why. He said: ‘You have to understand. This is something that nobody in the world yet understands. I can’t be distracted. I’m trying to make the best hammer I can make, the best hammer in the world. You can use my hammer to tear something down, or you can use it to build something up. I really don’t care what you do with my hammer. I just want to make the best possible hammer. And what you are doing is a wonderful bit of construction, but to me it’s a distraction.’
So that was pretty much the end of our conversation. There was no where else to go after that so I thanked him very much for his time and flew back to LA.”
February 27th, 2014
Save the Date!
CardioExchange Editors, Staff
Join Us!
CardioExchange Cocktail Reception at the ACC
Sunday, March 30, 2014
6:30 pm
Renaissance Hotel Room #12
Washington, DC
• Participate in a discussion about CardioExchange, social media, and community in cardiology
• Meet Harlan Krumholz and other members of the CardioExchange community
• Share drinks and appetizers
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February 27th, 2014
U.K. Geriatrician: Statins, Antihypertensives “Greatly” Overprescribed for Adults 80 and Older
Nicholas Downing, MD
“The data strongly suggest that we are over-treating many healthy patients aged 80+ regarding stroke prevention,” concludes U.K. geriatrician Kit Byatt in a perspective published in Evidence-Based Medicine.
Byatt offers a brief review of the evidence, noting that the large HYVET study in China and Europe showed only modest stroke-prevention benefits with antihypertensive therapy in those aged 80 and older. Similarly, the PROSPER trial, a large study of pravastatin in patients aged 70 to 82 in Europe, failed to find a significant stroke-prevention benefit with treatment. Byatt also notes that morbidity associated with statins may be underestimated
He writes: “We need actively to rethink our priorities and beliefs about stroke prevention, actively informing and involving the views of the key person, the patient. Most of the patients will probably eschew the modest potential benefit, preferring the reduced burden of polypharmacy and side effects judged as ‘minor’ by the prescriber.”
February 27th, 2014
Poor Medical Research: What Has Changed in 20 Years?
Harlan M. Krumholz, MD, SM
In a recent BMJ.com blog, Richard Smith, former Editor of the BMJ, comments on the Lancet series on waste in research and refers to an editorial by statistician Doug Altman – published 20 years ago. I wanted to quote from the Smith blog (which quotes from the Altman editorial) and get some discussion going on our site. I found it to be quite profound.
“Why, asked Altman, is so much research poor? Because ‘researchers feel compelled for career reasons to carry out research that they are ill equipped to perform, and nobody stops them.’ In other words, too much medical research was conducted by amateurs who were required to do some research in order to progress in their medical careers. Ethics committees, who had to approve research, were ill equipped to detect scientific flaws, and the flaws were eventually detected by statisticians, like Altman, working as firefighters. Quality assurance should be built in at the beginning of research not the end, particularly as many journals lacked statistical skills and simply went ahead and published misleading research.
‘The poor quality of much medical research is widely acknowledged,’ wrote Altman, ‘yet disturbingly the leaders of the medical profession seem only minimally concerned about the problem and make no apparent efforts to find a solution.’
Altman’s conclusion was: ‘We need less research, better research, and research done for the right reasons. Abandoning using the number of publications as a measure of ability would be a start.’”
What do you think?
February 25th, 2014
Is Post-MI Statin Therapy Appropriately Intensive?
Suzanne V. Arnold, MD, MHA
CardioExchange’s Harlan M. Krumholz interviews Suzanne V. Arnold about her research group’s study of statin initiation, intensification, and maximization after acute myocardial infarction. The study is published in Circulation.
THE STUDY
Researchers assessed statin use at admission and discharge for 4340 patients with acute MI at 24 U.S. hospitals from 2005 to 2008. Maximal therapy was defined as a statin with expected LDL-cholesterol lowering of at least 50%. Among statin-naive patients, 87% without a contraindication were prescribed a statin, with almost no variability across sites (median rate ratio, 1.02). Among patients who arrived on submaximal statins, 26% had their statin therapy intensified with modest site variability (median rate ratio, 1.47). Among all patients without a contraindication, 23% were discharged on maximal statin therapy, with substantial hospital variability (median rate ratio, 2.79).
THE INTERVIEW
Krumholz: Which of your study’s findings was most surprising to you?
Arnold: Very little of what we found was surprising. As a cardiology community, we have focused a lot on LDL numbers, to measure risk and the need for statins. I think with the MI performance measures, we at least were able to understand that all MI patients need a statin, regardless of LDL level — and our study documented high rates of statin initiation. Moving beyond just initiating statins to intensifying and maximizing statins required a deeper understanding of the statin trials, which were not as well known by clinical cardiologists. As such, physicians tended to make treatment decisions according to their perception of the patient’s risk — intensifying and maximizing statins in patients with high LDL levels and those with STEMI (despite no evidence that these patients were more likely to benefit from intensive statins). We also observed a lot of site-level variability in intensification and maximization, which again was not surprising, as such clinical decisions often follow local practice patterns. We are hopeful that the new lipid guidelines will emphasize the evidence-based imperative to get all MI patients on intensive statins during the MI hospitalization.
Krumholz: Why do you think intensification is not occurring?
Arnold: I think this primarily stems from a misperception about which patients are most likely to benefit from intensive statins. The prior trials showed that all MI patients were equally likely to benefit, regardless of patient characteristics. However, I think there is a misperception that patients who present with STEMI need more aggressive secondary prevention, which is why their statin regimens were more likely to be intensified. Similarly, patients with high LDL levels were thought to need more intensive statin therapy. However, LDL levels can be falsely low in a patient with acute MI, particularly in patients with severe MIs, which is one likely reason why we have not observed any association between LDL levels during MI and a differential benefit from statins. Again, I think the new guidelines will highlight the evidence for the general cardiology community.
Krumholz: Could it be patient choice? How do you present this decision to patients?
Arnold: Possibly, although I suspect this matters very little in the decision to prescribe intensive statins. When I talk to patients and go over the medications I will be prescribing them to take at home, some say, “But I don’t have high cholesterol. Why do I need that?” What I usually then discuss is that for a patient with an MI, cholesterol is deposited in the vessels of the heart, regardless of what the blood numbers read. Statins are the best medications we have for treating those cholesterol plaques in the heart —stabilizing them so they don’t grow and reducing the risk that they will rupture and cause another heart attack. So for patients who have heart attacks, it is really important to be on intensive doses of these medications, regardless of the blood numbers. I try to get patients to understand that the statin is treating the cholesterol plaques in the heart — not the blood numbers. This change of focus on what the medication is targeting seems to make patients more likely to accept taking it. It is a similar conversation for beta-blockers in patients without hypertension.
Krumholz: What is your sense of the trade-off in statin intensification (additional benefit and additional risk)?
Arnold: I think that intensive statins have a clear additional benefit over moderate statins in reducing the risks for recurrent MI and cardiovascular death, although to show an effect on mortality required combining the two major trials. Our pooled analysis documented an NNT of 95 patients with intensive statins to prevent 1 death — that is a fairly small NNT compared with many other secondary-prevention therapies. The more-intensive statins also increase the risk for myalgias, which cannot be ignored. The logical solution would be to start an intensive statin and, if myalgias occur, change to moderate statin therapy. However, if a patient gets myalgias with an intensive statin, he or she may be less willing to try moderate statins. Generally, I have had good luck with getting such patients to try moderate statins. However, I also admit that my personal practice is to use atorvastatin 40 mg in elderly patients who may be more likely to get a side effect (or, at least, whose mobility would be more compromised by a side effect).
I think the decision is more difficult in a patient with a remote cardiac event. The trials studied patients just after an MI, when event rates are highest and the expected benefit of aggressive secondary prevention would probably be greatest. Is there a time period after which the benefit of intensive statin therapy does not outweigh potential risks? We have already seen a suggestion of this with beta-blockers after MI. In the first few years after an MI, I think the case for intensive statins (or at least a trial of intensive statins) is strong. After that, questions remain. Certainly, if a patient has tolerated an intensive statin for a time after an MI, there seems to be no good reason to down-titrate. The question remains as to whether or not to intensify a statin in a patient with a more remote event.
JOIN THE DISCUSSION
In light of Dr. Arnold’s comments, share your thoughts on how well statin therapy is being delivered to patients after myocardial infarction.
February 25th, 2014
Study Raises Questions About Transfusions in PCI Patients
Larry Husten, PHD
A very large observational study raises important questions about the role of transfusions in PCI patients in the U.S.
In a study published in JAMA, researchers from Duke and Yale analyzed data from more than 2.25 million percutaneous coronary intervention (PCI) procedures at more than 1400 hospitals. The data came from the CathPCI Registry, a large ongoing study that includes a significant proportion of all cardiac catheterization procedures in the U.S.
The overall transfusion rate was 2.14%, but there was a wide variation in transfusion rates across hospitals, ranging from 0 to 13%. A vast majority of hospitals (96.3%) had a transfusion rate below 5%, and more than a quarter (25.5%) had a rate below 1%. After accounting for differences in patient characteristics, the median transfusion rate was 2.5%.
As anticipated, transfused patients were older, more likely to be female, and more likely to have other medical conditions. In addition, they were more likely to have an MI, stroke, or death in the hospital; this association remained significant after adjustment for differences and regardless of bleeding events. However, transfusion was found to be beneficial in patients who had bleeds and preprocedure hemoglobin levels below 10 g/dL.
In the discussion of their findings, the authors note that “there appeared to be patients who underwent transfusion in the absence of clinical bleeding events and patients who underwent transfusion with nearly normal postprocedure hemoglobin values.” Transfusions, they write, “may have been driven more by local practice patterns than by clinical necessity.”
Along with previous findings from smaller studies, their results suggest that “further research is needed to clearly delineate the appropriate use of transfusion in patients undergoing PCI.”
In an email interview, the senior author, Sunil Rao, acknowledged that the study “is observational and thus has limitations inherent to all observational studies.” Asked about his own clinical practice in this area, Rao said:
Regarding our own practice, we routinely use bleeding avoidance strategies (appropriate dosing, targeted anticoagulants, radial access) in order to reduce the risk for transfusion post PCI. In patients who are stable post PCI (no chest pain, no active bleeding) we follow our transfusion protocol that recommends transfusion only if the hemoglobin is equal to or less than 8 g/dL(hct equal to or less than 24%). This is based on other observational data and as we mention in the paper, these data can be subject to confounding. So we really need randomized trial data to guide practice.
NEJM Journal Watch — Recent Cardiology Articles- 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
- CTA-Guided Care in Stable Angina: Long-Term Results
- Patients Need Standardized Education for Accurate Home Blood Pressure Monitoring