November 7th, 2010
RE-LY Substudy Finds Dabigatran Effective in Secondary Stroke Prevention
Larry Husten, PHD
A substudy of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrates that dabigatran is as effective in AF patients for secondary stroke prevention as it is for overall stroke prevention. In their paper in the Lancet Neurology, Hans-Christoph Diener and the RE-LY study group report the results of the trial in the predefined subset of more than 3600 AF patients who had had a previous stroke or TIA.
The rate of stroke or systemic embolism was similar in all three groups (2.78% for warfarin, 2.32% for 110 mg dabigatran, 2.07% for 150 mg dabigatran). Compared to the warfarin group, the rate of major bleeding was lower in the low-dose dabigatran group (RR 0.66) and the same in the high-dose dabigatran group (RR 1.01). Intracranial bleeding was significantly lower in both dabigatran groups when compared to the warfarin group, prompting the authors to raise the possibility that dabigatran doesn’t cross the blood-brain barrier.
Compared to the warfarin group, net clinical benefit (defined as the composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major hemorrhage) was marginally lower in the low-dose dabigatran group (RR 0.81) but not the high-dose dabigatran group (RR 1.01). In an accompanying comment, Deirdre Lane and Gregory Lip write that, based on this analysis, “110 mg dabigatran might be the preferred treatment option in patients who have had a previous stroke or transient ischaemic attack.” They note, however, that the paper does not include head-to-head comparisons of the safety and efficacy of the 2 doses of dabigatran and recommend that physicians talk with their patients “regarding their preferences for treatment dose… to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa.” (It should be noted that the FDA recently approved the 150 mg dose of dabigatran, but not the 110 mg dose.)
For more of our coverage on dabigatran, check out the Dabigatran Resource Round-Up.
November 5th, 2010
Independent doctors?
John Mandrola, MD, FACC
John Mandrola is a cardiac electrophysiologist and blogger on matters medical and general. Here is a recent post from his blog Dr John M.
In response to my story on how physician consolidation and hospital ownership of doctors is affecting patient referral patterns, I received an email with this attached PDF file. (Smudges mine)
It is from a cardiac surgeon who doggedly chooses to remain independent. This document appears on his website and also ran in the local newspaper as an advertisement.
Hopefully, the employer of your doctor has also employed the ‘best’ specialists.
(The trouble is that in the eyes of some policy-makers and employers — perhaps the same ones that refer to doctors as “providers”— there is a belief that all cardiologists, or surgeons, or (insert any specialty) are interchangeable. And yes, if you look at doctors on spreadsheets of CPT codes and wRVUs, this would be true, but at the bedside, in the operating room, or in the EP lab whilst we use our varying degrees of skills, training, and experience, doctors differ vastly.)
Sorry, you all already knew that. It would be common sense.
November 5th, 2010
Meta-Analysis Turns Up Mixed Results for Vitamin E on Stroke Subtypes
Larry Husten, PHD
In a meta-analysis appearing in BMJ, vitamin E supplements had no effect on the overall rate of stroke but were associated with a small reduction in the risk of ischemic stroke and a slightly larger increase in the risk of hemorrhagic stroke. Markus Schürks and colleagues analyzed data from 9 trials including 118,765 subjects. Although the investigators found no overall effect of vitamin E on the risk for total stroke, the risk of hemorrhagic stroke was raised by 22% while the risk for ischemic stroke was cut by 10%. They cautioned that the absolute effect was small, resulting in 0.8 more hemorrhagic strokes and 2.1 fewer ischemic strokes per 1000 people treated.
Summarizing the clinical implications, they wrote: “Because the consequences of hemorrhagic stroke in terms of morbidity and mortality are generally more severe than those of ischemic stroke and high doses of vitamin E supplements may increase all cause mortality, a widespread and medically uncontrolled use of vitamin E should be cautioned.”
November 4th, 2010
CardioExchange and the Ethos of Community
Harlan M. Krumholz, MD, SM
We recently posted a blog that described the experience of a Fellow whose assessment of a patient and the need for a test was not seemingly given the fullest attention by the attending physician. Many of us remember such experiences in our training and the sense that there were issues beyond the patient that were influencing the decisions. We posted the blog to bring up issues of test ordering and the experience of Fellowship.
The blog was written from the viewpoint of the Fellow and our belief was that the views represented are common to many Fellows in many programs and are emblematic of the powerlessness that many Fellows feel in the course of their clinical training. What we did not intend was for the piece to implicate a program or an individual, but in retrospect it is clear that some readers might conclude — rightly or wrongly — that they could identify the physicians in the vignette. Neither the author nor the editors of CardioExchange meant to have the blog be personal in that way: The points were meant to generalize an experience told from one person’s perspective. The ultimate responsibility here rests with the editorial team, not the author.
We will be more vigilant in ensuring that we adhere to our aspiration of being a venue for the debate of ideas. We seek the high ground. We will continue to tackle challenging and controversial issues — but seek to do so with respect and to avoid any appearance of targeting individuals. In a fast moving and informal community, we must be equal to the task of ensuring that we will have the highest-quality content.
November 4th, 2010
Clopidogrel and CYP2C19: What’s All the Fuss About?
Richard A. Lange, MD, MBA and L. David Hillis, MD
You’ve heard a lot lately about so-called “clopidogrel resistance.” That sounds straightforward, but the underlying reason can be complex, possibly related to how the drug is metabolized by subjects with a certain genetic profile. We seek here to provide some perspective about clopidogrel’s metabolic and gene-related complexities. First, some brief background:
Clopidogrel, a thienopyridine, is a “prodrug” that is metabolized to its active form via the cytochrome P450 enzyme system — specifically, enzyme CYP2C19. A patient with certain genetic variants, or polymorphisms, can have diminished CYP2C19 activity (so-called “loss of function” alleles). The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition. About 25% of Caucasians have one copy of this variant, and about 2% have two copies. Higher percentages of black (3%–7%) and Japanese (11%) patients have two copies of CYP2C19*2.
Now let’s address some common questions about clopidogrel and CYP2C19:
1. Are all thienopyridines influenced by CYP2C19? No
Unlike clopidogrel (and ticlopidine), neither of the newer agents — prasugrel or ticagrelor — appears to be influenced by CYPC219 polymorphisms.
2. Is the CYP2C19 issue clinically important? Yes and No
Three studies of patients taking clopidogrel after PCI (TRITON-TIMI 38, PLATO, and a meta-analysis by Mega et al.) documented a 50% to 70% greater relative risk for adverse cardiovascular (CV) events, principally stent thrombosis, among patients with a loss-of-function allele (vs. those without such an allele). Most of the events occurred within one month after PCI.
In contrast, in the ACTIVE-A study of patients with atrial fibrillation and in the CURE trial of “conservatively managed” acute coronary syndrome (ACS) patients (only 15% of whom had PCI), clopidogrel recipients with a loss-of-function allele did not have greater risk for adverse CV events than those without the polymorphism.
3. Why the discrepancy between these two sets of studies? At least 3 possible explanations (if this were easy, we wouldn’t be blogging about it)
First, perhaps the interaction of clopidogrel and genetic polymorphisms that results in diminished CYP2C19 activity is clinically important in patients who are at high risk for a thrombotic event (such as those who receive a drug-eluting stent during PCI) but not in those at lower risk (such as patients with atrial fibrillation or medically treated ACS).
Second, a CYP2C19 genetic variant may put a patient at increased risk for adverse CV events regardless of whether he or she receives clopidogrel. The CHARISMA Genomics Substudy, for example, showed that even placebo recipients with a loss-of-function allele had a higher CV-event rate than those without the polymorphism.
Third, other genetic factors may be involved. Only 12% of the variation in response to clopidogrel is attributable to the CYP2C19*2 loss-of-function allele.
4. Should I routinely order genetic testing for my patients who take clopidogrel? No. It’s not yet ready for prime time.
Not only is genetic testing not routinely available, but when it is available, the results are not readily accessible (there’s no point-of-care testing). That makes the test not useful for patients who undergo nonelective PCI. Furthermore, in ACS patients undergoing PCI, the positive predictive value of the test is low (only 12% to 20%). Furthermore, at least 25 variants of the CYP2C19 gene have been identified, not to mention other genes that affect platelet responsiveness (i.e., CYP3A4 and ABCB1). In short, no single genetic test is a silver bullet.
5. What about the FDA warning? A classic example of pulling the trigger too early
The FDA’s “boxed warning” to use other antiplatelet medications or alternative dosing strategies for clopidogrel in patients with 2 loss-of-function alleles was based on observations from a study, involving 40 healthy subjects, in which poor metabolizers had diminished active metabolite exposure and higher platelet aggregation. The study reported no clinical outcomes. You gotta be kidding, right? We wish we were.
6. Does platelet-reactivity testing have any value? As far as we can tell right now, No.
According to a recently published white paper by the platelet gurus, “the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended.” They agree that a lack of consensus exists about the optimal method of quantifying platelet reactivity and that we still have no large-scale clinical studies showing that using any of these tests to adjust antiplatelet therapy is clinically beneficial.
7. What can I do as a clinician? There is something.
If you’re caring for a patient with presumed “clopidogrel resistance” (i.e., has had stent thrombosis), testing to identify genetic polymorphisms is reasonable. Alternative treatment strategies (higher clopidogrel dosing regimens or the use of other antiplatelet agents) should be considered in such an individual.
8. What research is in the pipeline? Six studies
Three ongoing investigations (GIANT, GeCCO, and TARGET-PCI) will attempt to find the best genetic-guided strategy for these higher-risk patients. Also, the ongoing GRAVITAS, ARCTIC, and TRIGGER-PCI trials will address whether we should routinely test platelet responsiveness to clopidogrel (rather than performing genetic testing).
Given all this information, what are your instincts as a clinician as you confront the clopidogrel/CYP2C19 issue?
November 3rd, 2010
Paricalcitol Reduces Albuminuria in Diabetic Nephropathy
Larry Husten, PHD
Selective vitamin D receptor activation with paricalcitol may help prevent progression of renal failure in patients with diabetic nephropathy who are already taking renin-angiotensin-aldosterone system (RAAS) inhibitors, according to a new study published online in the Lancet. In the VITAL study, U.S. and European investigators randomized 281 patients with type 2 diabetes and albuminuria who were already receiving RAAS inhibitors to placebo or to one of two doses of paricalcitol.
After 24 weeks, the urinary albumin-to-creatine ratio (UACR) declined by 20% and 24-hour urinary albumin excretion fell by 28% in patients receiving the higher dose of paricalcitol. No difference in adverse events across the groups was observed. The investigators concluded that paricalcitol might “be an important adjunctive treatment, providing optimum management of renal osteodystrophy, with little hypercalcaemia, and lowering residual albuminuria.”
In an accompanying editorial, Merlin Thomas and Mark Cooper call for “long-term and larger clinical trials” to test whether paricalcitol or similar drugs “can ultimately improve mortality and cardiovascular outcomes.”
November 3rd, 2010
Do Your Patients Wait to Fill Their Plavix and Effient Prescriptions After Drug-Eluting Stent Implantation?
Chris Smith, RN
I recently read an article in the journal Circulation that contained an alarming finding about patients who receive drug-eluting stents. Apparently, 1 in 6 did not fill their clopidogrel prescriptions immediately after discharge from a hospital in one of three large integrated health care systems. The median delay was 3 days.
Furthermore, during a median follow-up of 22 months, the risk for death or myocardial infarction was significantly higher among patients with any delay in filling their clopidogrel prescriptions than among those with no delay (raw incidence, 14.2% vs. 7.9%). Many of the events occurred within 30 days after discharge, and adjustment for delays in filling prescriptions for other guideline-recommended therapies did not alter the findings.
A bit of research in our hospital’s database revealed that since January 2008, five of the 12 DES patients readmitted to the hospital with stent thrombosis within 30 days after discharge had delayed, stopped, or never filled their prescriptions for an ADP-receptor inhibitor. A frequently cited reason was the cost of the medication.
Our AMI team met to determine the best approach to increase adherence. We initially focused on how to get the meds. We found that the makers of Plavix (clopidogrel) and Effient (prasugrel) offer coupons for free 14- and 30-day supplies, respectively, via sales representatives. In addition, long-term prescription-related financial assistance for patients is available from both companies. We’re in the process of educating our case managers about these offerings. Click here to access the Plavix application from Bristol-Myers Squibb and the Effient application from Eli Lilly.
Our goal is to use our outpatient pharmacy to get all our acute coronary syndrome patients discharged with their prescriptions filled. We pulled together a multidisciplinary team of people from the cath lab, telemetry, case management, the pharmacy, and cardiac rehab. The team has begun to develop a protocol and step-by-step algorithm to help facilitate the implementation of our adherence program.
That said, we have already identified a couple of hurdles: (1) How do we ensure that patients actually walk out of the hospital with the medication in hand? (2) How, in the case of Plavix, do we finance the additional 16-days needed to provide a full 30-day supply?
We’d love to hear from any of you whose facilities have implemented or are contemplating the implementation of such a program.
November 3rd, 2010
My Journey with Heart Failure
Mary Knudson, Health Journalist
Well-known science journalist Mary Knudson is the author of HeartSense, a blog about heart failure, from which the following post is taken. In this post, she describes her journey as a heart failure patient from bewildered dismay to self-empowerment; in an upcoming post, she questions the aptness of the designation “heart failure.”
I got to know something about heart failure the hard way, by having it. I also happen to be a health journalist, so when I got the stunning diagnosis in 2003, I began researching this condition that sounded so fatal. Not only was my diagnosis overwhelming, but my first encounters with the health care system were dismal. It took me three and a half months to find good care. My story is worth sharing, because it illustrates how important it can be for a patient to become knowledgeable about an illness and get involved in her own treatment plan.
In heart failure, the heart can no longer perform well enough to get adequate blood and oxygen to the body. With 6 million people living with heart failure in the United States alone, it is already a huge medical problem, and it will get bigger as baby boomers continue to hit their fifties and sixties. Heart failure is a serious condition that can be fatal, but I would learn that it can often be managed with the right treatment. My own research about heart failure changed my life.
In December 2002, I found myself getting fatigued and easily out of breath, with swollen ankles and a swollen abdomen. My asthma was normally under control, but I turned to my asthma specialist because of the shortness of breath. He noticed my swollen ankles and said he didn’t think my problem was asthma. I had begun to think the same thing. He advised me to immediately see my internist, who referred me to a cardiologist, who gave me a diagnosis in words that roll off the tongue of a heart specialist but shock the patient who hears them: “idiopathic dilated cardiomyopathy and biventricular congestive heart failure.” It was those last two words that got my attention.
I tried to get over my shock and digest the big words of the diagnosis, searching the internet to make some sense of what had happened to me. Cardiomyopathy, I learned, is a disease of the heart muscle, and dilated cardiomyopathy means that the heart is enlarged. When a heart stretches, it is trying to work harder, but an enlarged heart actually functions more poorly. The “idiopathic” in my diagnosis means doctors don’t know what caused my cardiomyopathy. Half of the people who are told they have dilated cardiomyopathy have no known reason that it developed. An echocardiogram, which uses sound waves to show the heart beating on a monitor, revealed that the amount of blood my heart pumped out to my body with each beat was only 15% to 20%, instead of the normal 55% to 65%. The left side of my heart was enlarged — the result of struggling to work harder.
My search to understand my condition led me to national treatment guidelines for heart failure developed by expert panels of the American College of Cardiology and the American Heart Association. I recommend that every person with heart failure and their loved ones read these guidelines. To my dismay, I saw that I was not on two of the basic medicines proven in clinical trials to treat heart failure and prolong life, an ACE inhibitor and a beta blocker. I turned to a second cardiologist. He insisted that I have an angiogram, in which a catheter is threaded through an artery in the groin up to the heart to see if the heart’s main arteries are blocked by fatty buildups that could prevent blood from getting through. The question he wanted to answer was whether I had severe coronary artery disease that could cause a heart attack. I didn’t agree to the angiogram immediately. I didn’t want to have this test, because I am extremely allergic to the dye used in the exam, so he suggested I see a heart failure specialist, which I did.
The specialist blew me away with his advice: I needed a heart transplant. He ordered a stress echocardiogram, the same sound-wave test I had gotten before in a cardiology group practice center, but this time, it would show how my heart functioned when challenged by activity. However, the doctor running the test stopped before getting to the stress part. “We found what we need to know,” he said. The specialist would come in to talk to me.
I waited for about half an hour, wondering what the heck. The specialist arrived, sat down beside me, and drew a rough outline of my heart on a piece of paper, shading an area from the left side down and around the bottom.
“This part of your heart is dead,” he said. “You have either had one large heart attack or several small ones.”
I felt shocked to my bones because this was news to me, and, then, oddly, I felt a deep embarrassment, almost shame. I was a veteran health journalist, and I had not known when I was having a heart attack? How incompetent of me.
The specialist agreed that I must have an angiogram and said he could give it to me. The test would take 30 minutes and would likely find several very occluded arteries, he said. The second cardiologist I had seen, the one who referred me to the specialist, had told me he could do the angiogram in 20 minutes and held out more hope than the specialist did that he could perform some intervention during the angiogram to open the dangerously occluded arteries he expected to find. I chose the 20-minute man, reluctantly agreeing to this dreaded test.
I warned this doctor who would perform the angiogram that I am very allergic to the dye he would use in the test. I had never had an angiogram, but the same iodine-based dye is used in CAT scans as a contrast medium, and years earlier, during a CAT scan, I suddenly couldn’t breathe. The doctor assured me that he could give me medicines before the procedure that would prevent any allergic reaction. I took the medicines, the procedure began, and I thought this isn’t so bad, piece of cake.
Then a technician called out, “Mary, how do you feel?”
“I feel strange,” I said. I had no pain or heaviness in my chest but felt a very abnormal and unsettling sensation in my heart. “Very strange.”
The next thing I knew, the procedure was over, and the doctor who administered my angiogram was hurrying out of the room. “But I have questions to ask you,” I said to the back of the departing cardiologist.
“You won’t remember the answers,” he said over his shoulder.
As soon as the doctor left the procedure room, a technician who had helped with the test spoke up. “We had to shock you,” she said.
I was dumbfounded. “I didn’t feel anything.”
“It’s a good thing you didn’t. It would have been very uncomfortable.”
I looked down and saw three burn marks on my chest and later found one on my left ribs. I had died on the exam table and been resuscitated with four electric shocks. But we found the answer to the doctor’s question, which I would soon learn.
My accidental departure from this world during the angiogram led the doctor who administered it to admit me for an overnight hospital stay for observation, but, although I asked to see him, he would not visit me. He turned my care over to the third cardiologist, the heart failure specialist. I’m a big believer in all’s well that ends well, and was glad to be alive.
The specialist came to my room and told me what the angiogram had revealed: my arteries were not at all blocked. I did not have coronary artery disease. Therefore, he said, reversing what he had told me days earlier, I could not have had a heart attack. My face lit up with a huge smile. “That’s great!” I nearly shouted.
“Not really,” he said, no smile on his face. “We could have fixed that.”
“So where do we go from here?” I asked, feeling deflated that he did not share my joy.
“Heart transplant,” he responded.
None of the three cardiologists I had seen, including this one, had put me on the two major recommended medicines for heart failure, an ACE inhibitor and a beta blocker. Yet, without seeing what these drugs could do to improve my own heart’s function, the specialist wanted to take my heart out of my body and sew in a new one.
No, no, no! You’re jumping the gun, fellah, I thought. I was so surprised that after getting such good news from a test that nearly cost me my life, he would want to proceed with the same plan as before the test. I knew I had to get away from this doctor and look once again for good care. It was now three months since my diagnosis of heart failure, and the clock was ticking. Without proper treatment, heart failure progresses and is deadly, and a person who has it can experience sudden death unless someone can get to them with a defibrillator to shock their heart back to work.
Frightened and very stressed, I asked myself Who do I trust? That’s not grammatically correct, but it was what my brain was asking. The answer came to me: a neurologist I had seen many years ago at Johns Hopkins Hospital. I contacted him and explained my situation. He contacted a colleague who was a senior cardiologist at Hopkins, who told me the person to see was Edward Kasper, then director of the Heart Failure and Transplant Service. Uh, oh, I thought, concerned about the “transplant” part of his title, but a doctor I trusted was sending me here, and I felt this was the right thing to do.
Dr. Kasper listened to my story and said that he would not consider a heart transplant. The first thing to do, he said, was to see how I did on an ACE inhibitor and a beta blocker, along with some other medicines for heart failure. And if those didn’t work well enough, there were other things to try, such as implanted devices to help the heart work better. A heart transplant was only a last resort. I was scheduled to begin teaching a university writing course in a few weeks. Would I be able to do that?
Yes, he said. He was sure I would be feeling much better soon. I thought he seemed almost nonchalant about my situation, which actually made me feel relieved. He expected me to get better.
I took my new medicines faithfully and began improving. My attitude toward heart failure changed as I relegated it to the background of my life and got back to teaching, writing, and co-editing a book. We decided I should get a biventricular pacemaker to correct an electrical timing problem that made my left ventricle beat out of sync. This problem, called a left bundle branch block, was not the cause of my heart failure, but the uneven beating of my left ventricle caused my heart to work harder. I recovered from heart failure. I still have my own heart, which returned to a normal size and is pumping blood out at a very normal 65%. I continue to take low doses of an ACE inhibitor and a beta blocker, avoid high-sodium foods, and exercise. Since we don’t know what caused my cardiomyopathy, which caused the heart failure, I want to do all I can to avoid its return.
My experience with heart failure and the health care system made me realize just how important we, the patients, can be in deciding on a treatment plan. The patient must truly be a partner with her doctor and not passively accept whatever any doctor says to do. To be a strong partner, you will need to educate yourself to become informed and then get involved in planning your treatment.
What turn might my life have taken if I had not done some research and continued looking for the best care? Getting the gift of a new heart is a miraculous second chance for those people with severe heart failure who have not responded to medicines and devices to help their heart work better. But a heart transplant also means a lifetime of taking many medications, having some serious side effects, and getting tested repeatedly. Let’s be sure that those who get this precious gift, need it. I, thankfully, did not.
November 2nd, 2010
Meta-Analysis Provides Little Support for Prophylactic ICD Use in Older Adults
Amy Herman
Prophylactic implantable cardioverter-defibrillator (ICD) therapy does not appear to significantly improve survival among older adults with severe left ventricular dysfunction, according to a meta-analysis in the Annals of Internal Medicine.
Researchers analyzed data from five randomized trials comparing ICD therapy with medical treatment among some 5800 adults with cardiomyopathy. Older adults (defined as 60 and older in some trials and 65 and older in others) accounted for nearly half the patients.
The researchers found that while ICD therapy lowered mortality in younger patients, it did not have a significant impact on mortality in elders. Overall, 17% of patients experienced complications from their ICDs.
The authors point to previous research showing that cardiac resynchronization therapy (CRT) seems to benefit the young and old alike, adding: “Taken together, these findings support that CRT alone may be the best device therapy in elderly persons with severe left ventricular dysfunction.”
November 2nd, 2010
Is Dabigatran More Cost-Effective Than Warfarin in AF?
Amy Herman
Dabigatran, newly approved by the FDA to prevent stroke in patients with atrial fibrillation (AF), might turn out to be a cost-effective alternative to warfarin, according to an Annals of Internal Medicine study. Using data from the RE-LY trial, James Freeman and colleagues modeled the quality-adjusted survival and cost-effectiveness of dabigatran compared with high- or low-dose warfarin among adults older than 65 with AF. Cost was estimated based on current pricing in the U.K., where dabigatran has been approved since 2008.
The researchers found that high-dose dabigatran was the most efficacious and cost-effective strategy. Depending on pricing in the U.S., they conclude, the new drug might prove to be a more cost-effective option than warfarin. (Last week, CardioExchange reported that dabigatran will cost about $237/month at U.S. pharmacies.)
Comments are closed on this post, but please join the conversation at our Dabigatran Resource Round-Up.
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